What is the significance of an elevated fecal calprotectin level?

Elevated Fecal Calprotectin: Clinical Significance

An elevated fecal calprotectin indicates active intestinal inflammation and requires clinical action based on the specific level and clinical context, with values >150 μg/g strongly suggesting inflammatory bowel disease requiring endoscopic assessment or treatment adjustment. 1

Interpretation by Calprotectin Level

Normal Range (<50 μg/g)

• Effectively rules out active inflammatory bowel disease with a negative predictive value approaching 1.0, making IBD highly unlikely in symptomatic patients 1, 2
• In patients with known IBD in symptomatic remission, levels <150 μg/g reliably exclude active inflammation and obviate the need for endoscopic assessment 1
• All patients with calprotectin <50 μg/g in one study had normal small bowel capsule endoscopy findings 3

Intermediate Range (50-150 μg/g)

• Values between 50-100 μg/g represent a gray zone where IBD is less likely but cannot be definitively excluded 1, 2
• One study found an 8% chance of developing IBD over 12 months in patients with levels 50-249 μg/g, compared to 1% in those with levels <50 μg/g 1
• Repeat measurement in 3-6 months is reasonable rather than immediate endoscopy in asymptomatic or mildly symptomatic patients 1, 2

Elevated Range (150-250 μg/g)

• In symptomatic patients, this level warrants endoscopic assessment rather than empiric treatment, according to the AGA 1
• For ulcerative colitis patients in symptomatic remission with calprotectin >150 μg/g, the false positive rate is substantial (22.4%), meaning endoscopic confirmation is needed before treatment escalation 1
• In Crohn's disease patients without symptoms, elevated calprotectin >150 μg/g has a false positive rate of 22.4% for detecting endoscopic activity 1

Markedly Elevated Range (>250 μg/g)

• Strongly suggests active inflammatory disease requiring urgent gastroenterology referral in newly diagnosed patients 1, 2
• Correlates well with endoscopic inflammation, with specificity of 73-74% for detecting moderate to severe endoscopic activity 1
• In patients with moderate to severe symptoms and calprotectin >150 μg/g, empiric treatment adjustment is appropriate without requiring immediate endoscopy, as the false positive rate is only 4.6% 4

Primary Diagnostic Applications

Differentiating IBD from IBS

• Fecal calprotectin has excellent utility for distinguishing IBD from irritable bowel syndrome due to its high negative predictive value 2, 5
• NICE recommends using calprotectin in the differential diagnosis of IBS versus IBD in adults with recent onset lower GI symptoms where cancer is not suspected 1
• Calprotectin is elevated in over 95% of patients with IBD and reliably differentiates IBD from IBS 6

Monitoring Disease Activity in Known IBD

• Serial monitoring every 6-12 months is recommended in patients with IBD in remission 2
• Elevated calprotectin in clinically inactive disease predicts future relapse with sensitivity and specificity exceeding 85% 6
• Provides objective evidence of mucosal healing or relapse to guide treatment escalation or de-escalation decisions 2, 7

Important Clinical Caveats

Non-IBD Causes of Elevation

• Calprotectin is not specific for IBD and can be elevated in multiple conditions 1, 2, 4:
  • Colorectal cancer and advanced adenomas
  • Infectious gastroenteritis
  • NSAID use within the past 6 weeks
  • Celiac disease
  • Hemorrhoids (can cause false elevations due to local bleeding) 2

Limitations in Specific Scenarios

• Calprotectin is not sensitive enough to exclude colorectal cancer, and patients with alarm symptoms (rectal bleeding, weight loss) require cancer pathway referral regardless of calprotectin level 2, 4
• In patients with moderate to severe symptoms, a calprotectin <150 μg/g does NOT exclude inflammation, with a false negative rate of 24.7% 4
• Normal CRP does not reliably rule out endoscopic inflammation in UC patients, particularly those who never had elevated CRP during initial flare 1

Practical Testing Considerations

Sample Collection and Handling

• The first stool passed in the morning should be used for optimal sampling 2
• Samples can be stored for no more than 3 days at room temperature before analysis 2
• Day-to-day variation exists, so clinical correlation is essential 7

When to Proceed Directly to Endoscopy

• Patients with alarm symptoms require endoscopy regardless of calprotectin level 4
• In young patients (<40 years) with mild symptoms and normal calprotectin, a diagnosis of IBS may be made without endoscopy 1
• In patients with mild IBD symptoms and elevated calprotectin >150 μg/g, endoscopic assessment is preferred over empiric treatment to confirm active inflammation 1, 4

Clinical Decision Algorithm

For newly symptomatic patients:

• Calprotectin <50 μg/g: IBD unlikely, consider IBS or functional disorder 1, 2
• Calprotectin 50-100 μg/g: Repeat in 3-6 months or consider routine gastroenterology referral 1, 2
• Calprotectin 100-250 μg/g: Routine gastroenterology referral for endoscopic evaluation 2
• Calprotectin >250 μg/g: Urgent gastroenterology referral 1, 2

For patients with known IBD:

• Asymptomatic with calprotectin <150 μg/g: Continue current therapy, recheck in 6-12 months 1, 2
• Asymptomatic with calprotectin >150 μg/g: Consider endoscopy or repeat in 3-6 months 1
• Mild symptoms with calprotectin >150 μg/g: Endoscopic assessment before treatment change 1
• Moderate-severe symptoms with calprotectin >150 μg/g: Empiric treatment escalation is appropriate 4