What is the significance of elevated lactoferrin with normal calprotectin in stool?

Elevated Lactoferrin with Normal Calprotectin: Clinical Significance

Elevated lactoferrin with normal calprotectin creates diagnostic uncertainty that reflects potential segmental inflammation or early mucosal changes not yet detected by calprotectin, and requires endoscopic assessment in symptomatic patients rather than empiric treatment adjustment. 1, 2

Understanding the Discordance

The discordance between these two neutrophil-derived proteins reflects their different diagnostic characteristics and what they detect:

• Lactoferrin has 83% sensitivity and 75% specificity for detecting moderate to severe endoscopic inflammation, meaning approximately 25% of elevated results may represent false positives 2, 3
• Calprotectin at 150 ± 50 mg/g has 71% sensitivity and 69% specificity for the same endpoint, with slightly different performance characteristics 2
• The two markers show 90% concordance overall, but when discordant, this pattern (elevated lactoferrin, normal calprotectin) may indicate segmental disease that calprotectin misses 2, 4
• Lactoferrin correlates more strongly with histological inflammation, while calprotectin correlates better with endoscopic findings in ulcerative colitis and Crohn's disease 5

Clinical Management Algorithm

For Symptomatic Patients (Mild Symptoms)

Proceed directly to endoscopic assessment rather than empiric treatment adjustment, as the discordance creates diagnostic uncertainty requiring direct visualization 1, 2

• Rule out confounding factors first:

  • NSAID use in the past 6 weeks can elevate both markers and should be documented 1, 2
  • Exclude infectious causes, particularly C. difficile and other enteric pathogens, as infections can cause elevated inflammatory markers 2, 6

• If endoscopy confirms active inflammation despite normal calprotectin:

  • Adjust treatment based on endoscopic findings 1, 2
  • Monitor both biomarkers going forward to establish which correlates better with the patient's specific disease activity pattern 1, 2

• If endoscopy shows no inflammation despite elevated lactoferrin:

  • Consider other causes such as medications or subclinical infections 1, 2
  • Repeat lactoferrin testing in 3-6 months to confirm normalization 1, 2
  • Consider that lactoferrin may detect molecular-level inflammation before it becomes visually apparent on endoscopy 3

For Asymptomatic Patients

Repeat biomarker measurement in 3-6 months rather than immediate endoscopy, as the pretest probability of significant inflammation is lower 1, 2

• If lactoferrin remains elevated on repeat testing:

  • Proceed with endoscopic assessment, potentially with biopsies from normal-appearing areas 3

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

  • Continue symptom monitoring only, with no further biomarker testing unless symptoms develop 3

For Patients with Moderate to Severe Symptoms

Consider treatment adjustment without routine endoscopic assessment if lactoferrin is elevated, even with normal calprotectin, as the pretest probability of inflammation is approximately 85% 2

Important Clinical Caveats

• Different collection and processing methods can affect stability and measurement of these biomarkers, potentially contributing to discordance 2
• Capsule endoscopy and standard colonoscopy can miss subtle mucosal inflammation, particularly in the small bowel or when inflammation is microscopic rather than macroscopic 3
• Elevated calprotectin in patients with normal colonoscopy does not predict significant GI disease over 3 years of follow-up, suggesting that biomarker elevation without endoscopic correlation may not always be clinically significant 7
• Both markers are not specific for IBD and may be elevated in various organic conditions, including upper GI diseases like gastritis 7, 8

Why This Pattern Occurs

The biological explanation for this discordance includes:

• Lactoferrin detects inflammation at a molecular level before macroscopic changes appear, potentially identifying early or resolving inflammation 3
• Segmental disease patterns may be captured differently by each marker based on their release mechanisms and stability in stool 1, 2
• Lactoferrin's stronger correlation with histological inflammation means it may remain elevated when microscopic inflammation persists despite endoscopically normal mucosa 5