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

Diagnostic Approach to Elevated Ferritin

The initial workup for hyperferritinemia should include complete iron studies (serum ferritin, transferrin saturation, serum iron, and total iron binding capacity), liver function tests, and evaluation for common causes including inflammation, infection, liver disease, and hereditary hemochromatosis. 1

Initial Evaluation

Step 1: Complete Iron Studies

• Measure serum ferritin
• Measure transferrin saturation (TSAT)
• Measure serum iron
• Measure total iron binding capacity (TIBC)

Step 2: Categorize Based on Transferrin Saturation

• TSAT < 45%: Suggests non-iron overload causes
• TSAT > 45%: Suggests potential iron overload

Diagnostic Algorithm

For TSAT < 45% (Normal Transferrin Saturation)

1. Rule out inflammatory conditions:

   • Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
   • Evaluate for chronic infections

2. Assess liver function:

   • Check liver enzymes (ALT, AST)
   • Screen for hepatitis B and C
   • Consider ultrasound for fatty liver disease

3. Consider other causes:

   • Alcohol use assessment
   • Hemolytic anemia workup (if indicated)
   • Assess for metabolic syndrome
   • Evaluate renal function in dialysis patients

For TSAT > 45% (Elevated Transferrin Saturation)

1. Genetic testing for hereditary hemochromatosis:

   • HFE gene mutations (C282Y and H63D) 1

2. If HFE testing negative but iron overload suspected:

   • Consider non-HFE hemochromatosis genetic testing
   • Consider liver biopsy with quantitative iron measurement

For Extremely Elevated Ferritin (>1000 μg/L)

1. Evaluate for organ damage:

   • Liver function tests
   • Consider liver biopsy (20-45% risk of cirrhosis) 1
   • Cardiac evaluation (ECG, echocardiography)
   • Consider cardiac MRI for iron quantification in severe cases

2. Consider rare causes:

   • Hemophagocytic lymphohistiocytosis (HLH)
   • Macrophage activation syndrome
   • Gaucher disease
   • Transfusion-dependent anemias

Interpretation of Ferritin Levels

Ferritin Level	Interpretation
<10 μg/L	Severe iron deficiency
<30 μg/L	Iron deficiency without inflammation
30-100 μg/L	Possible iron deficiency or anemia of chronic disease
50-100 μg/L	Target maintenance range for most patients
>100 μg/L	Possible anemia of chronic disease or iron overload
>1000 μg/L	High risk of cirrhosis if true iron overload exists [1]

Monitoring and Follow-up

• Repeat iron studies in 3 months to assess trends 1
• Annual monitoring if no iron overload detected
• More frequent monitoring (every 3 months) during treatment for confirmed iron overload

Special Considerations

• In ESRD patients: Monitor ferritin and TSAT every 1-3 months; hold IV iron if ferritin >800 ng/mL 1
• For confirmed iron overload: Consider therapeutic phlebotomy to reduce ferritin to 50-100 μg/L 1
• For transfusion-dependent patients: Consider chelation therapy when ferritin >1000 ng/mL 1

Common Pitfalls to Avoid

1. Misinterpreting isolated hyperferritinemia: Ferritin is an acute phase reactant; elevated levels don't always indicate iron overload

2. Overlooking non-HFE hemochromatosis: Genetic testing should extend beyond common HFE mutations when clinical suspicion is high

3. Neglecting liver assessment: Liver disease is a common cause of hyperferritinemia, especially with normal TSAT

4. Assuming HLH with extreme hyperferritinemia: While associated with HLH, extreme hyperferritinemia (>10,000 ng/mL) is more commonly due to chronic transfusion, liver disease, or hematologic malignancy 2

5. Missing metabolic causes: Non-alcoholic fatty liver disease is an increasingly common cause of hyperferritinemia