What are the causes of elevated fecal calprotectin?

Causes of Elevated Fecal Calprotectin

Elevated fecal calprotectin is primarily caused by intestinal inflammation, with inflammatory bowel disease (IBD) being the most significant cause, followed by colorectal cancer, infectious gastroenteritis, and non-steroidal anti-inflammatory drug use. 1

Primary Causes of Elevated Fecal Calprotectin

Inflammatory Conditions

• Inflammatory Bowel Disease (IBD)

  • Ulcerative colitis - typically shows higher calprotectin levels during active disease (median 327 μg/g during flares) 2
  • Crohn's disease - elevated levels correlate with clinical activity scores (median 405 μg/g during active disease) 2
  • Active IBD typically shows levels >250 μg/g, which correlates well with endoscopic inflammation 1

• Infectious Gastroenteritis

  • Bacterial, viral, or parasitic infections causing intestinal inflammation
  • Calprotectin cannot reliably distinguish between IBD and acute infection 1
  • Stool culture and/or endoscopic evaluation is necessary for differentiation 1

• Colorectal Cancer

  • Median levels around 105 μg/g 2
  • Important caveat: Fecal calprotectin is not sensitive enough to exclude colorectal cancer 1
  • Patients with rectal bleeding, change in bowel habit, weight loss, or iron-deficiency anemia should follow cancer pathway referral regardless of calprotectin levels 1

Medication-Induced

• Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Cause direct mucosal inflammation and increased intestinal permeability 1
  • Important to obtain medication history when interpreting elevated levels

Other Causes

• Microscopic colitis
• Diverticulitis
• Celiac disease (when active)
• Intestinal graft-versus-host disease
• Intestinal transplant rejection

Interpretation of Calprotectin Levels

Clinical Cutoff Values

• <50 μg/g: Generally considered normal 1
• 50-100 μg/g: Borderline, may warrant monitoring
• 100-250 μg/g: Indeterminate range - 8% chance of developing IBD within 12 months vs. 1% with levels <50 μg/g 1
• >250 μg/g: Strongly suggestive of active inflammation, correlates well with endoscopic inflammation 1

Sensitivity and Specificity at Different Cutoffs

• 50 μg/g cutoff:
  • Sensitivity: 90.6% for detecting endoscopically active disease
  • Specificity: 67% 1
• 150 μg/g cutoff:
  • Sensitivity: 81%
  • Specificity: 72% 1
• 250 μg/g cutoff:
  • Sensitivity: 76%
  • Specificity: 74% 1

Practical Considerations

Sample Collection and Processing

• First morning stool sample is recommended
• Samples should be stored for no more than 3 days at room temperature before analysis
• Variability exists between different assays and in different stool samples from the same patient 1

Common Pitfalls

• False positives:

  • In patients with known IBD in clinical remission, elevated calprotectin (>250 μg/g) has a false positive rate of 20.8% 1
  • Repeat testing may be beneficial - in one study, 53% of patients with initially elevated levels showed reduction upon repeat testing 1

• False negatives:

  • Patients with mild symptoms but normal calprotectin may still have active inflammation 1
  • Location matters - ileal Crohn's disease may have lower calprotectin levels despite active disease 3

Clinical Algorithm for Evaluating Elevated Calprotectin

1. Assess for alarm symptoms:

   • If rectal bleeding, change in bowel habit, weight loss, or iron-deficiency anemia present → refer via cancer pathway regardless of calprotectin level

2. For patients without alarm symptoms:

   • <50 μg/g: Unlikely to have significant inflammation; consider functional disorders
   • 50-250 μg/g: Consider repeat testing in 2-4 weeks

   • 250 μg/g: High likelihood of inflammatory condition; proceed to endoscopic evaluation

3. For known IBD patients:

   • Use calprotectin to monitor disease activity and response to treatment
   • Levels >250 μg/g suggest active inflammation requiring treatment adjustment
   • Consider that different IBD phenotypes may have different calprotectin patterns (colonic involvement typically has higher levels than isolated ileal disease)