What is the appropriate management for a patient with hyperferritinemia and iron deficiency?

Management of High Ferritin with Low Iron (Hyperferritinemia with Iron Deficiency)

This presentation represents functional iron deficiency (FID) in the setting of inflammation, where elevated ferritin masks true iron deficiency, and you should treat the iron deficiency with intravenous iron while addressing the underlying inflammatory condition. 1

Understanding the Paradox

The combination of high ferritin and low iron levels occurs when inflammation drives up ferritin (an acute-phase reactant) while simultaneously restricting iron availability through hepcidin upregulation. 1 This creates a state where:

• Iron is sequestered in storage sites (macrophages, reticuloendothelial system) and unavailable for erythropoiesis 1
• Serum ferritin loses its reliability as a marker of iron stores in the presence of inflammation 1, 2
• Transferrin saturation (TSAT) becomes the more accurate indicator of iron availability 2, 3

Diagnostic Approach

Essential Laboratory Workup

Obtain the following tests to characterize the iron deficiency and inflammation: 1

• Complete blood count with MCV, MCH, and reticulocyte count 1
• Serum ferritin (already elevated in your case) 1
• Transferrin saturation (TSAT) - critical for diagnosis 1, 2, 3
• Inflammatory markers: CRP and/or ESR 1

Diagnostic Thresholds for Iron Deficiency in Inflammatory States

In the presence of inflammation, iron deficiency is diagnosed when: 1

• Ferritin 100-300 μg/L with TSAT <20% indicates functional iron deficiency 1, 2, 3
• Ferritin <100 μg/L suggests absolute iron deficiency even with inflammation 1, 2
• Ferritin >150 μg/L makes absolute iron deficiency unlikely but functional deficiency remains possible if TSAT <20% 1

The European consensus on IBD specifically states that ferritin up to 100 μg/L may still be consistent with iron deficiency in the presence of inflammation. 1

Treatment Strategy

Intravenous Iron is the Treatment of Choice

Oral iron is inadequate and should not be used in inflammatory conditions with functional iron deficiency because: 1

• Inflammation impairs intestinal iron absorption via hepcidin 1
• The IRONOUT HF trial demonstrated oral iron fails to improve outcomes in inflammatory states 1
• Intravenous iron bypasses the hepcidin-mediated absorption block 1

IV Iron Dosing Options

Select from these evidence-based regimens: 1

• Ferric carboxymaltose: Up to 1000 mg per week, minimum 15-minute infusion 1
• Iron isomaltoside: Up to 20 mg/kg (maximum 1000 mg), minimum 15-minute infusion 1
• Iron sucrose: 200-500 mg per dose, 30-210 minute infusion 1

Special Consideration: Very High Ferritin (>500 μg/L)

Even with ferritin 500-1200 μg/L, if TSAT <25%, intravenous iron therapy improves outcomes. 1, 4 The DRIVE study demonstrated that hemodialysis patients with ferritin 500-1200 ng/mL and TSAT <25% had significant hemoglobin increases (16±13 vs 11±14 g/L, P=0.028) when given IV iron versus no iron. 1

This paradoxical combination of high ferritin with low TSAT is more strongly associated with inflammation than with true iron overload. 4

Monitoring Parameters

Track these values during treatment: 1, 2, 3

• TSAT is the primary monitoring parameter - target >20% 1, 2, 3
• Hemoglobin levels - expect improvement within 4-8 weeks 1
• Ferritin - may rise further initially but should stabilize 1
• Inflammatory markers (CRP) - to assess disease activity 1

Address the Underlying Inflammatory Condition

Simultaneously investigate and treat the cause of inflammation: 1

• Inflammatory bowel disease - optimize disease control 1
• Chronic kidney disease - manage uremia and inflammation 1, 4
• Heart failure - optimize GDMT 1
• Malignancy - if suspected based on clinical context 1
• Chronic infection - identify and treat 1

Critical Pitfalls to Avoid

• Do not withhold iron therapy based solely on elevated ferritin - this is the most common error 2, 3, 4
• Do not use oral iron in inflammatory states - it is ineffective 1
• Do not ignore TSAT - it is more reliable than ferritin in inflammation 2, 3
• Do not assume iron overload - only 10% of hyperferritinemia cases represent true iron overload 5, 6

When to Consider True Iron Overload

Suspect actual iron overload (not functional deficiency) only when: 5, 6

• TSAT >50% consistently 1
• Ferritin >1000 μg/L with high TSAT 1
• Evidence of hemochromatosis (genetic testing, family history) 1
• Absence of inflammatory markers 5, 6

In such cases, phlebotomy rather than iron supplementation would be indicated. 1