What does a positive stool calprotectin indicate and what are the recommended next steps for evaluation and management?

Positive Stool Calprotectin: Interpretation and Management

A positive fecal calprotectin indicates active intestinal inflammation and requires urgent gastroenterology referral for colonoscopy within 1–2 weeks if the level exceeds 250 μg/g, or within 2–4 weeks for levels between 100–250 μg/g, depending on symptom severity. 1

Immediate Clinical Significance

A positive calprotectin result strongly suggests active inflammatory disease in the gastrointestinal tract, with the degree of elevation directly correlating to the likelihood and severity of inflammation:

• Calprotectin >250 μg/g indicates active inflammatory disease with 82% specificity and warrants urgent gastroenterology referral within 1–2 weeks 1, 2
• Calprotectin 100–250 μg/g represents an intermediate range requiring clinical correlation with symptom severity 1, 2
• Calprotectin >150 μg/g in patients with moderate-to-severe symptoms has only a 4.6% false-positive rate, meaning 95.4% truly have moderate-to-severe endoscopic inflammation 1

The most common cause of elevated calprotectin is inflammatory bowel disease (IBD), with a sensitivity of 90.6% for detecting endoscopically active disease at a cut-off of 50 μg/g. 1

Essential Baseline Workup Before or Concurrent With Referral

Before proceeding to endoscopy, obtain the following investigations to exclude alternative diagnoses and assess disease severity:

• Stool culture including C. difficile testing to exclude infectious gastroenteritis, which can markedly elevate calprotectin 1, 2
• Complete blood count to detect anemia (suggesting chronic bleeding) or leukocytosis (indicating systemic inflammation) 1
• C-reactive protein and ESR to assess systemic inflammation, though 20% of active Crohn's patients may have normal CRP 1, 2
• Comprehensive metabolic panel to evaluate for dehydration and electrolyte abnormalities 1
• Celiac serology (tissue transglutaminase antibodies) to exclude celiac disease as an alternative diagnosis 1, 2
• Iron studies if anemia is present 2

Symptom-Based Management Algorithm

Patients With Moderate-to-Severe Symptoms

Moderate-to-severe symptoms include frequent rectal bleeding (score 2–3), markedly increased stool frequency, significant abdominal pain, or weight loss. 1

• If calprotectin >150 μg/g: Proceed directly to urgent gastroenterology referral within 1–2 weeks; the false-positive rate is only 4.6%, so empiric treatment adjustment can be considered in known IBD patients without requiring endoscopy first 1
• If calprotectin <150 μg/g: The false-negative rate is 26.4% in symptomatic patients, so endoscopic assessment is still required before altering therapy 1

Patients With Mild Symptoms

Mild symptoms include infrequent rectal bleeding, mildly increased stool frequency, or mild abdominal discomfort. 1

• If calprotectin >150 μg/g: Endoscopic assessment is required before empiric treatment adjustment because the false-positive rate increases to 15.5% in this intermediate pre-test probability group 1
• If calprotectin 100–250 μg/g: Consider repeat testing in 2–3 weeks to determine if elevation is persistent or transient 1, 2
• If repeat testing normalizes to <100 μg/g: Manage as irritable bowel syndrome in primary care 1, 2

Asymptomatic Patients or Those With Known IBD

• If calprotectin >150 μg/g: The false-positive rate is 22.4% in asymptomatic patients, so endoscopic evaluation should be considered 1
• If calprotectin <150 μg/g AND normal CRP: Active inflammation is effectively ruled out, eliminating the need for endoscopy 1

Critical Caveats and Common Pitfalls

NSAID Use

Recent NSAID use within the past 6 weeks can cause false-positive elevation of fecal calprotectin. 1, 2 Repeat testing after at least 6 weeks of NSAID cessation is recommended before proceeding to invasive investigations. 1

Non-IBD Causes of Elevation

Elevated calprotectin is not specific for IBD and can occur in:

• Infectious gastroenteritis 1, 2
• Colorectal cancer or advanced adenoma 1, 2
• Microscopic colitis 1
• Ischemic colitis 1
• Local bleeding from hemorrhoids 1, 2

Alarm Features Override Calprotectin Results

Presence of alarm features mandates referral via a suspected cancer pathway regardless of calprotectin level. 1, 2 Alarm features include:

• Rectal bleeding with abdominal pain 1
• Change in bowel habit with weight loss 1
• Iron-deficiency anemia 1
• Palpable abdominal or rectal mass 1
• Unexplained anal ulceration 1

Calprotectin is not sensitive enough to exclude colorectal cancer, so patients with concerning features require urgent colonoscopy. 1

Endoscopic Evaluation Recommendations

When colonoscopy is indicated, perform:

• Complete ileocolonoscopy with terminal ileum intubation rather than flexible sigmoidoscopy to assess the full extent of disease 1
• Multiple biopsies from both inflamed and normal-appearing mucosa to establish histologic diagnosis 1
• Cross-sectional imaging (MR or CT enterography) if Crohn's disease is suspected, to evaluate small bowel involvement and complications such as strictures or fistulas 1

Post-Diagnosis Monitoring Framework

If IBD is confirmed:

• Treatment intensity should match disease severity: Calprotectin >250 μg/g typically requires immunomodulator or biologic therapy rather than aminosalicylates alone 1
• Repeat calprotectin at 2–4 months after treatment initiation to assess biochemical response, targeting <150 μg/g as an indicator of adequate response 1
• Follow-up endoscopy at 6–12 months to confirm mucosal healing, as calprotectin normalization correlates with but does not guarantee endoscopic remission 1
• Serial calprotectin monitoring every 3–6 months in established IBD patients can facilitate early detection of impending flares 1, 2

Special Consideration: FIT Testing

If a fecal immunochemical test (FIT) for occult blood was also performed and is normal, this does not exclude IBD or other significant organic pathology. 1 FIT is optimized for detecting colorectal cancer but has poor sensitivity for inflammatory conditions. 1 The combination of markedly elevated calprotectin with normal FIT actually increases the likelihood of IBD rather than malignancy. 1