What is the recommended work‑up and management for a patient with an elevated fecal calprotectin level?

Management of Elevated Fecal Calprotectin

The management of elevated fecal calprotectin depends critically on symptom severity: patients with moderate-to-severe symptoms and calprotectin >150 μg/g should proceed directly to treatment adjustment without requiring endoscopy, while those with mild symptoms or asymptomatic patients require endoscopic confirmation before empiric treatment changes. 1

Initial Assessment and Baseline Testing

Before proceeding with management decisions, obtain the following baseline investigations 2:

• Complete blood count to identify anemia or leukocytosis
• C-reactive protein and ESR to assess systemic inflammation
• Comprehensive metabolic panel to evaluate for dehydration or electrolyte abnormalities
• Stool culture including Clostridioides difficile testing to exclude infectious causes that can elevate calprotectin 3, 2
• Celiac serology if not previously performed 2

Management Algorithm Based on Symptom Severity and Calprotectin Level

Patients with Moderate-to-Severe Symptoms

Moderate-to-severe symptoms are defined as frequent rectal bleeding (rectal bleeding score 2-3), significantly increased stool frequency, or PRO2 score >13 or PRO3 score >21. 1

Calprotectin >150 μg/g

• Proceed directly to treatment adjustment without endoscopic assessment, as the false-positive rate is only 4.6%, meaning 95.4% of these patients have true moderate-to-severe endoscopic inflammation 1, 2
• At calprotectin >250 μg/g, specificity improves to 82%, further supporting empiric treatment escalation 1, 3
• Initiate or intensify therapy based on disease type (Crohn's disease vs ulcerative colitis) and prior treatment history 3, 4

Calprotectin <150 μg/g

• Do not rely on normal biomarkers to exclude inflammation, as the false-negative rate is 26.4% in symptomatic patients 1
• Proceed with endoscopic assessment to confirm disease activity before treatment decisions 1

Patients with Mild Symptoms

Mild symptoms are defined as infrequent rectal bleeding, mildly increased stool frequency, or PRO2 score 8-13 or PRO3 score 13-21. 1

Calprotectin >150 μg/g

• Endoscopic assessment is required before empiric treatment adjustment, as the false-positive rate rises to 15.5% in this intermediate pretest probability scenario 1, 3, 2
• Neither elevated nor normal biomarkers alone are sufficiently accurate to determine endoscopic activity in mildly symptomatic patients 1

Calprotectin 100-250 μg/g (Intermediate Range)

• Repeat calprotectin testing after 2-3 weeks to differentiate persistent from transient elevation 2
• If repeat testing normalizes to <100 μg/g and symptoms align with functional disorder, manage as irritable bowel syndrome 2
• If strong clinical suspicion for IBD exists (family history, alarm features), proceed directly to gastroenterology referral without repeat testing 2

Calprotectin <100 μg/g

• Suggests functional bowel disorder such as irritable bowel syndrome 2
• Consider alternative diagnoses if symptoms persist: bile-acid malabsorption, microscopic colitis, or medication-induced symptoms 2

Patients in Symptomatic Remission

Calprotectin <150 μg/g with Normal CRP

• Rules out active inflammation, avoiding need for endoscopic evaluation 1
• Continue current therapy without adjustment 4

Calprotectin >150 μg/g

• Endoscopic assessment is required before treatment adjustment, as the false-positive rate is 22.4% in asymptomatic patients with known IBD 1, 2
• In patients without recent endoscopic confirmation of remission (ideally within 3 years), endoscopic evaluation is preferred over relying solely on biomarkers 1
• Consider repeat biomarker measurement in 3-6 months as an alternative to immediate endoscopy if recent endoscopic remission was documented 1

Endoscopic Evaluation When Indicated

When endoscopy is required, perform complete ileocolonoscopy with terminal ileum intubation 2:

• Obtain multiple biopsies even from normal-appearing mucosa to establish histologic diagnosis 2
• For suspected Crohn's disease, consider cross-sectional imaging (MR enterography or CT enterography) to evaluate small bowel involvement 2

Treatment Monitoring and Follow-Up

After initiating or adjusting therapy 3, 4:

• Repeat fecal calprotectin at 2-4 months to assess biochemical response, targeting <150 μg/g as indicator of adequate treatment 3, 2, 4
• Perform endoscopic assessment at 6-12 months to confirm mucosal healing, as calprotectin normalization correlates with but does not guarantee endoscopic remission 3, 2, 4
• Serial calprotectin monitoring every 3-6 months in established IBD patients facilitates early recognition of impending flares 2

Critical Pitfalls and Caveats

NSAID Use

• Recent NSAID use within 6 weeks can cause false-positive elevation 2
• Repeat testing after at least 6 weeks of NSAID cessation before proceeding to invasive investigations 2

Non-IBD Causes of Elevation

Elevated calprotectin may arise from 1, 2, 5:

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

Alarm Features Override Calprotectin

Presence of alarm features mandates cancer pathway referral regardless of calprotectin level 1, 2:

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

Calprotectin is not sensitive enough to exclude colorectal cancer, and these patients require urgent colonoscopy 1, 2

Biomarkers Have No Role in Dysplasia Surveillance

Fecal calprotectin and other inflammatory biomarkers cannot detect dysplasia and should not replace endoscopic surveillance protocols in IBD patients 3

Persistently Elevated Biomarkers After Initial Symptom Improvement

In patients whose symptoms recently resolved after treatment but biomarkers remain elevated, lack of normalization at 3-6 months likely indicates active inflammation and may warrant treatment adjustment without repeat endoscopy 1