What is stool calprotectin, how is it measured, what are the normal and abnormal cut‑offs for adults and children, and how is it used to diagnose, differentiate, and monitor inflammatory bowel disease?

Fecal Calprotectin: Clinical Use in Detail

What is Fecal Calprotectin?

Fecal calprotectin is a neutrophil-derived calcium- and zinc-binding protein that serves as a highly sensitive, non-invasive biomarker for intestinal inflammation, primarily used to differentiate inflammatory bowel disease (IBD) from functional disorders and to monitor disease activity. 1, 2

• Calprotectin is released from neutrophils during intestinal inflammation and remains stable in stool for up to 3 days at room temperature, making it practical for clinical use 1, 3
• The protein comprises approximately 60% of cytosolic proteins in neutrophils and is resistant to bacterial degradation 2

How is it Measured?

• Only a single stool specimen is required for fecal calprotectin testing 1
• Use the first stool passed in the morning and ensure analysis within 3 days at room temperature to avoid falsely elevated or degraded results 4, 1
• Measurement is performed using enzyme-linked immunosorbent assay (ELISA) or point-of-care lateral flow assays 4
• All major gastroenterology societies recommend quantitative fecal calprotectin assays exclusively; qualitative (positive/negative) tests have no clinical role 1

Normal and Abnormal Cut-offs

Adults

• < 50 µg/g: Normal; rules out IBD with 90.6% sensitivity and allows diagnosis of functional disorders (e.g., IBS) without endoscopy 4, 1
• 50–100 µg/g: Low-grade elevation; IBD unlikely but not excluded 4, 1
• 100–250 µg/g: Intermediate range; requires clinical correlation, repeat testing, or gastroenterology referral depending on symptom severity 4, 1
• > 250 µg/g: Strongly indicates active inflammatory disease with 82% specificity; warrants urgent gastroenterology referral 4, 1
• > 150 µg/g: Threshold used for treatment decisions in known IBD patients 1, 5

Children

• Normal reference ranges have been established in healthy children, though specific pediatric cut-offs are similar to adults 2
• Macroscopic and microscopic rectal sparing is more common in untreated children with UC compared to adults 4

Diagnostic Use

Differentiating IBD from IBS

Fecal calprotectin has excellent negative predictive value for ruling out IBD in symptomatic patients presenting with chronic diarrhea and abdominal pain. 4, 2

• For patients aged 16–40 with chronic diarrhea (>4 weeks): Calprotectin < 100 µg/g suggests IBS is likely and allows primary care management without endoscopy 4, 1
• Using a cut-off of 50–60 µg/g achieves 81% sensitivity and 87% specificity for detecting organic disease, with a positive likelihood ratio of 6.12 1
• The test reliably differentiates IBD from IBS because calprotectin is elevated in over 95% of patients with active IBD 6, 2

Initial Diagnostic Pathway

When IBD is suspected, initial investigations should include full blood count, electrolytes, liver and renal function, iron studies, vitamin D level, C-reactive protein, and fecal calprotectin. 4

• Levels 100–250 µg/g: Consider repeat testing in 2–3 weeks or routine gastroenterology referral depending on symptom severity 1, 7
• Levels > 250 µg/g: Urgent gastroenterology referral within 1–2 weeks for colonoscopy 1, 7
• Infectious diarrhea including C. difficile must be excluded before attributing elevated calprotectin to IBD 4

Endoscopic Correlation

• Fecal calprotectin correlates closely with endoscopic activity in both ulcerative colitis and Crohn's disease 4, 8, 2
• A cut-off of 50 µg/g provides 90.6% sensitivity for detecting endoscopically active disease 4
• Levels > 100 µg/g provide 78.2% specificity for endoscopically active disease 4
• In Crohn's disease, values > 250 µg/g predict large ulcers with 78.4% positive predictive value 1
• In ulcerative colitis, values > 250 µg/g indicate active mucosal disease (Mayo score > 0) with 100% specificity 1

Monitoring Disease Activity in Known IBD

Assessing Relapse vs. Remission

Fecal calprotectin is useful to confirm active inflammation when it is unclear whether new symptoms represent a relapse or other causes (particularly in Crohn's disease), serving as a non-invasive alternative to flexible sigmoidoscopy or colonoscopy. 4

• In patients with moderate-to-severe symptoms and calprotectin > 150 µg/g, the false-positive rate is only 4.6%, meaning 95.4% truly have moderate-to-severe endoscopic inflammation 1, 5
• In patients with mild symptoms and calprotectin > 150 µg/g, the false-positive rate increases to 15.5%; endoscopic assessment is recommended before empiric treatment adjustment 1, 5
• In asymptomatic IBD patients with calprotectin > 150 µg/g, the false-positive rate is 22.4%; endoscopic evaluation should be considered 1, 5

Predicting Relapse

• A low fecal calprotectin concentration predicts persistence of clinical remission, especially in non-symptomatic ulcerative colitis and Crohn's colitis 8
• At a given fecal calprotectin concentration in patients with quiescent IBD, the test has specificity and sensitivity exceeding 85% in predicting clinical relapse 6
• Serial calprotectin monitoring at 3–6 month intervals in patients in remission detects subclinical inflammation that predicts future relapse 1, 5

Monitoring Treatment Response

Fecal calprotectin provides objective evidence of response to treatment and mucosal healing. 4, 2

• A post-treatment value < 150 µg/g measured at 2–4 months after therapy initiation indicates an adequate therapeutic response 1, 5
• Persistently elevated values despite symptom improvement identify ongoing mucosal inflammation and signal the need for treatment escalation 1, 5
• Calprotectin concentrations around 75–100 µg/g correlate with histological remission 1
• Values ≤ 250 µg/g predict endoscopic remission (CDEIS ≤ 3) with 96.6% negative predictive value 1

Treatment Decision Algorithm Based on Symptoms and Calprotectin

For patients with moderate-to-severe symptoms (frequent rectal bleeding, markedly increased stool frequency) and calprotectin > 150 µg/g: Proceed directly to treatment adjustment without endoscopic confirmation 1, 5

For patients with mild symptoms and calprotectin > 150 µg/g: Endoscopic assessment is required before empiric treatment adjustment 1, 5

For asymptomatic patients in remission with calprotectin < 150 µg/g and normal CRP: Active inflammation is effectively ruled out, eliminating the need for endoscopy 5

Important Caveats and Pitfalls

Non-IBD Causes of Elevation

Fecal calprotectin is sensitive but not specific for IBD; multiple conditions can elevate this marker. 7, 5

• NSAID use within the past 6 weeks can significantly elevate calprotectin through direct mucosal injury; repeat testing after at least 6 weeks of NSAID cessation is recommended 1, 7
• Acute infectious gastroenteritis markedly raises calprotectin levels; stool cultures should exclude infection before interpretation 1, 7
• Colorectal neoplasia (cancer and advanced adenomas) elevates calprotectin and must be excluded, particularly in patients over 50 or with alarm symptoms 7, 5
• Hemorrhoids can cause false elevations due to local bleeding and inflammation 1, 7
• Untreated celiac disease causes intestinal inflammation that elevates calprotectin; celiac serology should be checked 7

Alarm Features Override Calprotectin

Presence of alarm features (rectal bleeding with abdominal pain, change in bowel habit with weight loss, iron-deficiency anemia, palpable mass) mandates referral via a suspected cancer pathway regardless of calprotectin level. 7, 5

• Calprotectin is not sensitive enough to exclude colorectal cancer or advanced adenoma 1, 5
• Patients with alarm symptoms require urgent colonoscopy even if calprotectin is normal 4, 5

Limitations in Specific Contexts

• Current evidence is insufficient to support routine fecal calprotectin measurement in patients with acute infectious diarrhea 1
• Variability exists between different assays and in levels from different stool samples from one patient during a single day 4
• In patients with mild symptoms and calprotectin < 150 µg/g, active inflammation cannot be reliably excluded (false-negative rate 24.7%); endoscopy may still be warranted if clinical suspicion remains high 5

Practical Clinical Algorithm

For New Patients with Chronic Diarrhea (>4 weeks)

1. Measure fecal calprotectin (first morning stool, analyze within 3 days) 4, 1
2. Exclude infection: Stool culture including C. difficile 4
3. Check celiac serology: Tissue transglutaminase antibodies 7
4. Review medications: Discontinue NSAIDs if possible and retest after 6 weeks if recently used 1, 7

If calprotectin < 100 µg/g: Treat as IBS in primary care 4, 1

If calprotectin 100–250 µg/g:

• Moderate-to-severe symptoms → Urgent gastroenterology referral (1–2 weeks) 1
• Mild symptoms → Repeat testing in 2–3 weeks or routine referral 1

If calprotectin > 250 µg/g: Urgent gastroenterology referral (1–2 weeks) for colonoscopy 1, 7

For Known IBD Patients with New Symptoms

If moderate-to-severe symptoms + calprotectin > 150 µg/g: Escalate treatment without endoscopy 1, 5

If mild symptoms + calprotectin > 150 µg/g: Perform endoscopy before treatment change 1, 5

If asymptomatic + calprotectin > 150 µg/g: Consider endoscopy (22.4% false-positive rate) 1, 5

For Monitoring IBD in Remission

• Measure calprotectin every 6–12 months in asymptomatic patients 1, 5
• If calprotectin < 150 µg/g and normal CRP: Continue current therapy 5
• If calprotectin > 150 µg/g: Consider endoscopy or repeat in 3–6 months 5
• After treatment escalation: Recheck at 2–4 months; target < 150 µg/g 1, 5