Can calprotectin levels be normal in a patient with inflammatory bowel disease (IBD)?

Can Calprotectin Be Normal in IBD?

Yes, calprotectin can be normal in patients with inflammatory bowel disease, particularly in those with true clinical remission, but also in a significant minority of patients with active endoscopic inflammation—creating a false-negative scenario that requires careful clinical interpretation.

Understanding False-Negative Calprotectin Results

Patients in True Remission

• Calprotectin levels <50 μg/g reliably indicate absence of active inflammation in patients with IBD who are in symptomatic remission, with a sensitivity of 90.6% for detecting endoscopically active disease 1
• In asymptomatic UC patients on stable maintenance therapy, approximately 15% still have moderate to severe endoscopic inflammation despite being symptom-free 1
• Calprotectin <150 μg/g suggests minimal inflammation and can reliably rule out active inflammation in patients in symptomatic remission 2

False-Negative Rates in Symptomatic Patients

• In Crohn's disease patients with moderate to severe symptoms (PRO2 >13 or PRO3 >21): Normal calprotectin (<150 μg/g) has a false-negative rate of 26.4%, meaning over one-quarter of symptomatic patients with normal calprotectin actually have endoscopic activity 1
• In Crohn's disease patients with mild symptoms: The false-negative rate is even higher at 24.7% when calprotectin is <150 μg/g 1
• In UC patients with mild symptoms (infrequent rectal bleeding and/or increased stool frequency): Approximately 50% have moderate to severe endoscopic inflammation, yet some will have normal or low calprotectin 1

Clinical Scenarios Where Normal Calprotectin Occurs Despite Active IBD

Isolated Small Bowel Disease

• Calprotectin may be falsely normal in patients with predominantly small bowel Crohn's disease, as the marker is less sensitive for proximal disease 2
• For these patients, complementing calprotectin with other monitoring methods (such as cross-sectional imaging) is recommended 2

Coexisting IBS-Like Symptoms

• IBD patients in remission who have coexisting IBS-like symptoms (fulfilling Rome II criteria in 24.6% of UC and 21.4% of CD patients) can have normal calprotectin despite symptoms 3
• This underscores calprotectin's utility in distinguishing true inflammatory flares from functional symptoms 3, 4

Guideline-Based Management Approach

When Calprotectin is Normal but Symptoms Persist

For patients with mild symptoms and normal biomarkers (calprotectin <150 μg/g, CRP <5 mg/L):

• The AGA recommends endoscopic assessment of disease activity rather than empiric treatment adjustment 1
• This is critical because a significant proportion of symptomatic patients with normal calprotectin may have endoscopic activity and would be incorrectly classified as being in remission 1

For patients with moderate to severe symptoms and normal biomarkers:

• The AGA suggests endoscopic assessment of disease activity rather than empiric treatment adjustment, given the 26.4% false-negative rate 1
• Do not assume symptoms are functional without endoscopic confirmation 1

Optimal Cutoff Values for Different Clinical Contexts

For ruling out inflammation (high negative predictive value):

• Use calprotectin <50 μg/g in asymptomatic patients or those recently achieving remission 1
• At this threshold, sensitivity is 92% but specificity is only 60% 1, 5

For confirming inflammation (high positive predictive value):

• Use calprotectin >250 μg/g, which provides specificity of 82% but sensitivity drops to 80% 1
• At 100 μg/g, sensitivity is 84% with specificity of 66% 1

Common Pitfalls to Avoid

Don't Rely Solely on Calprotectin in Symptomatic Patients

• Never dismiss symptoms in a patient with normal calprotectin without considering endoscopic evaluation, especially in Crohn's disease where false-negative rates exceed 24% 1
• Symptoms alone are inadequate for monitoring, but normal biomarkers don't exclude active disease 2

Technical Factors Affecting Results

• Variability exists between different assays, between stool samples from the same patient during one day, and related to interval between stools 1
• Use the first stool passed in the morning and store for no more than 3 days at room temperature before analysis 1

Consider Alternative Diagnoses

• Normal calprotectin in a symptomatic IBD patient may indicate coexisting IBS, medication side effects, bile acid malabsorption (especially post-ileocecal resection), or stricturing disease without active inflammation 3, 4

Monitoring Strategy for Patients with Normal Calprotectin

• For patients in symptomatic remission with calprotectin <150 μg/g, no intervention is needed but continue monitoring every 3-6 months 6, 2
• For stable disease with consistent symptomatic remission, test calprotectin every 6-12 months 2
• If discordance exists between symptoms and biomarkers, repeat measurement in 3-6 months before proceeding to endoscopy 2