What is the role of calprotectin in assessing intestinal inflammation, particularly in distinguishing between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)?

Calprotectin: Role in Assessing Intestinal Inflammation

Fecal calprotectin is an excellent non-invasive biomarker for distinguishing inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS), with a sensitivity of 90.6% at cutoffs >50 μg/g and high negative predictive value for ruling out IBD in symptomatic patients. 1

Diagnostic Utility: IBD vs IBS Differentiation

Calprotectin reliably separates organic inflammation from functional disorders:

• Normal levels (<50 μg/g) have high negative predictive value for IBD, effectively ruling out inflammatory disease in undiagnosed symptomatic patients 1
• Calprotectin levels are markedly elevated in IBD patients (median 175-465 μg/g) compared to IBS patients (median 54 μg/g), making it highly effective at distinguishing these conditions 2, 3
• The test consistently differentiates IBD from IBS because IBS patients maintain low calprotectin levels despite similar symptom profiles 4, 5

Threshold Interpretation and Clinical Action

The specific calprotectin level determines your next clinical step:

Levels <100 μg/g

• Suggests IBS is likely; IBD effectively ruled out 1
• Manage as functional disorder in primary care without gastroenterology referral 1

Levels 100-250 μg/g (Intermediate Range)

• Consider repeat testing in 2-3 weeks or routine gastroenterology referral based on symptom severity 1
• This range has moderate specificity (66%) for active endoscopic inflammation 6
• Represents 8% risk of developing IBD over 12 months compared to 1% with levels <50 μg/g 7

Levels >250 μg/g

• Urgent gastroenterology referral required 1
• Provides 82% specificity for differentiating active IBD from remission 6
• Strongly indicates need for colonoscopy with biopsies 1

Monitoring Disease Activity in Known IBD

Calprotectin correlates closely with endoscopic inflammation and guides treatment decisions:

• A cutoff of 50 μg/g provides 90.6% sensitivity for detecting endoscopically active disease 6, 1
• Levels >100 μg/g provide 78.2% specificity for active inflammation 6
• In patients with moderate to severe symptoms, calprotectin >150 μg/g reliably suggests moderate to severe endoscopic inflammation and can guide treatment escalation without immediate endoscopy 1, 8
• In patients with mild symptoms and calprotectin >150 μg/g, endoscopic assessment is recommended rather than empiric treatment adjustment 1, 8
• Serial monitoring every 3-6 months in asymptomatic IBD patients facilitates early recognition of impending flares 1, 8

Calprotectin predicts clinical outcomes:

• Clinically inactive disease with raised calprotectin predicts future relapse 6, 1
• Levels <150 μg/g suggest minimal inflammation and can reliably exclude active disease in asymptomatic patients 1
• The biomarker provides objective evidence of mucosal healing, which has become a treatment goal in IBD 3

Critical Limitations and Confounding Factors

Calprotectin is sensitive but not specific—multiple conditions elevate levels:

• NSAID use within the past 6 weeks significantly elevates calprotectin through direct mucosal injury; repeat testing after cessation is appropriate 1, 7
• Colorectal cancer and advanced adenomas elevate calprotectin, making it inappropriate for patients with alarm features (rectal bleeding with abdominal pain, change in bowel habit, weight loss, iron-deficiency anemia)—these patients require cancer pathway referral regardless of calprotectin level 6, 1
• Infectious gastroenteritis causes transient elevation 1, 7
• Hemorrhoids can cause false elevations due to local bleeding and inflammation 1, 7
• Untreated celiac disease elevates calprotectin through intestinal inflammation 7

Practical Collection and Testing Considerations

Proper specimen handling is essential for accurate results:

• Use the first stool passed in the morning routinely 6, 1
• Store samples no more than 3 days at room temperature before analysis 6, 1
• Variability exists between different assays and in levels throughout the day 6

Essential Workup Before or Concurrent with Gastroenterology Referral

Complete these baseline tests when calprotectin is elevated:

• Complete blood count (assess for anemia, thrombocytosis indicating inflammation) 1
• C-reactive protein (complementary inflammatory marker, though 20% of active Crohn's patients have normal CRP) 1
• Celiac serology (tissue transglutaminase antibodies) to exclude celiac disease 1, 7
• Stool culture to exclude infectious causes 1
• Urea and electrolytes if diarrhea is prominent 1

When Calprotectin Should NOT Be Used

Avoid calprotectin testing in these scenarios:

• Patients with alarm features (rectal bleeding with abdominal pain, change in bowel habit, weight loss, iron-deficiency anemia) require direct cancer pathway referral and colonoscopy 6, 1
• When IBD relapse is clinically obvious, measurement is unnecessary—proceed directly to treatment 6
• Calprotectin is not sensitive enough to exclude advanced colorectal adenoma or colorectal carcinoma 6, 1