Why check C-Reactive Protein (CRP) in a patient with hypoferritinemia?

Why Check CRP in a Patient with Low Ferritin

CRP should be checked in patients with low ferritin to determine whether the low ferritin represents true iron deficiency or is being falsely lowered by the absence of inflammation, since ferritin is an acute-phase reactant that rises with inflammation and can mask underlying iron deficiency when elevated. 1

The Dual Nature of Ferritin

Ferritin serves two distinct roles that complicate its interpretation:

• As an iron storage marker: Ferritin reflects body iron stores, with levels <15 μg/L indicating absolute iron deficiency in the absence of inflammation 1
• As an acute-phase reactant: Ferritin increases during inflammatory processes independent of iron status, potentially masking true iron deficiency 1

Critical Diagnostic Thresholds Change with Inflammation

The interpretation of ferritin values fundamentally shifts based on inflammatory status:

Without Inflammation (Normal CRP):

• Ferritin <15 μg/L confirms absolute iron deficiency 1
• Ferritin is a reliable indicator of iron storage levels 1
• No adjustment needed for interpretation 1

With Inflammation (Elevated CRP):

• The lower limit of ferritin consistent with normal iron stores increases to 100 μg/L 1
• Ferritin 30-100 μg/L with transferrin saturation <16% suggests combined iron deficiency and anemia of chronic disease 1
• Ferritin >100 μg/L with transferrin saturation <16% suggests anemia of chronic disease alone 1

Clinical Algorithm for Low Ferritin Evaluation

Step 1: Measure CRP simultaneously with ferritin 1

Step 2: Interpret based on inflammatory status:

• If CRP is normal (or other inflammatory markers like ESR are normal): Low ferritin reliably indicates iron deficiency requiring treatment 1

• If CRP is elevated: The ferritin threshold for diagnosing iron deficiency must be raised, and additional testing may be needed 1

Step 3: Consider additional markers when inflammation is present:

• Soluble transferrin receptor (sTfR) - elevated in iron deficiency, normal/low in anemia of chronic disease 1, 2
• Reticulocyte hemoglobin content (<30 pg suggests iron deficiency) 1, 2
• Transferrin saturation (<16% suggests functional iron deficiency) 1

Common Clinical Pitfalls

Inflammation can increase ferritin by 30-90% depending on the phase of inflammation 3:

• Incubation phase (elevated CRP only): 30% increase 3
• Early convalescence (both CRP and AGP elevated): 90% increase 3
• Late convalescence (elevated AGP only): 36% increase 3

Without checking CRP, you risk:

• Missing iron deficiency in patients with concurrent inflammation where ferritin appears "normal" but is actually elevated by inflammation 1
• Incorrectly attributing low-normal ferritin values to adequate iron stores when inflammation is absent 1

Disease-Specific Considerations

In inflammatory bowel disease: CRP measurement is mandatory because iron deficiency and anemia of chronic disease frequently coexist, making ferritin interpretation impossible without knowing inflammatory status 1

In chronic kidney disease: CRP helps assess whether elevated ferritin reflects true iron stores or inflammation, particularly in hemodialysis patients where ferritin is less reliable 1

In hemochromatosis evaluation: CRP must be checked before genetic testing in patients with elevated ferritin, as inflammation is one of the most common causes of hyperferritinemia (>90% of cases) 1

The Bottom Line

Ferritin cannot be interpreted in isolation. CRP provides the essential context to determine whether ferritin accurately reflects iron stores or is being influenced by inflammation, directly impacting treatment decisions between iron supplementation versus addressing underlying inflammatory conditions. 1