What are the causes of elevated ferritin (iron storage protein) levels with normal iron levels?

Causes of Elevated Ferritin with Normal Iron Levels

Hyperferritinemia with normal iron levels is most commonly caused by inflammatory conditions, liver disease, malignancy, or metabolic disorders rather than true iron overload disorders. 1, 2

Common Causes of Elevated Ferritin with Normal Iron Levels

Inflammatory Conditions

• Acute and chronic inflammation: Ferritin is an acute phase reactant that increases during inflammatory states 3, 4
  • Rheumatologic disorders (adult-onset Still's disease, systemic juvenile idiopathic arthritis)
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome
  • Inflammatory bowel disease
  • Chronic infections

Liver Disease

• Non-alcoholic fatty liver disease (NAFLD): Ferritin >1.5× upper limit of normal is associated with more severe NAFLD and advanced fibrosis 5
• Alcoholic liver disease: Excessive alcohol consumption can elevate both ferritin and transferrin saturation 6
• Viral hepatitis: Chronic viral hepatitis can cause elevated ferritin levels 1

Malignancies

• Various malignancies can cause hyperferritinemia 2, 7
• Malignancy is the most frequent cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 2

Metabolic Disorders

• Metabolic syndrome: Often associated with elevated ferritin levels 6, 1
• Diabetes mellitus: Common in patients with hyperferritinemia 1

Other Causes

• Anemia of chronic disease: Increased hepcidin leads to iron sequestration despite normal or high ferritin 3
• Renal failure: Can cause elevated ferritin levels
• Hemolysis: Release of ferritin from damaged cells 4

Diagnostic Approach

1. Assess transferrin saturation (TSAT):

   • TSAT >45% suggests true iron overload disorders 1
   • TSAT <20% with elevated ferritin suggests anemia of chronic disease or functional iron deficiency 3
   • Normal TSAT with elevated ferritin suggests inflammatory or hepatic causes

2. Evaluate liver function:

   • Elevated liver enzymes may indicate liver disease as the cause 1, 5
   • Consider hepatitis serology and autoimmune markers 1

3. Screen for inflammatory markers:

   • C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)
   • Elevated inflammatory markers support inflammation as the cause 3, 4

4. Consider imaging:

   • MRI can quantify hepatic iron concentration non-invasively 6, 1
   • Liver ultrasound to evaluate for steatosis, hepatomegaly, and structural abnormalities 1

Management Considerations

• For inflammatory causes: Treat the underlying inflammatory condition
• For NAFLD/metabolic syndrome: Weight loss through dietary modification and increased physical activity 6
• For alcoholic liver disease: Alcohol reduction or abstinence 1
• For true iron overload: Consider phlebotomy if evidence of tissue iron accumulation 6, 1

Important Caveats

• Ferritin is primarily a leakage product from damaged cells, making it both a marker of inflammation and cellular damage 4
• Extremely elevated ferritin (>10,000 μg/L) is rare (0.08% of ferritin requests) and warrants investigation for malignancy, multiple blood transfusions, severe liver disease, or Still's disease 7
• In patients with inflammatory conditions, the standard threshold for iron deficiency (<30 μg/L) does not apply; a threshold of <100 μg/L or TSAT <20% should be considered 3
• MRI should be used to quantify hepatic iron concentrations in patients with unclear cause of hyperferritinemia, especially with biochemical evidence of iron overload 6