What are the causes of high fecal calprotectin levels?

Causes of High Fecal Calprotectin Levels

Elevated fecal calprotectin is primarily caused by inflammatory bowel disease (IBD), but can also be due to infectious gastroenteritis, colorectal cancer, and NSAID use, requiring appropriate diagnostic workup based on clinical presentation. 1, 2

Primary Causes of Elevated Fecal Calprotectin

• Inflammatory Bowel Disease (IBD): Both Crohn's disease and ulcerative colitis consistently show significantly elevated calprotectin levels, with higher values correlating with disease activity and endoscopic inflammation 3, 4
• Infectious Gastroenteritis: Acute bacterial, viral, or parasitic infections can cause significant elevation in fecal calprotectin, making it difficult to distinguish from IBD in acute presentations 2, 5
• Colorectal Neoplasms: Colorectal cancer and advanced adenomas can elevate fecal calprotectin, though not as consistently or dramatically as IBD 3, 4
• NSAID Use: Regular use of non-steroidal anti-inflammatory drugs within the past 6 weeks can cause elevated calprotectin levels due to drug-induced enteropathy 1

Interpretation of Elevated Calprotectin Levels

• <50 μg/g: Generally considered normal with high negative predictive value for ruling out IBD 1
• 50-100 μg/g: Mildly elevated, may represent non-specific low-grade inflammation 1
• 100-250 μg/g: Moderately elevated, warrants consideration of repeat testing or routine referral to gastroenterology 1, 2
• >250 μg/g: Significantly elevated, indicates need for urgent referral to gastroenterology and has better specificity (82%) for active IBD 3, 1

Clinical Approach to Elevated Calprotectin

For Patients with Acute Diarrhea:

• Calprotectin will not reliably distinguish between IBD and infectious gastroenteritis 2
• Stool culture and/or flexible sigmoidoscopy/colonoscopy are appropriate diagnostic investigations 3, 2

For Patients with Bloody Diarrhea:

• Flexible sigmoidoscopy is indicated regardless of calprotectin result 2
• In patients under 50 years, elevated calprotectin with bloody diarrhea strongly predicts IBD or colorectal cancer but does not discriminate between the two 3

For Patients with Suspected IBD:

• Calprotectin correlates well with endoscopic inflammation in both ulcerative colitis and Crohn's disease 3, 6
• In known IBD patients, elevated calprotectin can predict relapse, especially in ulcerative colitis 7
• Post-operative elevation in Crohn's disease patients is indicative of disease recurrence 7

For Patients with Suspected Colorectal Cancer:

• Calprotectin is not sensitive enough to exclude advanced colorectal adenoma or colorectal carcinoma 3
• In patients with rectal bleeding, abdominal pain, change in bowel habit, weight loss, or iron-deficiency anemia, cancer pathway referral should be strongly considered rather than relying on calprotectin 3, 2

Important Considerations for Calprotectin Testing

• First morning stool should be used for sampling 3
• Samples should be stored for no more than 3 days at room temperature before analysis 3
• Variability exists between different assays and even between different stool samples from the same patient 3
• Repeat testing may be valuable in patients with initially elevated calprotectin (≥100 μg/g), as 53% show reduction upon retesting after approximately 18 days 3

Pitfalls in Interpretation

• Calprotectin levels may not be significantly elevated when a pathogen is detected in patients with IBD (median 299 vs 255 mg/kg, P = 0.207) 5
• The relationship between pathogen detection and calprotectin levels is nonlinear and varies by IBD status 5
• Different patterns of mucosal inflammatory activity may explain why the association between raised calprotectin and relapse is not universal 7
• Changes in calprotectin levels over time may be more predictive of disease activity than absolute values 7