What is the treatment for high ferritin (iron storage protein) levels with low iron?

High Ferritin with Low Iron: Functional Iron Deficiency

The combination of high ferritin with low iron (low transferrin saturation) most commonly represents functional iron deficiency due to inflammation, where ferritin is elevated as an acute-phase reactant while iron remains sequestered and unavailable for erythropoiesis. 1

Understanding the Paradox

This seemingly contradictory pattern occurs because:

• Ferritin is an acute-phase reactant that rises independently of iron stores during infection, inflammation, chronic disease, or tissue damage (hepatitis, cirrhosis, neoplasia, arthritis), masking true iron status 1
• Inflammation-driven hepcidin elevation blocks intestinal iron absorption and sequesters iron in macrophages, creating functional iron deficiency despite apparent adequate stores 1
• In hemodialysis patients specifically, ferritin ≥500 ng/mL with transferrin saturation <25% is more strongly associated with inflammation than with actual iron stores 2

Diagnostic Approach

Essential Laboratory Assessment

Measure the following to clarify iron status:

• Transferrin saturation (TSAT): Low TSAT (<20%) indicates iron-restricted erythropoiesis regardless of ferritin level 1
• C-reactive protein (CRP): Elevated CRP confirms inflammation as the cause of high ferritin 3, 2
• Complete blood count: Assess for anemia and mean cell volume 1
• Consider reticulocyte hemoglobin content (CHr): CHr <30 pg is highly predictive of iron-restricted erythropoiesis 1

Key Diagnostic Thresholds

• Functional iron deficiency: TSAT <20% with ferritin 30-800 ng/mL in the presence of inflammation 1
• Inflammation marker: Ferritin >500 ng/mL with TSAT <25% strongly suggests inflammatory etiology 1, 2

Treatment Strategy

When to Treat with Iron

Intravenous iron should be administered when TSAT is <20-25% even with elevated ferritin levels (up to 500-800 ng/mL), particularly in patients with anemia and ongoing inflammation. 1

Specific Clinical Contexts:

Chronic Kidney Disease/Hemodialysis Patients:

• Administer IV iron when ferritin is 200-500 ng/mL and TSAT <20% 1
• Even with ferritin 500-1200 ng/mL, IV iron improves hemoglobin if TSAT <25% (based on DRIVE trial showing 16 g/L vs 11 g/L increase, P=0.028) 1
• Withhold iron when ferritin >1000 ng/mL or TSAT >50% 1

Cancer-Related Anemia:

• Offer IV iron with erythropoiesis-stimulating agents (ESAs) when TSAT is 20-50% and ferritin is 30-800 ng/mL 1
• IV iron monotherapy may benefit patients with ferritin <500 ng/mL who decline ESAs 1
• Even patients with ferritin >500 ng/mL and low TSAT (mean 14.2%) showed benefit in observational studies 1

Congestive Heart Failure:

• Treat iron deficiency (TSAT <20% with ferritin <300 ng/mL) with IV iron regardless of anemia status 1
• IV ferric carboxymaltose improves functional capacity and quality of life 1

Critically Ill Patients:

• In anemic critically ill patients with low hepcidin levels confirming true iron deficiency, administer 1 g IV iron as a single dose using carbohydrate-based products 1

Preferred Iron Formulations

• Ferric carboxymaltose: 1 g as single dose over 15 minutes for rapid whole-body iron replacement 1
• Iron sucrose or ferric gluconate: Multiple smaller doses (125 mg per session) 1
• Avoid high molecular weight iron dextran due to higher reaction risk 1

Safety Monitoring

• Monitor ferritin levels: Preferably keep <500 ng/mL in children/adolescents to avoid toxicity 1
• Upper safety threshold: Clinical judgment required when ferritin >800 ng/mL; balance hemoglobin improvement probability against infection/cardiovascular risks 1
• Recheck iron studies 8-10 weeks after IV iron (not earlier, as ferritin remains falsely elevated immediately post-infusion) 1, 3

Critical Pitfalls to Avoid

• Do NOT supplement iron when ferritin is normal/high WITHOUT confirming low TSAT - this is potentially harmful and ineffective 1, 3
• Do NOT assume high ferritin always means iron overload - only 10% of hyperferritinemia cases represent true iron overload 4
• Do NOT use oral iron for functional iron deficiency - inflammation blocks intestinal absorption via hepcidin; IV route is required 1
• Do NOT ignore the clinical context - ferritin interpretation requires integration with hemoglobin, TSAT, inflammatory markers, and underlying disease 1