What is the initial workup for a patient with hyperferritinemia (elevated ferritin levels)?

Initial Workup for Hyperferritinemia

The initial workup for a patient with elevated ferritin levels must first rule out common causes of hyperferritinemia before considering genetic testing or more specialized investigations. 1

Step 1: Identify Common Causes of Hyperferritinemia

When encountering a patient with elevated ferritin, investigate these common causes first:

• Inflammatory conditions:

  • Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1
  • Assess for rheumatologic conditions, infections, or malignancies 2, 3

• Liver disease:

  • Check liver enzymes (AST, ALT) 1
  • Evaluate for alcoholic liver disease, viral hepatitis, and non-alcoholic fatty liver disease (NAFLD) 1

• Cell necrosis:

  • Check AST, ALT, and creatine kinase (CK) 1

• Metabolic syndrome:

  • Assess blood pressure, BMI, cholesterol, triglycerides, and serum glucose 1

• Malignancy:

  • Consider appropriate imaging based on clinical suspicion 1
  • Note that malignancy is the most frequent condition associated with markedly elevated ferritin (>1000 μg/L) 2

• Chronic alcohol consumption 1

Step 2: Complete Iron Studies

Order comprehensive iron studies:

• Serum iron
• Total iron binding capacity (TIBC)
• Transferrin saturation
• Ferritin 4

Step 3: Evaluate for Hereditary Hemochromatosis

If transferrin saturation is increased (>45% in females, >50% in males) and other causes have been ruled out:

• Perform genetic HFE testing for C282Y and H63D polymorphisms 1
• Note that diagnosis of HFE hemochromatosis requires both genetic confirmation and evidence of increased iron stores 1

Step 4: Consider Specialized Testing

For cases where the diagnosis remains unclear:

• Reticulocyte hemoglobin content (CHr) - values <30 pg suggest iron-restricted erythropoiesis 4
• Soluble transferrin receptor (sTfR) - high in iron deficiency, normal/low in anemia of chronic disease 4

Important Clinical Considerations

1. Degree of hyperferritinemia matters:

   • Extremely high ferritin levels (>10,000 μg/L) may suggest hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), though these are rare causes 3, 5
   • Most cases of markedly elevated ferritin are due to malignancy, iron overload syndromes, or infection 2, 6

2. Multiple etiologies are common:

   • 41% of patients with hyperferritinemia have multiple causes 6
   • Higher ferritin levels correlate with multiple underlying causes 6

3. Liver biopsy considerations:

   • For C282Y homozygous patients, liver biopsy should be considered if:
     • Serum ferritin above 1000 μg/L
     • Elevated AST
     • Hepatomegaly
     • Age over 40 years 1

4. Family screening:

   • Siblings of patients with HFE-related hemochromatosis should undergo screening due to 25% chance of susceptibility 1

Interpretation of Ferritin Levels

Ferritin Level	Interpretation
<30 μg/L	Iron deficiency in the absence of inflammation
30-100 μg/L	Possible iron deficiency or anemia of chronic disease with inflammation
>100 μg/L	Anemia of chronic disease or iron overload
>1000 μg/L	Consider malignancy, iron overload, severe inflammation, or infection
>10,000 μg/L	Consider HLH/MAS, though other causes remain more common [5]

By following this algorithmic approach to hyperferritinemia, clinicians can efficiently identify the underlying cause and determine appropriate management strategies while avoiding unnecessary testing.