How to manage a patient with hyperferritinemia and anemia?

Management of Hyperferritinemia with Anemia

This presentation of ferritin 500 ng/mL with hemoglobin 8.38 g/dL requires immediate investigation to differentiate between functional iron deficiency (where iron is present but unavailable for erythropoiesis) versus true iron overload with concurrent anemia from another cause—the critical next step is measuring transferrin saturation to guide management. 1

Immediate Diagnostic Workup

Essential Laboratory Tests

• Measure transferrin saturation (TSAT) immediately 1

  • If TSAT <25%: This indicates functional iron deficiency despite elevated ferritin, and iron supplementation may be beneficial 1
  • If TSAT >45-50%: This suggests true iron overload; investigate for hemochromatosis and other causes 1, 2

• Assess for inflammatory conditions 3, 4

  • Check C-reactive protein (CRP), liver enzymes (AST, ALT), and creatine kinase 1
  • Ferritin is an acute phase reactant and can be markedly elevated in malignancy, infection, and inflammatory diseases 3, 4

Critical Clinical Context

Rule out common causes of hyperferritinemia first 1:

• Chronic alcohol consumption
• Active inflammation or infection (check CRP)
• Cell necrosis (check AST, ALT, CK)
• Malignancy (most common cause of ferritin >1000 ng/mL) 3
• Non-alcoholic fatty liver disease/metabolic syndrome (check BMI, glucose, lipids, blood pressure) 1
• Chronic kidney disease 1

Management Based on Transferrin Saturation

If TSAT <25% (Functional Iron Deficiency)

Iron supplementation is indicated despite elevated ferritin 1:

• In dialysis patients or those with chronic kidney disease: Intravenous iron can increase hemoglobin even with ferritin 500-1200 ng/mL when TSAT is low 1

  • The DRIVE study demonstrated significant hemoglobin improvement (16±13 vs 11±14 g/L, P=0.028) with IV iron in patients with ferritin 500-1200 ng/mL and TSAT <25% 1
  • Monitor ferritin and hold iron when ferritin exceeds 1000 ng/mL or TSAT exceeds 50% 1

• In non-dialysis patients:

  • Trial oral iron (ferrous sulfate 200 mg three times daily) 1
  • If oral iron is not tolerated or ineffective, consider intravenous iron 1
  • Ascorbic acid 250-500 mg twice daily may enhance absorption 1

If TSAT >45-50% (True Iron Overload)

Do NOT give iron supplementation 1:

• Test for HFE gene mutations (C282Y and H63D) 1

• Investigate alternative causes of anemia:

  • Gastrointestinal blood loss (requires endoscopy) 1
  • Coeliac disease (check tissue transglutaminase antibodies) 1
  • Chronic disease/inflammation 3, 4
  • Hematologic disorders 1

• If hemochromatosis confirmed: Phlebotomy is contraindicated when hemoglobin <11 g/dL 1

  • Decrease phlebotomy frequency if hemoglobin <12 g/dL 1
  • Address the anemia cause first before resuming iron depletion therapy 1

Monitoring Strategy

Hemoglobin monitoring is mandatory 1:

• Check hemoglobin at each treatment session or monthly 1
• Target hemoglobin should guide iron therapy decisions alongside ferritin and TSAT 1

Ferritin targets depend on clinical context 1:

• In CKD patients receiving erythropoiesis-stimulating agents: Maintain ferritin 200-500 ng/mL to optimize response while avoiding toxicity 1
• In iron-refractory iron deficiency anemia (IRIDA): Do not exceed ferritin 500 ng/mL to avoid iron overload toxicity, especially in children 1

Critical Pitfalls to Avoid

• Never assume elevated ferritin always means iron overload—it is an acute phase reactant and rises with inflammation, infection, and malignancy 1, 3, 4
• Do not withhold iron based solely on ferritin level—transferrin saturation is essential to determine if iron is functionally available 1
• Avoid iron supplementation if TSAT >50% without investigating for hemochromatosis 1
• In patients with true iron overload, correct the anemia before attempting phlebotomy therapy 1
• Monitor for infection risk—while controversial, some evidence suggests neutrophil dysfunction with IV iron when TSAT <20% and ferritin >650 ng/mL 1