In an adult with an unexplained elevated fecal calprotectin, what is the appropriate diagnostic work‑up and management?

Elevated Fecal Calprotectin: Diagnostic Work-Up and Management

In an adult with unexplained elevated fecal calprotectin, the diagnostic approach is determined by the specific calprotectin level and symptom severity, with values >250 μg/g requiring urgent gastroenterology referral for colonoscopy, values 100-250 μg/g warranting either repeat testing or routine referral based on clinical suspicion, and values <100 μg/g suggesting functional disease that can be managed in primary care. 1

Initial Assessment and Baseline Testing

Before or concurrent with gastroenterology referral, obtain the following baseline investigations in primary care:

• Complete blood count to assess for anemia (suggesting chronic blood loss) and thrombocytosis (indicating systemic inflammation) 1, 2
• C-reactive protein (CRP) as a complementary inflammatory marker, though note that 20% of active Crohn's disease patients may have normal CRP 3
• Comprehensive metabolic panel including urea and electrolytes to assess for dehydration and electrolyte abnormalities 1, 2
• Coeliac serology (tissue transglutaminase antibodies) to exclude celiac disease as a cause of chronic diarrhea 1, 3
• Stool culture and C. difficile testing to exclude infectious causes, as enteric infections can markedly elevate calprotectin 1, 2, 3

Interpretation by Calprotectin Level

Calprotectin <100 μg/g

• IBS is likely and the patient can be treated as IBS in primary care without further investigation 1
• The negative predictive value is excellent at this threshold, effectively ruling out IBD in most scenarios 4
• If symptoms persist despite IBS treatment, consider alternative diagnoses including bile acid malabsorption, microscopic colitis, or medication-related symptoms 1

Calprotectin 100-250 μg/g (Intermediate Range)

This intermediate range requires clinical judgment based on symptom severity and pre-test probability of IBD:

• For patients with moderate-to-severe symptoms (rectal bleeding, significant abdominal pain, weight loss, frequent diarrhea): proceed with urgent gastroenterology referral for colonoscopy within 1-2 weeks 1, 2
• For patients with mild or minimal symptoms: consider repeat calprotectin testing after 2-3 weeks to determine if elevation is persistent or transient 1, 3
• If strong clinical suspicion of IBD exists (family history, alarm features), proceed directly to gastroenterology referral rather than repeat testing 1
• If repeat testing shows normalization (<100 μg/g) and symptoms are consistent with IBS, manage as functional disorder 1

Calprotectin >250 μg/g

• Urgent referral to gastroenterology for colonoscopy is required, as this level strongly suggests active inflammatory disease 1, 2
• At this threshold, specificity for detecting endoscopically active disease is 78.2%, with positive predictive value approaching 95% in symptomatic patients 2, 3
• Referral should occur within 1-2 weeks for symptomatic patients 2

Critical Caveats and Pitfalls

NSAID Use

• NSAID use within the past 6 weeks can falsely elevate calprotectin levels 1, 3
• If NSAID use is documented, repeat testing after NSAID cessation for at least 6 weeks is appropriate before proceeding with invasive investigation 1

Non-IBD Causes of Elevation

Calprotectin is not specific for IBD and can be elevated in:

• Infectious gastroenteritis (can markedly raise levels) 2, 3, 5
• Colorectal cancer (calprotectin is not sensitive enough to exclude malignancy) 1, 3
• Microscopic colitis 1
• Ischemic colitis 2
• Local bleeding from hemorrhoids (can cause false elevations) 2

Alarm Features Override Calprotectin Results

• If alarm features are present (rectal bleeding with abdominal pain, change in bowel habit, weight loss, iron-deficiency anemia, abdominal/rectal/anal mass, unexplained anal ulceration), refer via suspected cancer pathway according to local protocols regardless of calprotectin level 1, 4
• A normal fecal immunochemical test (FIT) does not exclude IBD, as FIT is optimized for detecting colorectal cancer but has poor sensitivity for inflammatory conditions 2

Endoscopic Evaluation

When colonoscopy is indicated:

• Complete ileocolonoscopy with terminal ileum intubation is preferred over flexible sigmoidoscopy to assess full disease extent 2
• Multiple biopsies should be obtained even from normal-appearing mucosa to establish histologic diagnosis 2
• If Crohn's disease is suspected based on clinical features, consider cross-sectional imaging (MR enterography or CT enterography) to evaluate small bowel involvement and complications such as strictures or fistulas 2, 3

Expected Diagnostic Outcomes

At different calprotectin thresholds, the likelihood of finding endoscopic inflammation varies:

• At >250 μg/g: approximately 95% of symptomatic patients will have true moderate-to-severe endoscopic inflammation 2
• At 100-250 μg/g: specificity is 66% for detecting active endoscopic inflammation, necessitating further investigation 3
• Possible diagnoses include moderate-to-severe ulcerative colitis, Crohn's disease, microscopic colitis, ischemic colitis, or colorectal neoplasia with associated inflammation 2

Post-Diagnosis Management Framework

If IBD is confirmed on colonoscopy:

• Treatment intensity should match disease severity, with calprotectin levels >250 μg/g typically requiring immunomodulator or biologic therapy rather than aminosalicylates alone 2
• Repeat calprotectin at 2-4 months after treatment initiation to assess biochemical response, with target <150 μg/g indicating adequate treatment response 2
• Follow-up endoscopy at 6-12 months to confirm mucosal healing, as calprotectin normalization correlates with but does not guarantee endoscopic remission 2
• In established IBD patients, serial calprotectin monitoring at 3-6 month intervals can facilitate early recognition and treatment of impending disease flares 2, 3

Special Considerations for Symptomatic Patients

The interpretation of calprotectin must account for symptom severity:

• 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 2
• In asymptomatic patients with known IBD and calprotectin >150 μg/g, the false positive rate is 22.4%, suggesting endoscopic evaluation should be considered 2
• In patients with mild symptoms and calprotectin <150 μg/g, active inflammation cannot be reliably ruled out (very low certainty evidence), and endoscopy may still be warranted if clinical suspicion remains high 4