What is the management approach for elevated ferritin levels?

Management of Elevated Ferritin Levels

The management approach for elevated ferritin should begin with determining the underlying cause, as 90% of cases are due to non-iron overload conditions where phlebotomy is not the treatment of choice. 1

Initial Diagnostic Workup

• Measure transferrin saturation (TS) alongside ferritin to better assess iron status - this is crucial for distinguishing between true iron overload, anemia of chronic disease, and inflammatory conditions 2
• Consider common causes of elevated ferritin:
  • Inflammatory conditions (acute phase response)
  • Liver disease (alcoholic, viral hepatitis, NAFLD)
  • Malignancy
  • Metabolic syndrome and obesity
  • Hereditary hemochromatosis (HFE-related)
  • Other iron overload syndromes 3, 4

Diagnostic Algorithm

Step 1: Evaluate Iron Status

• If TS ≥ 45% with elevated ferritin: Consider iron overload disorders 3
• If TS < 45% with elevated ferritin: Consider inflammatory conditions, anemia of chronic disease, or liver disease 3, 2

Step 2: Risk Stratification Based on Ferritin Level

• Ferritin < 1000 μg/L: Lower risk of organ damage 3, 1
• Ferritin > 1000 μg/L: Higher risk of advanced fibrosis/cirrhosis in iron overload conditions 3

Step 3: HFE Genetic Testing

• For patients with elevated TS (≥45%) and ferritin, perform HFE mutation analysis to identify C282Y homozygotes or other genetic variants 3

Management Based on Diagnosis

For Confirmed Hemochromatosis (C282Y Homozygotes with Iron Overload)

• Therapeutic phlebotomy is the cornerstone of treatment 3
• Weekly phlebotomy (removal of 500 mL blood) until ferritin reaches 50-100 μg/L 3
• Maintenance phlebotomy to keep ferritin between 50-100 μg/L 3
• Consider liver biopsy if ferritin >1000 μg/L to assess for advanced fibrosis or cirrhosis 3

For Secondary Iron Overload

• Treat underlying cause when possible 3
• Consider iron chelation therapy with deferasirox for transfusional iron overload when:
  • Patient has received at least 100 mL/kg of packed red blood cells
  • Serum ferritin consistently >1000 μg/L 5
• Monitor for adverse effects of chelation therapy, including renal dysfunction, hepatotoxicity, and auditory/ocular abnormalities 5
• If ferritin falls below 500 μg/L during chelation therapy, interrupt treatment and monitor monthly 5

For Inflammatory/Non-Iron Overload Causes

• Focus on treating the underlying condition (infection, inflammation, liver disease) 2, 4
• Avoid unnecessary phlebotomy or chelation therapy 1
• Monitor ferritin levels to assess response to treatment of underlying condition 2

Special Considerations

• In patients with both iron overload and liver disease (e.g., hepatitis C, alcoholic liver disease, NAFLD), address both conditions 3
• For patients with ferritin >1000 μg/L without clear etiology, referral to a gastroenterologist, hematologist, or physician with expertise in iron disorders is recommended 1
• In patients undergoing hematopoietic stem cell transplantation, elevated ferritin (>1500 μg/L) is associated with increased mortality and may warrant consideration of pre-transplant iron reduction 6, 7

Monitoring

• For patients on phlebotomy: Check hemoglobin/hematocrit before each procedure and ferritin every 10-12 phlebotomies 3
• For patients on chelation: Monitor serum ferritin monthly, along with renal function, liver function, and auditory/ophthalmologic assessments 5
• For all patients: Avoid vitamin C supplements and iron supplements in those with confirmed iron overload 3

Common Pitfalls

• Assuming all elevated ferritin represents iron overload - remember that ferritin is an acute phase reactant 3, 4
• Initiating phlebotomy without confirming the diagnosis of hemochromatosis 1
• Overlooking the significance of ferritin >1000 μg/L, which warrants more thorough evaluation for organ damage 3
• Failing to screen first-degree relatives of patients with HFE-related hemochromatosis 3