What is the recommended treatment for elevated lactoferrin levels and ongoing digestive issues despite clear colonoscopy, endoscopy, and capsule endoscopy results?

Elevated Lactoferrin with Clear Endoscopy: Diagnostic and Management Approach

Your lactoferrin level of 11.5 μg/g is elevated (normal <7.25 μg/g), and despite negative endoscopic evaluations, this warrants further investigation rather than empiric treatment, with repeat biomarker testing in 3-6 months being the most appropriate next step. 1, 2

Understanding Your Elevated Lactoferrin

Your fecal lactoferrin of 11.5 μg/g exceeds the diagnostic threshold of 7.25 μg/g used to detect intestinal inflammation. 1 However, the clinical significance must be interpreted in context:

• Lactoferrin has 83% sensitivity and 75% specificity for detecting moderate to severe endoscopic inflammation in inflammatory bowel disease (IBD). 2 This means approximately 25% of elevated results may not reflect true endoscopic inflammation, which appears consistent with your negative endoscopic findings.

• The modest elevation (11.5 vs. threshold of 7.25) suggests either mild inflammation below endoscopic detection thresholds, segmental disease that was missed, or a false positive result. 2

Why Your Endoscopies Were Clear

Several important considerations explain the discordance between your elevated lactoferrin and negative endoscopic findings:

• Capsule endoscopy, colonoscopy, and upper endoscopy can miss subtle mucosal inflammation, particularly in the small bowel or when inflammation is microscopic rather than macroscopic. 1

• Fecal biomarkers can detect inflammation at a molecular level before it becomes visually apparent on endoscopy. 3

• Your lactoferrin elevation is relatively modest, suggesting if inflammation exists, it may be mild (below the Mayo Endoscopic Score 2-3 threshold used in most studies). 1

Recommended Management Strategy

Immediate Steps:

Rule out infectious causes first - even with negative initial workup, ensure comprehensive stool testing for:

• Clostridioides difficile (C. diff)
• Enteric bacterial pathogens
• Parasitic infections 2, 4

Primary Recommendation:

Repeat fecal lactoferrin measurement in 3-6 months rather than proceeding to empiric treatment or repeat endoscopy. 1, 2 This approach is specifically recommended by the American Gastroenterological Association (AGA) for patients with:

• Mild or absent symptoms
• Elevated biomarkers
• No endoscopic confirmation of inflammation 1

If Lactoferrin Remains Elevated on Repeat Testing:

Proceed with repeat endoscopic assessment, potentially with biopsies from previously normal-appearing areas. 1, 2 The rationale:

• Persistent elevation increases likelihood of true inflammation 1
• Histologic examination may reveal microscopic inflammation missed on visual inspection 1
• This establishes whether lactoferrin correlates with your specific disease pattern 2

If Symptoms Worsen Before Repeat Testing:

Immediate endoscopic reassessment is warranted if you develop:

• Frequent rectal bleeding
• Significant increase in stool frequency (≥4 bowel movements above baseline)
• Abdominal pain with fever or tenderness 1

Important Considerations About Your Case

Factors That Can Elevate Lactoferrin Without IBD:

• Recent NSAID use (within 6 weeks) - you've confirmed avoidance, which is appropriate 2
• Alcohol consumption - you've confirmed avoidance, which is appropriate 2
• Subclinical infections not detected on routine testing 2, 4
• Microscopic colitis - requires histologic diagnosis, not visible endoscopically 1

Why Empiric Treatment Is Not Recommended:

The AGA specifically advises against empiric treatment in patients with elevated biomarkers but no endoscopic confirmation of inflammation. 1 The reasoning:

• Risk of unnecessary immunosuppression and treatment-related complications 1
• False positive rate of 12.5% for elevated lactoferrin in intermediate probability scenarios 1
• Need to establish definitive diagnosis before committing to long-term therapy 1

Monitoring Strategy Going Forward

If repeat lactoferrin normalizes (<7.25 μg/g):

• Continue monitoring symptoms
• No further biomarker testing needed unless symptoms develop 1

If repeat lactoferrin remains elevated and endoscopy confirms inflammation:

• Treatment should be adjusted based on endoscopic findings 2
• Monitor both lactoferrin and fecal calprotectin going forward to determine which correlates better with your disease activity 2
• Repeat biomarkers 2-4 months after treatment initiation 4

Critical Pitfall to Avoid

Do not dismiss ongoing digestive symptoms simply because endoscopy was clear. 1 The combination of symptoms plus elevated lactoferrin warrants continued investigation, as:

• Functional disorders (like IBS) should have normal lactoferrin (<7.25 μg/g) 3
• Your elevated level suggests organic pathology even if not yet endoscopically visible 3
• Early detection and treatment of IBD improves long-term outcomes 1