What are the causes and follow-up tests for hyperferritinemia (elevated iron levels)?

Causes and Follow-up Tests for Hyperferritinemia (Elevated Iron Levels)

Hyperferritinemia requires a systematic diagnostic approach to identify the underlying cause, with follow-up testing determined by initial findings of transferrin saturation and inflammatory markers.

Initial Diagnostic Approach

First-line Testing

• Measure fasting transferrin saturation (TS) and serum ferritin simultaneously 1
• Check inflammatory markers (C-reactive protein, ESR) 2
• Complete blood count to assess for anemia 2
• Liver function tests (AST, ALT) 1

Interpretation of Initial Results

• High TS (>45% in women, >50% in men) + High Ferritin = Suspect iron overload disorders 1
• Normal/Low TS + High Ferritin = Suspect non-iron overload causes 2

Common Causes of Hyperferritinemia

Iron Overload Disorders

1. Hereditary Hemochromatosis (HFE-HC)

   • C282Y homozygosity is the most common genetic cause 1
   • Compound heterozygosity (C282Y/H63D) less commonly causes significant iron overload 1

2. Secondary Iron Overload

   • Chronic transfusions 3
   • Ineffective erythropoiesis (thalassemia, sideroblastic anemia) 4
   • Parenteral iron administration 1

Non-Iron Overload Causes

1. Inflammatory Conditions

   • Chronic inflammation (elevated CRP) 2
   • Rheumatic conditions (adult-onset Still's disease) 4
   • Hemophagocytic lymphohistiocytosis (HLH) 3

2. Liver Disease

   • Alcoholic liver disease 1
   • Non-alcoholic fatty liver disease (NAFLD) 5
   • Viral hepatitis 5

3. Other Common Causes

   • Malignancy (solid tumors and hematologic) 3
   • Metabolic syndrome 1
   • Renal failure 2
   • Acute or chronic infections 2

Follow-up Testing Algorithm

For Suspected Iron Overload (High TS + High Ferritin)

1. HFE Genetic Testing

   • Test for C282Y and H63D mutations 1
   • If C282Y homozygous: Confirms hereditary hemochromatosis 1
   • If other genotypes: Consider secondary causes or rare non-HFE hemochromatosis 1

2. Liver Assessment

   • Liver biopsy indicated if:
     • Serum ferritin >1000 μg/L
     • Elevated liver enzymes
     • Age >40 years
     • Hepatomegaly 1
   • MRI for hepatic iron quantification as non-invasive alternative 4

For Non-Iron Overload Causes (Normal/Low TS + High Ferritin)

1. Evaluate for Liver Disease

   • Complete liver panel
   • Ultrasound for steatosis 5
   • Viral hepatitis serologies 1

2. Evaluate for Inflammatory Conditions

   • Comprehensive inflammatory markers (CRP, ESR)
   • Consider specialized testing for specific inflammatory conditions if clinically indicated 2

3. Evaluate for Malignancy

   • Age-appropriate cancer screening
   • Consider hematology consultation for suspected hematologic malignancy 3

4. Metabolic Evaluation

   • Fasting glucose, lipid panel
   • Assessment for metabolic syndrome 1, 5

Management Based on Diagnosis

For Confirmed Iron Overload

• Therapeutic phlebotomy:

  • Induction phase: Weekly phlebotomy (400-500 mL) until ferritin reaches 50-100 μg/L
  • Maintenance phase: Individualized frequency based on reaccumulation rate 2

• Iron chelation therapy (if phlebotomy contraindicated):

  • Starting dose of deferasirox: 14 mg/kg/day (adjust for renal function)
  • Monitor ferritin monthly, adjust dose every 3-6 months 2

For Non-Iron Overload Causes

• Treat the underlying condition (inflammation, liver disease, etc.)
• Monitor ferritin levels every 3 months during treatment 2

Important Clinical Considerations

• Ferritin interpretation depends on inflammatory status:

  • Without inflammation: <30 μg/L indicates iron deficiency
  • With inflammation: <100 μg/L may still indicate iron deficiency despite "normal" values 2

• Thresholds for suspecting iron overload:

  • Men: >300 μg/L
  • Women: >200 μg/L 2

• Extreme hyperferritinemia (>10,000 ng/mL) is most commonly due to chronic transfusion (35%), liver disease (27%), and hematologic malignancy (16%) 3

• In patients with chronic liver disease, hyperferritinemia is significantly associated with hepatic steatosis 5