What is the fecal calprotectin test and how is it used to differentiate inflammatory bowel disease from functional gastrointestinal disorders?

Fecal Calprotectin Test: Clinical Utility and Interpretation

What is Fecal Calprotectin?

Fecal calprotectin is a neutrophil-derived protein that serves as a highly sensitive, non-invasive biomarker for detecting intestinal inflammation, with its primary clinical value being the differentiation of inflammatory bowel disease (IBD) from functional disorders like irritable bowel syndrome (IBS). 1

• Calprotectin is a calcium- and zinc-binding protein from the S-100 family, predominantly found within neutrophils that migrate into gastrointestinal tissue during inflammatory processes 2
• Fecal concentrations are approximately six times higher than plasma levels, making stool measurement particularly useful for detecting intestinal inflammation 3
• The test correlates closely with both endoscopic and histological disease activity in IBD 4, 5

Diagnostic Performance for IBD vs IBS

At a cutoff of 50-60 μg/g, fecal calprotectin demonstrates 81% sensitivity and 87% specificity for detecting organic disease, with a positive likelihood ratio of 6.12, making it excellent for ruling out IBD when negative. 1

• The test has a 90.6% sensitivity for detecting endoscopically active IBD at cutoffs >50 μg/g 6, 4
• Normal levels (<50 μg/g) have high negative predictive value, effectively ruling out IBD in symptomatic patients 4, 7
• Elevated levels (>95%) are found in patients with active IBD and reliably differentiate IBD from IBS 8, 2

Interpretation of Specific Thresholds

Values <50 μg/g: Rule out active inflammation with high confidence; IBD is unlikely 4, 9

Values 50-250 μg/g (intermediate range):

• Represent an indeterminate zone with 8% chance of developing IBD over 12 months compared to 1% with levels <50 μg/g 6
• At 50-60 μg/g cutoff: 81% sensitivity, 87% specificity for organic disease 1
• Consider repeat testing in 4-6 weeks or proceed to colonoscopy based on symptom severity 6, 4

Values >150 μg/g:

• In patients with moderate-to-severe symptoms: 95.4% have true moderate-to-severe endoscopic inflammation (only 4.6% false positive rate) 9
• In patients with mild symptoms: 84.5% have endoscopic inflammation (15.5% false positive rate) 9
• In asymptomatic patients with known IBD: 77.6% have endoscopic inflammation (22.4% false positive rate) 9
• This threshold has 78.2% specificity for endoscopically active disease 6, 4

Values >250 μg/g:

• Strongly suggest active inflammation requiring endoscopic assessment 6, 9
• Have 82% specificity for active disease 6
• Typically require immunomodulator or biologic therapy rather than aminosalicylates alone 9

Clinical Applications Beyond Diagnosis

For monitoring IBD activity: Serial calprotectin measurements at 3-6 month intervals facilitate early recognition of impending disease flares before symptoms develop 4, 9

• Persistently elevated levels in clinically inactive disease predict future relapse 4, 5
• The test has >85% sensitivity and specificity for predicting clinical relapse in quiescent IBD 8
• Calprotectin normalization provides evidence of mucosal healing, which is a therapeutic goal in IBD management 4, 7
• In patients with known IBD in remission, measure calprotectin every 6-12 months 4

Important Non-IBD Causes of Elevation

NSAID use within the past 6 weeks significantly elevates calprotectin through direct mucosal injury, including over-the-counter ibuprofen, naproxen, and aspirin at anti-inflammatory doses. 6, 4

Other causes include:

• Colorectal neoplasia (must be excluded, particularly with alarm symptoms or age >50) 6
• Untreated celiac disease 6
• Infectious gastroenteritis 1, 4, 9
• Hemorrhoids causing local bleeding and inflammation 6, 4
• Microscopic colitis 6

Practical Testing Considerations

Use the first stool passed in the morning and ensure analysis within 3 days at room temperature to avoid falsely elevated or degraded results. 6, 4

• Only a single stool specimen is required for initial testing 1
• Different commercial assays have marked performance differences; laboratories should understand their specific assay characteristics 2, 3
• Age, medications (especially NSAIDs), and day-to-day variation can affect results 3

Clinical Decision Algorithm

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

• <100 μg/g: IBS is likely; manage as functional disorder
• 100-250 μg/g: Consider repeat testing in 2-3 weeks or routine gastroenterology referral based on symptom severity
• >250 μg/g: Urgent gastroenterology referral for colonoscopy

For patients with moderate-to-severe symptoms and calprotectin >150 μg/g: Treatment adjustment can proceed without initial endoscopy, as 95.4% have true moderate-to-severe endoscopic inflammation 9

For patients with mild symptoms and calprotectin >150 μg/g: Endoscopic assessment is recommended before empiric treatment adjustment 4, 9

Critical Limitations

Calprotectin is not sensitive enough to exclude colorectal cancer or advanced adenomas; patients with alarm symptoms (rectal bleeding, weight loss, iron-deficiency anemia) require cancer pathway referral regardless of calprotectin level. 4, 9

• The test is highly sensitive but not specific for IBD 6
• Infectious gastroenteritis can markedly elevate levels, requiring exclusion with stool cultures and C. difficile testing 1, 9
• In acute infectious diarrhea, there are insufficient data to recommend routine calprotectin measurement 1
• Fecal leukocyte examination and lactoferrin should not be used to establish the cause of acute infectious diarrhea 1