What causes low iron levels with high ferritin levels?

Low Iron with High Ferritin: Causes and Implications

The combination of low iron levels with high ferritin is most commonly caused by inflammation or chronic disease, where inflammatory cytokines increase ferritin production while simultaneously reducing iron availability for erythropoiesis through hepcidin-mediated mechanisms. 1, 2

Pathophysiological Mechanisms

Inflammation-Driven Process

• Inflammatory cytokines (TNF-α, IL-6) trigger:
  • Increased hepcidin production by the liver
  • Iron sequestration in the reticuloendothelial system (RES)
  • Reduced intestinal iron absorption
  • Impaired iron release from macrophages 3, 2

Diagnostic Interpretation

• Ferritin as an acute phase reactant: During inflammation, ferritin levels rise independently of iron stores 1, 4
• Transferrin saturation (TSAT) provides better insight into circulating iron available for erythropoiesis 3
• When TSAT is low (<20%) but ferritin is high (>300 ng/mL), anemia of inflammation is typically present 3

Common Clinical Scenarios

1. Chronic Inflammatory Conditions

   • Inflammatory bowel disease (13-90% prevalence)
   • Chronic kidney disease (24-85%)
   • Heart failure (37-61%)
   • Cancer (18-82%) 5, 2

2. Acute Inflammatory States

   • Infections (bacterial or viral)
   • Sepsis 4

3. Hyperferritinemic Syndromes

   • Adult-onset Still's disease
   • Macrophage activation syndrome
   • Catastrophic antiphospholipid syndrome 4

4. Malignancies

   • Most common cause of markedly elevated ferritin (>1000 μg/L) 6

5. Iron Overload Conditions

   • Hemochromatosis
   • Multiple blood transfusions 6

Diagnostic Approach

Key Laboratory Tests

• Complete iron panel:
  • Serum iron
  • Ferritin
  • Transferrin saturation (TSAT)
  • Total iron binding capacity (TIBC) 1

Additional Helpful Tests

• Inflammatory markers: CRP, ESR
• Soluble transferrin receptor (sTfR): Remains normal in functional iron deficiency but elevated in true iron deficiency 3
• Reticulocyte hemoglobin content (CHr): CHr <30 pg is predictive of iron-restricted erythropoiesis 3

Clinical Implications

• Functional iron deficiency: Despite adequate iron stores (high ferritin), iron is unavailable for erythropoiesis
• Treatment challenges: Oral iron supplementation may be ineffective due to hepcidin-mediated blockade of iron absorption 1, 2
• Increased morbidity: In heart failure patients, this pattern is associated with increased hospitalization and mortality 3

Management Considerations

• Address underlying inflammation: Treating the primary inflammatory condition is essential
• Intravenous iron: Consider when oral iron is ineffective due to inflammation-induced malabsorption 1, 2
• Higher ferritin cutoffs: In inflammatory states, use higher ferritin thresholds (up to 100 μg/L) to diagnose iron deficiency 1
• Monitor transferrin saturation: More reliable than ferritin for assessing iron availability during inflammation 3

Common Pitfalls

• Misinterpreting high ferritin as adequate iron stores in inflammatory states
• Overlooking functional iron deficiency when ferritin is normal or elevated
• Ineffective oral iron therapy in patients with hepcidin-mediated iron sequestration
• Failure to investigate underlying causes of inflammation 1

The discordance between iron and ferritin levels highlights the complex interplay between iron metabolism and inflammatory processes, requiring careful clinical interpretation beyond standard reference ranges.