Functional Iron Deficiency
Functional iron deficiency is a state where total body iron stores are adequate or even elevated (reflected by normal or high ferritin levels), but iron is sequestered and unavailable for erythropoiesis due to inflammation-driven hepcidin upregulation that blocks iron release from storage sites. 1
Pathophysiology
Functional iron deficiency occurs through a distinct mechanism from absolute iron deficiency:
- Inflammatory cytokines (TNF-α, IL-6) stimulate hepatic hepcidin production, which binds to ferroportin on enterocytes and macrophages, blocking iron export from these cells 1, 2
- Iron becomes trapped in reticuloendothelial macrophages despite adequate total body stores, creating iron-restricted erythropoiesis 1
- Ferritin levels rise as an acute-phase reactant during inflammation, masking the functional iron deficit and appearing falsely reassuring 1
- Transferrin saturation drops because circulating iron is reduced even though storage iron is present 1
Diagnostic Criteria
The diagnosis depends critically on the presence of inflammation:
In Inflammatory Conditions (IBD, CKD, CHF)
- Ferritin 30-100 μg/L with transferrin saturation <20% indicates combined absolute and functional iron deficiency 1
- Ferritin >100 μg/L with transferrin saturation <20% indicates pure functional iron deficiency (anemia of chronic disease) 1
- Ferritin up to 300 μg/L may still represent iron deficiency if transferrin saturation is <20% in the setting of active inflammation 3, 4
Key Laboratory Pattern
- Normal or elevated ferritin (typically 100-700 ng/mL in CKD, can be higher in other inflammatory states) 3, 5
- Low transferrin saturation (<20%) 1, 3
- Low serum iron despite adequate stores 1
- Elevated inflammatory markers (CRP, ESR) confirming the inflammatory state 1
Clinical Contexts Where This Occurs
Functional iron deficiency is particularly common in:
- Chronic kidney disease patients on erythropoiesis-stimulating agents, where pharmacologically stimulated erythropoiesis outpaces iron mobilization from stores 3, 5, 4
- Inflammatory bowel disease with active inflammation, where hepcidin blocks iron absorption and release 1, 3
- Chronic heart failure, where chronic inflammation impairs iron availability 3, 4
- Cancer and chronic infections, where inflammatory cytokines drive hepcidin production 2, 4
Critical Distinction from Absolute Iron Deficiency
Absolute iron deficiency means depleted total body iron stores:
- Ferritin <30 μg/L (or <100 μg/L in CKD) 1, 6, 4
- Transferrin saturation <20% 6, 4
- Responds to oral iron supplementation 6, 4
Functional iron deficiency means adequate stores but poor availability:
- Ferritin >100 μg/L with transferrin saturation <20% 1, 3
- Oral iron is largely ineffective because hepcidin blocks intestinal absorption 3, 2
- Intravenous iron bypasses the hepcidin block and can improve erythropoiesis 3, 5, 2
Management Implications
The treatment approach differs fundamentally from absolute iron deficiency:
- Intravenous iron is preferred over oral iron because it bypasses the hepcidin-mediated intestinal absorption block 3, 5, 2
- In CKD patients with ferritin 100-700 ng/mL and transferrin saturation <20%, IV iron can improve hemoglobin despite elevated ferritin 3, 5
- In heart failure patients, IV iron improves functional capacity and quality of life even without anemia when transferrin saturation <20% 4
- Treating the underlying inflammatory condition is essential to reduce hepcidin and restore normal iron metabolism 2
Common Pitfall to Avoid
Never assume adequate iron status based on ferritin alone in inflammatory conditions. 1, 3 Ferritin is an acute-phase reactant that rises with inflammation independent of actual iron availability for erythropoiesis. Always measure transferrin saturation simultaneously to distinguish functional iron deficiency (high ferritin, low transferrin saturation) from true iron sufficiency (high ferritin, normal transferrin saturation >20%). 1