How to manage a patient with iron deficiency and elevated ferritin?

Management of Functional Iron Deficiency with Elevated Ferritin

This patient has functional iron deficiency (iron-restricted erythropoiesis) indicated by severely low transferrin saturation (7%) despite elevated ferritin (225 ng/mL), and should be treated with intravenous iron therapy after confirming inflammatory status with C-reactive protein measurement. 1

Understanding This Iron Profile Pattern

The combination of low serum iron (17 µg/dL), low TIBC (232 µg/dL), critically low transferrin saturation (7%), and elevated ferritin (225 ng/mL) represents functional iron deficiency rather than true iron overload. 1

• Transferrin saturation <20% is the critical diagnostic threshold that indicates inadequate iron availability for red blood cell production, regardless of ferritin levels. 1
• Inflammatory cytokines stimulate hepcidin production, which blocks intestinal iron absorption and sequesters iron in reticuloendothelial macrophages, making stored iron unavailable for erythropoiesis despite adequate ferritin levels. 2
• Ferritin acts as both an iron storage marker and an acute-phase inflammatory protein, becoming falsely elevated during inflammation even when functional iron deficiency exists. 1, 3

Immediate Diagnostic Steps

Measure C-reactive protein (CRP) to confirm inflammatory status and identify the underlying cause of inflammation. 2

• If CRP is elevated with ferritin >100 ng/mL and TSAT <20%, this confirms anemia of chronic disease with functional iron deficiency. 2

• Screen for underlying inflammatory conditions including:

  • Chronic heart failure (NYHA class II-IV) 2
  • Chronic kidney disease (check creatinine clearance) 2
  • Inflammatory bowel disease 2
  • Active malignancy 3
  • Chronic infections 3

• Check complete blood count to assess for anemia (hemoglobin <12 g/dL in females, <13 g/dL in males). 2

Treatment Strategy

Intravenous iron is strongly preferred over oral iron because inflammation impairs intestinal iron absorption via hepcidin upregulation, making oral supplementation ineffective. 1

IV Iron Dosing Protocols

• For heart failure patients: Ferric carboxymaltose has demonstrated reduction in cardiovascular death and heart failure hospitalizations in patients with TSAT <20%. 1
• For hemodialysis patients: Ferric gluconate 125 mg over 8 consecutive hemodialysis sessions has shown hemoglobin increases even with ferritin 500-1200 ng/mL. 2, 1
• General approach: Consider weekly IV iron 50-125 mg for 8-10 consecutive doses. 1

Why IV Iron Works Despite Elevated Ferritin

• IV iron bypasses the hepcidin-mediated intestinal block and delivers iron directly to erythroid precursors. 1
• Safety data exists for IV iron administration up to ferritin 1200 ng/mL in dialysis patients, with organ damage from iron overload requiring dramatically higher sustained ferritin levels (>1000 ng/mL) and >20 grams total excess iron. 2, 1
• In the DRIVE study, patients with ferritin 500-1200 ng/mL and TSAT <25% showed significant hemoglobin increases (16±13 vs 11±14 g/L; P=0.028) with IV iron compared to controls. 2

Monitoring Response to Treatment

Assess hemoglobin response after 8-10 doses of IV iron (approximately 8-10 weeks). 2, 1

• If hemoglobin increases by ≥1 g/dL, this confirms functional iron deficiency and appropriate response. 2
• If no erythropoietic response occurs, an inflammatory block is likely dominant and further IV iron should be discontinued until inflammation resolves. 1
• Serial ferritin measurements during therapy can help: decreasing ferritin suggests functional iron deficiency, while abrupt ferritin increase with TSAT drop suggests inflammatory block. 1

Critical Pitfalls to Avoid

• Do NOT withhold IV iron solely because ferritin is >100 ng/mL when TSAT is <20%, as this represents functional iron deficiency requiring treatment. 1
• Do NOT use oral iron as first-line therapy in inflammatory states because hepcidin elevation blocks oral iron absorption, making it ineffective. 1
• Do NOT continue IV iron indefinitely without response—stop iron and address underlying inflammation if no hemoglobin increase after 8-10 doses. 1
• In heart failure patients specifically, TSAT <20% with ferritin up to 400 ng/mL is a reliable predictor of benefit from IV iron therapy. 1

Safety Monitoring

• Monitor for infusion reactions, which occur in approximately 4% of patients receiving IV iron. 2
• Ferritin >500 ng/mL does not preclude benefit from IV iron if TSAT remains low. 2, 1
• Re-check iron studies (ferritin, TSAT, hemoglobin) 8-10 weeks after completing IV iron course, not earlier, as ferritin levels are falsely elevated immediately post-infusion. 2