What is the significance of low transferrin (Transport protein for iron), Total Iron Binding Capacity (TIBC), and iron levels with normal ferritin levels in a patient?

Anemia of Chronic Disease/Inflammation

The combination of low transferrin, low TIBC, and low serum iron with normal ferritin is pathognomonic for anemia of chronic disease (ACD) or functional iron deficiency in the setting of inflammation, not true iron deficiency. 1

Key Diagnostic Pattern

This laboratory pattern indicates:

• All iron transport markers (transferrin, TIBC, serum iron) are suppressed by inflammation, which is the hallmark of ACD rather than absolute iron deficiency 1
• Normal ferritin excludes simple iron deficiency, as ferritin <15 μg/L is required for diagnosis of absolute iron deficiency in the absence of inflammation 1
• In true iron deficiency, you would expect elevated transferrin and TIBC as the body attempts to maximize iron capture, not decreased values 2, 3

Pathophysiology

Inflammation drives hepcidin production, which blocks iron release from stores and reduces transferrin synthesis, creating a functional iron restriction despite adequate or even elevated body iron stores 1. This explains why:

• Transferrin/TIBC are decreased (not increased as in true deficiency) 1
• Serum iron is low (trapped in stores, cannot be mobilized) 1
• Ferritin remains normal or elevated (acute phase reactant + reflects adequate stores) 1

Essential Next Steps

Immediately measure inflammatory markers (CRP, ESR) to confirm the presence of inflammation, as this will validate the diagnosis of ACD and guide management 2.

Calculate transferrin saturation (TSAT) using the formula: (serum iron ÷ TIBC) × 100 2:

• TSAT <20% with inflammation suggests functional iron deficiency 1
• TSAT <16% may warrant iron supplementation even with normal ferritin if inflammation is present 2

Consider measuring hepcidin if available, as elevated hepcidin is the most reliable indicator distinguishing ACD from true iron deficiency in inflammatory states 1

Critical Pitfall to Avoid

Do not treat this as simple iron deficiency based solely on low serum iron—the normal ferritin and low (not high) transferrin/TIBC definitively exclude uncomplicated iron deficiency 1, 3. Iron supplementation in the presence of normal or elevated ferritin is not recommended and potentially harmful 1.

When Iron Supplementation May Still Be Indicated

If ferritin is <100 μg/L in the context of chronic inflammation with TSAT <20%, functional iron deficiency coexists with inflammation, and iron therapy may be beneficial 1:

• Ferritin <45 μg/L warrants consideration of iron therapy even with inflammation (specificity 0.92 for true deficiency) 1
• Ferritin >150 μg/L essentially excludes iron deficiency even with inflammation present 1

In hemodialysis patients specifically, iron therapy may be considered even with ferritin 500-1200 μg/L if TSAT <25% and ESA resistance is present, though this requires careful risk-benefit assessment 1

Underlying Cause Investigation

Focus diagnostic efforts on identifying the source of inflammation or chronic disease, not on gastrointestinal blood loss evaluation (which would show low ferritin) 1:

• Chronic infections
• Autoimmune/inflammatory conditions
• Malignancy
• Chronic kidney disease 1, 4

Low TIBC itself is associated with protein-energy wasting, inflammation, and increased mortality risk in chronic disease states, making it both a diagnostic marker and prognostic indicator 4