Which test, if negative, can help rule out inflammatory bowel disease (IBD)?

Fecal Calprotectin Rules Out Inflammatory Bowel Disease When Negative

A negative fecal calprotectin test (<50 μg/g) effectively rules out inflammatory bowel disease (IBD) in patients with gastrointestinal symptoms, with a pooled sensitivity of 93-95% and negative predictive value exceeding 90%. 1, 2, 3

Why Fecal Calprotectin is the Answer

Fecal calprotectin has an exceptionally low negative likelihood ratio (0.015), meaning a negative result virtually excludes IBD in most clinical scenarios. 4 This makes it the single most useful test for ruling out IBD when negative, far superior to other inflammatory markers.

Performance Characteristics

• Sensitivity for IBD diagnosis: 93% in adults, 92-95% in children at the 50 μg/g cutoff 1, 2, 3
• Specificity: 94-96% for differentiating IBD from IBS in adults 1, 2
• Negative predictive value: Consistently >90%, with some studies showing up to 96% 2, 5
• Key advantage: The negative likelihood ratio of 0.015 means a negative test reduces the probability of IBD by approximately 98.5% 4

Comparison with Other Tests

C-Reactive Protein (CRP)

CRP is significantly inferior for ruling out IBD. At the 5-6 mg/L cutoff, CRP has only 73% sensitivity and 78% specificity. 1 Critically, approximately 20% of patients with active Crohn's disease have normal CRP levels, making it unreliable for exclusion. 1, 2

Erythrocyte Sedimentation Rate (ESR)

ESR performs even worse, with sensitivity ranging from only 54-78% and specificity of 46-95%. 1 The pooled negative likelihood ratio of 0.6 is far too high to confidently rule out disease. 1

Why Calprotectin Wins

Unlike CRP and ESR, which are systemic inflammatory markers that can be normal despite active intestinal inflammation, fecal calprotectin directly measures neutrophilic intestinal inflammation by detecting a protein released from white blood cells in the inflamed bowel. 5 This direct measurement of intestinal inflammation explains its superior performance.

Clinical Application Algorithm

Step 1: Determine Pre-Test Probability

The usefulness of fecal calprotectin depends on clinical context. 4 Consider:

• Age 16-40 with new lower GI symptoms >4 weeks: Appropriate testing population 2
• Alarm features present (rectal bleeding with abdominal pain, weight loss, iron-deficiency anemia): Refer via cancer pathway regardless of calprotectin 2, 6

Step 2: Interpret Results Based on Cutoff Values

Calprotectin <50 μg/g (or <100 μg/g per some guidelines):

• IBD is effectively ruled out 2, 6
• Manage as IBS in primary care without gastroenterology referral 2, 6
• No colonoscopy needed in absence of alarm features 2

Calprotectin 100-250 μg/g:

• Intermediate zone requiring either repeat testing in 2-3 weeks or routine gastroenterology referral 2, 6
• 53% of patients with initially elevated levels show reduction on repeat testing 6

Calprotectin >250 μg/g:

• Urgent gastroenterology referral warranted 2, 6
• High likelihood of active inflammatory disease requiring endoscopic evaluation 2

Step 3: Avoid Common Pitfalls

NSAID use within 6 weeks can falsely elevate calprotectin. 2, 6, 7 If documented NSAID use, repeat testing after cessation is appropriate before making clinical decisions. 2

Acute diarrhea/gastroenteritis: Calprotectin cannot discriminate between IBD and infectious gastroenteritis in the acute setting. 6 Stool culture should be obtained first. 2

Other causes of elevation: Calprotectin is elevated in colorectal cancer, microscopic colitis, and liver cirrhosis. 2, 7 It is not sensitive enough to exclude colorectal cancer, so alarm features mandate cancer pathway referral regardless of calprotectin level. 2, 6

Celiac disease: False-negative results occur with celiac disease, which does not cause significant neutrophilic inflammation. 7 Always obtain celiac serology (tissue transglutaminase antibodies) alongside calprotectin testing. 2

Proper Testing Technique

• Use the first morning stool for optimal accuracy 2
• Store samples no more than 3 days at room temperature before analysis 2
• Ensure patient has not used NSAIDs for at least 6 weeks prior to testing 2, 6

When Calprotectin is Negative: Next Steps

With calprotectin <100 μg/g and no alarm features, confidently diagnose IBS and initiate IBS-directed therapy without further invasive testing. 2, 6 The excellent negative predictive value means colonoscopy can be safely avoided in this population, sparing patients from unnecessary invasive procedures. 3