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

Calprotectin in Assessing Intestinal Inflammation

Fecal calprotectin is an excellent non-invasive biomarker for distinguishing IBD from IBS, with a threshold <50 μg/g having 90.6% sensitivity and high negative predictive value to rule out IBD, while levels >100-250 μg/g should trigger colonoscopy to confirm IBD diagnosis. 1

Diagnostic Utility: IBD vs IBS Differentiation

The primary clinical value of calprotectin lies in its ability to exclude IBD in symptomatic patients, making it particularly useful in primary care settings before gastroenterology referral. 1

Threshold Interpretation for Initial Diagnosis

• <50 μg/g: Essentially rules out IBD with 90.6% sensitivity and high negative predictive value, making IBS the likely diagnosis in symptomatic patients 1
• 50-100 μg/g: Suggests IBS is likely; can manage as IBS in primary care if symptoms are consistent 1
• 100-250 μg/g: Intermediate range requiring either repeat testing in 2-3 weeks or routine gastroenterology referral depending on symptom severity 1
• >250 μg/g: Strongly indicates active IBD requiring urgent gastroenterology referral and colonoscopy, with 82% specificity for active disease 2, 1

The American Gastroenterological Association recommends higher thresholds (100-250 μg/g) to trigger colonoscopy, which improves positive predictive value with minimal reduction in negative predictive value. 1

Correlation with Endoscopic Activity

Calprotectin correlates strongly with endoscopic inflammation in both ulcerative colitis and Crohn's disease, making it a validated surrogate marker for mucosal disease activity. 2, 1, 3

• A cutoff of 50 μg/g provides 90.6% sensitivity for detecting endoscopically active disease 2, 1
• A cutoff of 100 μg/g provides 78.2% specificity for active inflammation 2, 1
• A cutoff of 250 μg/g provides 82% specificity but lower sensitivity (80%) for differentiating active IBD from remission 2

In established IBD, calprotectin levels ≤250 μg/g predicted endoscopic remission with 94.1% sensitivity and 62.2% specificity in Crohn's disease. 3

Monitoring Disease Activity in Known IBD

For patients with established IBD in clinical remission, calprotectin should be measured every 6-12 months to detect subclinical inflammation that predicts future relapse. 1

Interpretation in Symptomatic IBD Patients

• Moderate to severe symptoms with calprotectin >150 μg/g: Reliably indicates moderate to severe endoscopic inflammation (95.4% positive predictive value); treatment can be escalated empirically without immediate endoscopy 1, 4
• Mild symptoms with calprotectin >150 μg/g: Endoscopic assessment is recommended before treatment adjustment due to 15.5% false positive rate 1, 4
• Asymptomatic patients with calprotectin >150 μg/g: Consider endoscopy as 22.4% false positive rate exists, but elevated levels predict future relapse 1, 4
• Calprotectin <150 μg/g in symptomatic patients: Does not exclude inflammation, with 24.7% false negative rate in moderate to severe symptoms 4

Critical Practical Considerations

Sample Collection Requirements

The British Society of Gastroenterology recommends using the first stool passed in the morning, stored for no more than 3 days at room temperature before analysis, to minimize variability. 2, 1

Important Confounders and Limitations

NSAID use within the past 6 weeks significantly elevates calprotectin through direct mucosal injury and must be documented; repeat testing after NSAID cessation is appropriate if use is identified. 1, 5

Other conditions that elevate calprotectin include:

• Colorectal cancer and advanced adenomas 2, 1
• Infectious gastroenteritis 1, 5
• Hemorrhoids (due to local bleeding and inflammation) 1, 5
• Untreated celiac disease 5
• Microscopic colitis 5

When Calprotectin Should NOT Be Used

In patients with alarm features (rectal bleeding with abdominal pain, change in bowel habit, weight loss, or iron-deficiency anemia), cancer pathway referral is required regardless of calprotectin level, as it is not sensitive enough to exclude colorectal cancer or advanced adenomas. 2, 1

Clinical Algorithm for New Lower GI Symptoms

For patients aged 16-40 with new lower GI symptoms >4 weeks where IBD is suspected:

1. Measure fecal calprotectin along with complete blood count, CRP, celiac serology, and stool culture 1
2. <100 μg/g: Treat as IBS if symptoms consistent 1
3. 100-250 μg/g: Repeat testing in 2-3 weeks or routine gastroenterology referral based on symptom severity 1
4. >250 μg/g: Urgent gastroenterology referral for colonoscopy 1
5. Any alarm features present: Cancer pathway referral regardless of calprotectin level 2, 1

Distinguishing IBS-like Symptoms in IBD Remission

In IBD patients who are in clinical remission but report IBS-like symptoms, calprotectin helps distinguish true remission with functional overlay from occult inflammation requiring treatment intensification. 6 Elevated calprotectin in this context indicates subclinical inflammation rather than pure functional symptoms, warranting closer monitoring or treatment adjustment. 6