What does high ferritin mean?

Understanding High Ferritin Levels

High ferritin levels are most commonly caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome, which account for over 90% of cases in outpatients, rather than true iron overload. 1

Common Causes of Hyperferritinemia

• Inflammatory conditions: Acute and chronic inflammation can significantly elevate ferritin as it acts as an acute phase reactant 1, 2
• Liver disorders: Alcoholic liver disease, viral hepatitis, NAFLD, and acute hepatitis can all cause elevated ferritin 1, 3
• Metabolic syndrome: One of the most common causes of hyperferritinemia in outpatients 1, 3
• Malignancies: Both solid tumors and lymphomas can cause elevated ferritin levels 1, 4
• Iron overload disorders: Hereditary hemochromatosis (HFE and non-HFE types) and secondary iron overload conditions 5, 1
• Extreme elevations: Very high ferritin levels (>10,000 μg/L) may suggest adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 2, 4

Diagnostic Approach to Elevated Ferritin

Initial Evaluation

• Always measure transferrin saturation (TS) alongside ferritin to properly evaluate iron status 2
• If TS ≥45% and ferritin is elevated: Consider iron overload disorders and proceed with HFE genotype testing 2
• If TS <45% and ferritin is elevated: More likely due to inflammatory conditions, liver disease, or other non-iron overload causes 2, 3

Further Evaluation Based on Transferrin Saturation

• High TS (≥45%) with elevated ferritin:

  • Perform HFE genetic testing for C282Y and H63D mutations 1
  • Consider liver biopsy or MRI for hepatic iron concentration if ferritin >1000 μg/L with abnormal liver tests 5, 2

• Normal/Low TS (<45%) with elevated ferritin:

  • Check inflammatory markers (CRP, ESR) 2
  • Assess liver enzymes (ALT, AST) 2
  • Evaluate for metabolic syndrome, alcohol consumption, and malignancy 1, 3

Important Clinical Considerations

• Serum ferritin has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions 1
• Iron overload is NOT the most common cause of elevated ferritin in the general population 6, 7
• Ferritin >1000 μg/L with elevated liver enzymes and platelets <200,000/μL may predict cirrhosis in C282Y homozygotes 1, 2
• Extremely high ferritin levels (>10,000 μg/L) should raise suspicion for adult-onset Still's disease or hemophagocytic syndromes 2, 4
• In chronic kidney disease, elevated ferritin (500-1200 μg/L) with low transferrin saturation (<25%) may still benefit from intravenous iron for anemia management 2

Common Pitfalls to Avoid

• Using ferritin alone without transferrin saturation to diagnose iron overload 2
• Assuming all elevated ferritin indicates hemochromatosis - 90% of cases are due to non-iron overload conditions 7
• Overlooking the need for liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 2
• Initiating phlebotomy without confirming true iron overload 2, 7
• Missing rare genetic causes of hyperferritinemia such as hereditary hyperferritinemia/cataract syndrome or ferroportin disease 8