Elevated Ferritin with Normal Iron: Clinical Significance
Elevated ferritin with normal serum iron most commonly indicates inflammation, cellular damage, or metabolic dysfunction rather than iron overload, and requires measurement of transferrin saturation to distinguish between these conditions. 1
Understanding the Paradox
Ferritin is fundamentally an acute-phase reactant that rises during inflammation independent of actual iron stores. 2 The protein acts as a leakage product from damaged cells, dumping most of its iron content when released into serum, which explains why serum ferritin can be elevated while circulating iron remains normal. 3
The key diagnostic step is measuring transferrin saturation (TS) alongside ferritin—never interpret ferritin in isolation. 1
Diagnostic Algorithm Based on Transferrin Saturation
If TS < 45% (Most Common Scenario)
This pattern indicates secondary hyperferritinemia, accounting for over 90% of cases. 1 The elevated ferritin reflects:
Inflammation/infection: Ferritin rises as part of the acute-phase response, with proinflammatory cytokines triggering hepcidin elevation that sequesters iron in storage sites while restricting availability for erythropoiesis. 4, 5
Metabolic syndrome/NAFLD: One of the most common causes in outpatients, where ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload. 1
Chronic alcohol consumption: Causes ferritin elevation through hepatocellular damage and altered iron metabolism. 1
Malignancy: The most frequent cause in one large series of markedly elevated ferritin (>1000 μg/L), particularly solid tumors and lymphomas. 6
Cell necrosis: From muscle injury, acute hepatitis, or other tissue damage releases ferritin into circulation. 1, 3
If TS ≥ 45%
This pattern suggests primary iron overload and warrants HFE genetic testing for C282Y and H63D mutations to evaluate for hereditary hemochromatosis. 1 Consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) if iron overload is confirmed but C282Y homozygosity is excluded. 1
Special Consideration: Functional Iron Deficiency
In inflammatory states, ferritin can be elevated (100-700 μg/L) while patients remain functionally iron deficient. 4 This occurs because:
- Hepcidin blocks iron release from storage sites despite adequate total body iron. 4
- Iron availability for erythropoiesis is restricted even with normal or high ferritin. 2, 4
- In inflammatory bowel disease, ferritin <100 μg/L indicates iron deficiency, while ferritin >100 μg/L with TS <16% suggests anemia of chronic disease. 2
- In chronic kidney disease, ferritin 100-700 ng/mL with TS <20% may represent functional iron deficiency that responds to IV iron therapy. 7
Risk Stratification by Ferritin Level
<1000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced liver fibrosis in hemochromatosis. 1
1000-10,000 μg/L: Higher risk if true iron overload present; requires evaluation of liver enzymes and platelet count. 1
>10,000 μg/L: Rarely represents simple iron overload; consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or severe infection requiring urgent specialist referral. 1, 6
Essential Laboratory Workup
Order simultaneously with ferritin: 1
- Transferrin saturation (fasting morning sample preferred)
- Complete blood count with differential
- Liver enzymes (ALT, AST)
- Inflammatory markers (CRP, ESR) to detect occult inflammation
- Complete metabolic panel
Critical Pitfalls to Avoid
Never diagnose iron overload based on ferritin alone without checking transferrin saturation. 1 Ferritin has high sensitivity but low specificity for iron stores due to its acute-phase reactant properties. 1
Do not assume adequate iron stores in inflammatory conditions when ferritin is elevated. In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency. 2, 4
Recognize that ferritin elevation reflects cellular damage and oxidative stress, not just iron status. 3 The correlation with disease severity often relates to inflammation and cell injury rather than iron accumulation. 5
In chronic inflammatory conditions (IBD, CHF, CKD), use disease-specific thresholds: ferritin <100 μg/L or TS <20% indicates iron deficiency, not the standard <30 μg/L threshold. 4
Treatment Approach
Treat the underlying condition causing ferritin elevation, not the elevated ferritin itself. 1
- For metabolic syndrome/NAFLD: weight loss and metabolic management. 1
- For inflammatory conditions: disease-specific anti-inflammatory therapy. 1
- For functional iron deficiency with TS <20% despite elevated ferritin: consider IV iron supplementation in appropriate clinical contexts (CKD, IBD, CHF). 7, 4
- For confirmed iron overload (TS ≥45%): therapeutic phlebotomy if C282Y homozygote with ferritin <1000 μg/L and normal liver enzymes. 1