Why Inflammation Affects Ferritin Cutoff Values in Diagnosing Iron Deficiency Anemia
In the presence of inflammation, serum ferritin up to 100 μg/L may still be consistent with iron deficiency, whereas without inflammation, a cutoff of <30 μg/L is appropriate for diagnosing iron deficiency. 1, 2
Pathophysiology of Ferritin in Inflammation
- Inflammation causes increased production of hepcidin in the liver, triggered by various inflammatory cytokines 1
- Hepcidin reduces iron export from macrophages into the reticuloendothelial system by reducing ferroportin 1
- This creates a situation of functional iron deficiency for erythropoiesis despite adequate iron stores 1
- Ferritin is an acute-phase reactant that increases during inflammatory processes, falsely suggesting normal iron status in patients who actually have iron deficiency 1
Diagnostic Criteria Based on Inflammatory Status
Without Inflammation:
- Serum ferritin <30 μg/L is the appropriate diagnostic criterion for iron deficiency 1, 2
- Some guidelines suggest that <15 μg/L is highly specific (specificity 0.99) for absolute iron deficiency 2
- A threshold of <45 μg/L may provide optimal balance between sensitivity and specificity in clinical practice 2
With Inflammation:
- Serum ferritin up to 100 μg/L may still be consistent with iron deficiency 1
- If serum ferritin is between 30-100 μg/L in the presence of inflammation, a combination of true iron deficiency and anemia of chronic disease is likely 1, 2
- Transferrin saturation <20% should be considered alongside ferritin for accurate diagnosis 1, 2
Clinical Implications
- Relying on standard ferritin cutoffs during inflammation can lead to missed diagnoses of iron deficiency 3, 4
- In one study, using a cutoff of ≤50 μg/L in patients with inflammation had only a 22% negative predictive value for iron deficiency 3
- Even with extreme hyperferritinemia (as high as 26,387 μg/L in one case report), iron deficiency can still coexist 5
Additional Diagnostic Considerations
- Measurement of soluble transferrin receptor (sTfR) can help differentiate between iron deficiency and anemia of chronic disease, as sTfR is high in iron deficiency but normal or low in anemia of chronic disease 1, 6
- sTfR is not influenced by inflammation, making it a valuable supplement to ferritin measurement 6
- Complete blood count with MCV, reticulocytes, serum ferritin, transferrin saturation, and CRP should be included in the minimum workup 1
Practical Approach to Diagnosis
- Always assess inflammatory status (CRP, ESR, leukocyte count) alongside ferritin levels 1
- In patients with active inflammation, do not rule out iron deficiency even with ferritin levels up to 100 μg/L 1, 2
- Consider the possibility of mixed anemia (both iron deficiency and anemia of chronic disease) when ferritin is between 30-100 μg/L with inflammation present 1
- Use transferrin saturation <16-20% as an additional marker to support the diagnosis of iron deficiency in inflammatory states 1