Why would serum iron levels be low with elevated ferritin (iron storage protein) levels?

Low Serum Iron with Elevated Ferritin: Causes and Clinical Significance

The most common causes of low serum iron with elevated ferritin are inflammatory conditions, anemia of chronic disease, and chronic infections, which require evaluation of transferrin saturation (TSAT) to distinguish from iron overload disorders. 1

Pathophysiology and Mechanisms

Serum iron and ferritin typically move in the same direction, but several clinical scenarios can cause them to diverge:

Inflammatory Conditions

• Ferritin is an acute phase reactant that increases during inflammation regardless of iron status 2, 1
• Inflammatory cytokines trigger increased hepcidin production, which:
  • Blocks iron absorption from the gut
  • Prevents iron release from macrophages and storage sites
  • Results in functional iron deficiency despite adequate or high iron stores 3

Anemia of Chronic Disease

• Characterized by low serum iron, decreased transferrin saturation (<20%), and normal or elevated ferritin 4
• Common in chronic inflammatory conditions, infections, and malignancies
• Impaired erythropoietin production and responsiveness contribute to the anemia 4

Functional Iron Deficiency

• Occurs when iron stores are adequate but cannot be mobilized effectively for erythropoiesis
• Often seen in patients receiving erythropoietin therapy, where iron demand exceeds supply 2
• TSAT <20% with ferritin >100 ng/mL is diagnostic 2, 1

Diagnostic Approach

Key Laboratory Tests

• Transferrin saturation (TSAT) = (serum iron ÷ TIBC) × 100

  • TSAT <20% with elevated ferritin suggests functional iron deficiency or anemia of chronic disease 1
  • TSAT >45% suggests iron overload 1

• Inflammatory markers

  • C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
  • Elevated inflammatory markers support inflammation as the cause of high ferritin 1

• Ferritin thresholds

  • <30 μg/L: Iron deficiency without inflammation
  • 30-100 μg/L: Possible iron deficiency with inflammation

  • 100 μg/L: Anemia of chronic disease or iron overload 1

Differential Diagnosis

1. Anemia of chronic disease/inflammation

   • Common in chronic kidney disease, inflammatory bowel disease, heart failure
   • TSAT <20%, ferritin 100-700 ng/mL 2

2. Chronic infections

   • Bacterial, viral, or fungal infections
   • Elevated ferritin as acute phase reactant 5

3. Malignancies

   • Most frequent cause of markedly elevated ferritin (>1000 μg/L) 5

4. Liver disorders

   • Hepatitis, cirrhosis, alcoholic liver disease
   • Ferritin released from damaged hepatocytes 1, 6

5. Metabolic syndrome and NAFLD

   • Associated with hyperferritinemia without true iron overload 1

Management Approach

For Inflammatory Causes

• Identify and treat the underlying inflammatory condition
• Monitor ferritin and TSAT every 3-6 months 1
• Consider specialist referral if ferritin exceeds 1000 μg/L 1

For Functional Iron Deficiency

• In patients with chronic kidney disease receiving erythropoietin:
  • IV iron supplementation may be beneficial despite elevated ferritin
  • Weekly IV iron (50-125 mg) for 8-10 doses can help determine if there's an erythropoietic response 2
  • If no response occurs, an inflammatory block is likely present 2

For Anemia of Chronic Disease

• Recombinant erythropoietin therapy can correct the anemia but cannot correct true iron deficiency 4
• Treatment of underlying condition is the primary approach

Clinical Pearls and Pitfalls

• Pearl: Serum ferritin may represent leakage from damaged cells rather than reflecting true iron stores 6

• Pitfall: Using standard ferritin thresholds (<30 μg/L) to diagnose iron deficiency in inflammatory conditions will miss many cases; higher thresholds (100 μg/L) should be used 3

• Pearl: The combination of TSAT and ferritin provides better diagnostic accuracy than either test alone 1

• Pitfall: Extremely high ferritin levels (>10,000 μg/L) may suggest hemophagocytic syndromes or adult-onset Still's disease, but more commonly indicate malignancy or infection 5