What is the management approach for elevated ferritin (iron) levels?

Management of Elevated Ferritin Levels

The management of elevated ferritin levels requires a systematic diagnostic approach to identify the underlying cause, with therapeutic phlebotomy being the cornerstone treatment for confirmed iron overload disorders like hemochromatosis. 1

Diagnostic Approach

Initial Assessment

• Evaluate both ferritin and transferrin saturation together, as the combination of elevated ferritin (>1000 ng/mL) and high transferrin saturation (>45%) strongly suggests true iron overload, particularly hemochromatosis 1
• This pattern distinguishes true iron overload from other causes of isolated hyperferritinemia such as inflammation, malignancy, or liver disease 2
• When ferritin exceeds 1000 μg/L with elevated transferrin saturation, there is significant risk of organ damage, particularly liver fibrosis 3

Common Causes of Hyperferritinemia

• Primary iron overload disorders: Hereditary hemochromatosis (HFE gene mutations) 3
• Secondary iron overload: Transfusion-dependent anemias, ineffective erythropoiesis 3
• Non-iron overload causes: Inflammatory conditions, malignancy, liver disease, metabolic syndrome 4
• In a study of 627 patients with ferritin >1000 μg/L, malignancy was the most common cause (153/627), followed by iron-overload syndromes (136/627) 4

Diagnostic Testing

• HFE gene testing for C282Y and H63D mutations should be performed in patients with elevated ferritin and transferrin saturation 1
• If ferritin >1000 μg/L with elevated liver enzymes, liver biopsy should be considered to assess for fibrosis/cirrhosis 3
• MRI should be used to quantify hepatic iron concentrations in patients with unclear cause of hyperferritinemia, biochemical iron overload, or positive liver iron staining 3
• Cardiac MRI can be performed in patients with hemochromatosis and signs of heart disease 3

Treatment Approach

For Confirmed Hemochromatosis

• Therapeutic phlebotomy is the cornerstone of treatment for confirmed hemochromatosis 3
• Initial phlebotomy schedule: Weekly removal of one unit of blood (450-500 mL, containing approximately 200-250 mg iron) 3
• Target ferritin level: 50-100 μg/L 3
• Maintenance phlebotomy (typically 3-4 times per year) once target ferritin is reached 1
• Dietary adjustments are unnecessary, but vitamin C supplements and iron supplements should be avoided 3

For Secondary Iron Overload

• For transfusion-dependent anemias: Consider iron chelation therapy when serum ferritin levels reach 1,000 ng/mL or when transfusion need is ≥2 units/month for >1 year 3
• Iron chelation options:
  • Deferoxamine: 20-40 mg/kg/day for patients with secondary iron overload due to dyserythropoiesis 3
  • Deferasirox: Oral alternative for secondary iron overload 3
• Phlebotomy is NOT indicated for primary hemochromatosis, as stated in deferoxamine prescribing information 5

For Non-Iron Overload Hyperferritinemia

• Treat the underlying condition (inflammation, malignancy, liver disease) 2
• In patients with metabolic syndrome and hyperferritinemia, weight loss through dietary modification and increased physical activity is recommended 3

Special Considerations

Anemia and Heart Failure

• In patients with congestive heart failure and anemia with iron deficiency, intravenous iron may be beneficial 3
• Iron deficiency in heart failure is associated with increased mortality (RR 1.47), hospitalization (RR 1.28), and CHF hospitalization (RR 1.43) 3

Monitoring

• Regular monitoring of ferritin levels during treatment is essential 1
• Monitor for reaccumulation of iron and adjust maintenance phlebotomy schedule accordingly 3
• Ongoing surveillance for complications (diabetes, arthropathy, cardiac issues) is recommended 1

Family Screening

• First-degree relatives should be screened with serum ferritin, transferrin saturation, and HFE genetic testing if the patient is confirmed to have hemochromatosis 1
• Siblings have a 25% chance of being affected if the proband has hereditary hemochromatosis 1

Common Pitfalls

• Not distinguishing between true iron overload and other causes of hyperferritinemia 6
• Initiating treatment without confirming the diagnosis 3
• Overlooking secondary causes of iron overload when HFE genetic testing is negative 2
• Failing to consider non-iron overload causes of hyperferritinemia, which are actually more common than true iron overload 4