Which biomarker is elevated in anemia and most consistent with iron deficiency anemia?

Biomarkers in Iron Deficiency Anemia

Serum transferrin receptor (sTfR) is the biomarker that is elevated in anemia and most consistent with iron deficiency anemia. 1

Diagnostic Biomarkers for Iron Deficiency Anemia

Elevated Biomarkers in Iron Deficiency Anemia

• Serum transferrin receptor (sTfR): Significantly elevated in iron deficiency anemia and provides superior discrimination, particularly in chronic disease 1
• Total iron-binding capacity (TIBC): Raised in iron deficiency anemia 1
• Red cell distribution width (RDW): High (>14%) in iron deficiency anemia 2
• sTfR/log10 ferritin ratio: Provides superior discrimination to either test alone, especially in chronic inflammatory conditions 1
• Red cell zinc protoporphyrin: Elevated in iron deficiency 1
• Percentage of hypochromic red cells: Increased in iron deficiency 1

Decreased Biomarkers in Iron Deficiency Anemia

• Serum ferritin: Most specific test for iron deficiency (typically <15 μg/L indicates absent iron stores) 1, 2
• Transferrin saturation: Low (<20%) in iron deficiency 1, 2
• Serum iron: Low in iron deficiency 1
• Mean cell hemoglobin (MCH): Reduced (hypochromia) 1
• Mean cell volume (MCV): Reduced (microcytosis) 1, 2
• Hemoglobin: Low (defining feature of anemia) 1
• Reticulocyte hemoglobin (Retic-Hb): Low in iron deficiency 1

Diagnostic Algorithm for Iron Deficiency Anemia

1. Initial screening: Complete blood count showing anemia (Hb <13 g/dL for men, <12 g/dL for women) 2, 3

2. First-line iron studies:

   • Serum ferritin (most specific test)
     • <15 μg/L: Highly specific for iron deficiency (specificity 0.99) 1
     • <30 μg/L: Indicative of low iron stores 1, 2
     • 30-100 μg/L with inflammation: May still indicate iron deficiency 1
   • Transferrin saturation <20%: Supportive of iron deficiency 1, 2

3. Additional confirmatory tests (especially in inflammatory conditions):

   • Elevated serum transferrin receptor (sTfR): Best marker for iron deficiency in otherwise healthy subjects 1
   • Elevated sTfR/log10 ferritin ratio: Superior discrimination in chronic disease 1
   • Elevated TIBC: Good predictor of iron deficiency (better than iron or saturation) 4
   • Elevated RDW (>14%): Helps distinguish iron deficiency from thalassemia trait 2

Special Considerations

Inflammatory Conditions

• In inflammatory states (check C-reactive protein), ferritin acts as an acute-phase reactant and may be falsely normal or elevated 1, 2
• In these cases:
  • Ferritin up to 100 μg/L may still be consistent with iron deficiency 1
  • sTfR is less affected by inflammation and more reliable 1
  • sTfR/log10 ferritin ratio provides better discrimination 1

Diagnostic Accuracy

• MCV has strong predictive value when very low (≤75 fl) for iron deficiency (83% predictive value) 5
• TIBC or transferrin measurement alone outperforms iron measurement and saturation indices in predicting iron deficiency (ROC area: transferrin/TIBC 0.94, iron 0.77, saturation 0.87) 4

Common Pitfalls to Avoid

• Relying solely on hemoglobin/hematocrit: These are late indicators of iron deficiency 1
• Misinterpreting normal ferritin in inflammatory conditions: Ferritin can be normal or elevated despite iron deficiency in inflammatory states 1
• Overlooking functional iron deficiency: Patients may have functional iron deficiency despite normal ferritin levels 2
• Not considering other causes of microcytosis: Thalassemia and anemia of chronic disease can also present with low MCV 1, 2
• Using inappropriate cutoffs: Different ferritin cutoffs should be used depending on the presence of inflammation (15 μg/L without inflammation, up to 100 μg/L with inflammation) 1

In conclusion, while several biomarkers are altered in iron deficiency anemia, serum transferrin receptor stands out as the biomarker that is specifically elevated and most consistent with iron deficiency anemia, particularly in the context of inflammatory conditions where ferritin may be unreliable.