What is the significance and management of elevated ferritin levels?

Management of Elevated Ferritin Levels: Significance and Approach

Elevated ferritin levels require a systematic diagnostic approach to determine the underlying cause, with management strategies tailored to the specific etiology and risk of organ damage. 1

Diagnostic Approach

• Measure transferrin saturation (TS) alongside ferritin to distinguish between true iron overload and inflammatory conditions 1, 2
• If TS ≥45% with elevated ferritin, consider iron overload disorders such as hereditary hemochromatosis 2, 1
• If TS <45% with elevated ferritin, consider inflammatory conditions, anemia of chronic disease, or liver disease 1, 2
• 90% of elevated serum ferritin cases are due to non-iron overload conditions where venesection therapy is not the treatment of choice 3

Common Causes of Elevated Ferritin

• Inflammatory conditions (acute phase reactant) 4, 1
• Liver disease (alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease) 2, 5
• Malignancy (most common cause of markedly elevated ferritin in one study) 4
• Iron overload syndromes (hereditary hemochromatosis) 2, 1
• Metabolic syndrome and obesity 3, 5
• Chronic kidney disease 2

Risk Stratification Based on Ferritin Levels

• Ferritin <1000 μg/L: Lower risk of organ damage in iron overload conditions 2, 1
• Ferritin >1000 μg/L: Higher risk of advanced fibrosis/cirrhosis in iron overload conditions 2
• Ferritin >1000 μg/L in NAFLD: Independent predictor of advanced hepatic fibrosis 5
• Ferritin >1500 μg/L before stem cell transplantation: Associated with increased mortality 6

Management Based on Etiology

For Confirmed Hemochromatosis (C282Y homozygotes with iron overload):

• Therapeutic phlebotomy is the cornerstone of treatment 1, 2
• Weekly phlebotomy (removal of 500 mL blood) until ferritin reaches 50-100 μg/L 1
• Maintenance phlebotomy to keep ferritin between 50-100 μg/L 1
• Liver biopsy should be considered if ferritin >1000 μg/L with elevated liver enzymes to assess for cirrhosis 2

For Transfusional Iron Overload:

• Consider iron chelation therapy when serum ferritin consistently exceeds 1000 μg/L and patient has received significant transfusions (≥100 mL/kg of packed RBCs) 7, 2
• Deferasirox starting dose: 14 mg/kg/day orally for patients with eGFR >60 mL/min/1.73m² 7
• Monitor serum ferritin monthly and adjust dose every 3-6 months 7
• If ferritin falls below 500 μg/L, interrupt chelation therapy 7

For Non-Iron Overload Causes:

• Treat the underlying condition (inflammation, infection, malignancy) 1, 3
• For NAFLD with elevated ferritin: Focus on metabolic risk factors, weight loss, and management of diabetes 5, 8
• For anemia of chronic disease: Address the underlying inflammatory condition 2

Monitoring

• For patients on phlebotomy: Check hemoglobin/hematocrit before each procedure and ferritin every 10-12 phlebotomies 1
• For patients on chelation therapy: Monitor blood counts, liver function, renal function, and ferritin monthly 7
• For patients with NAFLD and elevated ferritin: Monitor for progression of liver disease 5, 8

When to Refer

• Ferritin >1000 μg/L when cause remains unclear 3
• Patients with suspected hemochromatosis for genetic testing and management 2, 1
• Patients with transfusion-dependent anemias for chelation therapy evaluation 2, 7
• Patients with liver disease and elevated ferritin for hepatology assessment 2, 5

Common Pitfalls to Avoid

• Failing to measure transferrin saturation alongside ferritin 1, 2
• Initiating phlebotomy based solely on elevated ferritin without confirming iron overload 3
• Overlooking non-iron overload causes of hyperferritinemia 4, 3
• Administering iron supplements to patients with confirmed iron overload 1
• Failing to screen first-degree relatives of patients with HFE-related hemochromatosis 1