What is the management of hyperferritinemia?

Management of Hyperferritinemia

The management of hyperferritinemia requires first identifying the underlying cause through systematic evaluation of serum ferritin and transferrin saturation, followed by appropriate treatment based on etiology. 1, 2

Diagnostic Approach

Initial Evaluation

• Measure both serum ferritin and transferrin saturation (TS) together to properly evaluate iron status 1, 2
• Assess for common causes of hyperferritinemia when ferritin is elevated 1:
  • Chronic alcohol consumption 1
  • Inflammation (check CRP, ESR) 1, 2
  • Cell necrosis (check AST, ALT, CK) 1
  • Malignancy (check ESR, consider imaging) 1, 2
  • Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome 1

Diagnostic Algorithm Based on Transferrin Saturation

• If TS ≥ 45% and elevated ferritin: Proceed to HFE genetic testing 1, 2
• If TS < 45% and normal ferritin: No further evaluation needed 1, 2
• If TS < 45% with elevated ferritin: Evaluate for non-iron overload causes 1, 2

Specific Testing

• HFE genetic testing for C282Y and H63D mutations when transferrin saturation is increased 1
• Liver biopsy consideration for C282Y homozygotes with:
  • Serum ferritin > 1000 μg/L 1
  • Elevated liver enzymes 1
  • Hepatomegaly 1
  • Age > 40 years 1

Management Based on Etiology

Hereditary Hemochromatosis

• For confirmed HFE-related hemochromatosis with elevated iron stores: Therapeutic phlebotomy 1, 2
  • Target ferritin < 50 μg/L 2
  • Each liter of blood removed contains approximately 0.5g of iron 1
  • Monitor ferritin monthly during treatment 2

Secondary Iron Overload

• For transfusional iron overload: Consider iron chelation therapy with deferasirox 3
  • Monitor for adverse effects:
    • Renal toxicity (monitor eGFR) 3
    • Hepatic toxicity (monitor transaminases) 3
    • Gastrointestinal ulceration 3
    • Bone marrow suppression 3
  • Contraindicated in patients with eGFR < 40 mL/min/1.73m² 3
  • Reduce dose if serum ferritin falls below 1000 μg/L at two consecutive visits 3
  • Interrupt therapy if serum ferritin falls below 500 μg/L 3

Inflammatory Conditions

• For hyperferritinemia due to inflammatory conditions: Treat the underlying condition 2
• Consider Adult-onset Still's disease when ferritin levels are extremely high (>10,000 ng/mL) 1, 2
  • Very high ferritin levels (4,000-30,000 ng/mL) are common in Still's disease 1
  • Glycosylated ferritin fraction is often less than 20% in Still's disease 1

Extreme Hyperferritinemia (>6,000 μg/L)

• Consider hemophagocytic lymphohistiocytosis (HLH) 2, 4
• Evaluate for:
  • Fever 4
  • Cytopenia 4
  • Major liver disturbances 4
  • Hemophagocytosis on bone marrow examination 4

Special Considerations

• Family screening is mandatory for siblings of patients with HFE-related hemochromatosis 1
• Avoid iron supplementation in patients with elevated ferritin 2
• Monitor liver and renal function more frequently in patients receiving iron chelation therapy 3
• Consider specialist referral for patients with evidence of organ damage 2

Common Pitfalls to Avoid

• Relying on ferritin alone without transferrin saturation to diagnose iron overload 2
• Overlooking the need for liver biopsy in patients with ferritin > 1000 μg/L and abnormal liver tests 1, 2
• Assuming all hyperferritinemia is due to iron overload (only ~10% of cases in routine practice) 5
• Continuing iron chelation therapy when ferritin levels fall below target range, which can lead to overchelation 3
• Failing to consider rare but serious conditions like HLH in patients with extreme hyperferritinemia 4