What conditions can cause significantly elevated ferritin (Ferritin) levels in the thousands with normal iron studies?

Causes of Elevated Ferritin with Normal Iron Studies

Significantly elevated ferritin levels in the thousands with normal iron studies are most commonly caused by inflammatory conditions, malignancies, liver disease, and certain genetic disorders rather than true iron overload. 1, 2

Primary Causes to Consider

1. Inflammatory Conditions

• Acute and Chronic Inflammation
  • Ferritin acts as an acute phase reactant that increases during inflammation 3
  • Common inflammatory conditions include:
    • Rheumatologic disorders (adult-onset Still's disease, systemic juvenile idiopathic arthritis) 2
    • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2
    • Catastrophic antiphospholipid syndrome 4
    • Septic shock 4

2. Malignancies

• Most frequent cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 2
• Particularly common in:
  • Acute leukemia
  • Malignant lymphoma
  • Hepatocellular carcinoma
  • Pancreatic cancer 5
• Malignancies typically show a higher serum ferritin-to-iron ratio than normal subjects 5

3. Liver Disease

• Necroinflammatory Liver Conditions
  • Alcoholic liver disease
  • Chronic viral hepatitis (B and C)
  • Nonalcoholic fatty liver disease (NAFLD) 1
  • Acute hepatitis 5
• Liver damage causes release of stored ferritin into circulation

4. Other Important Causes

• Chronic Kidney Disease

  • Dialysis patients often have elevated ferritin due to inflammation rather than iron overload 6
  • Malnutrition-inflammation complex syndrome in hemodialysis patients 6

• Infections

  • Bacterial and viral infections can cause hyperferritinemia 4
  • Tuberculosis may have elevated ferritin despite iron deficiency 7
  • COVID-19 (severe cases show markedly elevated ferritin) 4

• Rare Genetic Disorders

  • Hereditary hemochromatosis variants (non-HFE related) 1
  • Aceruloplasminemia
  • Ferroportin disease

Diagnostic Approach

When encountering elevated ferritin with normal iron studies:

1. Assess for inflammation

   • Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
   • Elevated inflammatory markers suggest ferritin elevation due to inflammation 7, 6

2. Evaluate liver function

   • Check liver enzymes (ALT, AST)
   • Elevated liver enzymes with ferritin >1000 μg/L increases risk of cirrhosis in hemochromatosis 1

3. Screen for malignancy

   • Consider age-appropriate cancer screening
   • Evaluate for lymphadenopathy, organomegaly, or other signs of malignancy
   • Extremely high ferritin levels (>10,000 μg/L) are often seen in malignancy 2

4. Consider specialized testing

   • HFE gene testing if hereditary hemochromatosis is suspected
   • MRI for hepatic iron concentration if non-HFE iron overload is suspected

Clinical Pearls and Pitfalls

• Pearl: Ferritin levels in the thousands with normal transferrin saturation strongly suggest a non-iron-overload cause 1
• Pitfall: Assuming elevated ferritin always indicates iron overload can lead to inappropriate iron restriction
• Pearl: In inflammatory states, ferritin up to 100 μg/L may still be consistent with iron deficiency 3
• Pitfall: Failing to recognize that extremely high ferritin can occur in seemingly indolent conditions 2
• Pearl: A ferritin-to-iron ratio is more useful than absolute ferritin levels in distinguishing malignant from non-malignant causes 5

Remember that while iron overload conditions like hemochromatosis typically present with both elevated ferritin and elevated transferrin saturation, the combination of very high ferritin with normal iron studies should prompt investigation for inflammatory, malignant, and hepatic causes.