What is the management approach for a patient with hyperferritinemia (elevated iron) and low ferritin levels?

Management of High Iron with Low Ferritin Levels

The management of a patient with elevated iron levels and low ferritin requires investigation for underlying causes, particularly focusing on conditions that affect iron metabolism, with initial treatment focusing on addressing the primary disorder rather than iron supplementation.

Understanding the Clinical Paradox

High iron levels with low ferritin represents an unusual clinical scenario, as ferritin typically serves as the primary storage protein for iron. This paradoxical presentation requires careful evaluation:

Possible Underlying Conditions

1. Iron Metabolism Disorders:

   • Ferroportin disease with loss-of-function mutations 1
   • Early stages of aceruloplasminemia (ACP) 1
   • Iron-refractory iron deficiency anemia (IRIDA) 1

2. Inflammatory Conditions with Iron Sequestration:

   • Chronic inflammatory states where iron is poorly utilized despite adequate stores 2
   • Conditions with elevated hepcidin causing restricted iron availability 2

Diagnostic Approach

Initial Laboratory Evaluation

• Complete blood count with red cell indices
• Serum iron
• Total iron-binding capacity (TIBC)
• Transferrin saturation
• C-reactive protein (to assess inflammation) 3
• Liver function tests

Additional Testing Based on Initial Results

• Genetic testing for TMPRSS6 mutations (IRIDA) 1
• CP gene mutations (aceruloplasminemia) 1
• SLC40A1 mutations (ferroportin disease) 1
• Liver MRI to assess iron accumulation in suspected iron overload 1

Management Strategy

For Ferroportin Disease (LOF mutations)

• Phlebotomy with extended intervals if anemia develops 1
• Consider erythropoietin (EPO) supplementation in patients who develop anemia during phlebotomies 1
• Monitor ferritin levels to avoid excessive iron depletion 1

For Aceruloplasminemia

• Consider iron chelation therapy 1
• Mild anemia associated with ACP typically does not require specific treatment 1

For Iron-Refractory Iron Deficiency Anemia

• Intravenous iron supplementation may be required 1
• Monitor serum ferritin levels to avoid exceeding 500 μg/L, especially in children and adolescents 1

For Inflammatory Conditions

• Treat the underlying inflammatory condition 2
• Consider IV iron if transferrin saturation is <20% despite elevated serum ferritin (up to 1200 ng/ml) 1

Monitoring and Follow-up

• Regular monitoring of hemoglobin, serum iron, ferritin, and transferrin saturation
• For patients receiving iron therapy, check ferritin levels monthly during initial treatment and every 6 months during maintenance 3
• Family screening for genetic conditions:
  • For IRIDA: Screen siblings and spouse if consanguinity exists 1
  • For ferroportin disease: Screen first-degree relatives due to autosomal dominant inheritance 1
  • For ACP: Screen siblings due to autosomal recessive inheritance 1

Important Caveats

• Ferritin is an acute-phase reactant that increases with inflammation, potentially masking iron deficiency 2
• Standard thresholds for iron deficiency (<30 μg/L) may not apply in inflammatory conditions 2
• In inflammatory states, a serum ferritin threshold of <100 μg/L or TSAT <20% should be considered diagnostic for iron deficiency 2
• Long-term daily oral or IV iron supplementation with normal/high ferritin values is not recommended and potentially harmful 4
• The DRIVE study showed that IV iron can increase hemoglobin in patients with high ferritin (500-1200 ng/ml) but low transferrin saturation (<25%), though safety data is limited 1

Remember that this unusual presentation warrants specialist consultation, particularly with hematology, to ensure appropriate diagnosis and management of these rare conditions.