What is the appropriate work-up and management for a patient with elevated ferritin (iron storage protein) levels?

Evaluation and Management of Elevated Ferritin

The appropriate work-up for elevated ferritin should begin with complete iron studies including serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin to determine the underlying cause, followed by targeted treatment based on whether true iron overload exists or if hyperferritinemia is due to inflammation. 1

Initial Diagnostic Approach

1. Complete Iron Studies:

   • Serum ferritin
   • Serum iron
   • Total iron binding capacity (TIBC)
   • Transferrin saturation (TSAT)
   • Consider specialized testing: reticulocyte hemoglobin content (CHr) and soluble transferrin receptor (sTfR) to differentiate true iron deficiency from functional iron deficiency 1

2. Additional Laboratory Testing:

   • Liver function tests (ALT, AST, bilirubin)
   • Complete blood count with platelets
   • Blood glucose/HbA1c
   • Inflammatory markers (C-reactive protein)
   • Vitamin D levels 1

3. Interpretation of Ferritin Levels:

   • <30 μg/L: Iron deficiency without inflammation
   • 30-100 μg/L: Possible iron deficiency or anemia of chronic disease

   • 100 μg/L: Possible anemia of chronic disease or iron overload

   • 1000 μg/L: High risk of cirrhosis (20-45%) 1

Diagnostic Algorithm

Step 1: Determine if True Iron Overload Exists

• Iron overload likely if:

  • Elevated ferritin AND elevated transferrin saturation (>45% in women, >50% in men)
  • Even upper reference interval TSAT (30-45% women, 35-50% men) with elevated ferritin can indicate iron overload 2

• Iron overload unlikely if:

  • Normal transferrin saturation with elevated ferritin
  • Evidence of inflammatory condition, liver disease, or malignancy 3, 4

Step 2: Rule Out Common Causes of Hyperferritinemia

• Inflammatory conditions: Infections, autoimmune disorders, malignancies
• Liver disease: Alcoholic liver disease, NAFLD, viral hepatitis
• Metabolic disorders: Diabetes, metabolic syndrome
• Malignancies: Particularly hematologic malignancies
• Blood transfusions: Especially in patients with sickle cell disease 3, 2
• Hereditary conditions: Hemochromatosis, hereditary hyperferritinemia 5

Management Based on Etiology

1. For Confirmed Iron Overload:

• Therapeutic phlebotomy:

  • Primary treatment for iron overload
  • Remove 400-500 mL blood (200-250 mg iron) weekly or biweekly
  • Target ferritin level: 50-100 μg/L
  • Can be performed even in patients with advanced fibrosis or cirrhosis 1

• Chelation therapy (if phlebotomy contraindicated):

  • Indicated for ferritin levels >1,000 ng/mL, transfusion-dependent patients
  • Options include deferasirox, deferoxamine, deferiprone
  • Deferasirox dosing:
    • Initial dose: 14 mg/kg/day for patients with eGFR >60 ml/min/1.73m²
    • Adjust dose every 3-6 months based on serum ferritin trends
    • Maximum dose: 28 mg/kg/day 1, 6
  • Monitor:
    • Monthly serum ferritin, liver function, renal function
    • Baseline and regular auditory and ophthalmic examinations 6

2. For Hyperferritinemia Without Iron Overload:

• Focus on treating the underlying condition:

  • Manage inflammatory disorders
  • Address liver disease
  • Treat malignancy if present 1

• Lifestyle modifications:

  • Weight loss
  • Regular physical activity
  • Dietary modifications (reduce red meat)
  • Limit alcohol intake
  • Avoid iron supplements and iron-fortified foods 1

• Consider vitamin D supplementation:

  • Cholecalciferol 50,000 IU weekly for 8-12 weeks
  • Maintenance dose: 1,000-2,000 IU daily 1

Monitoring and Follow-up

• For patients with iron overload:

  • Monitor every 3 months during initial treatment
  • Annual follow-up after stabilization
  • Regular assessment of ferritin and transferrin saturation levels 1

• For patients without iron overload:

  • Regular monitoring of iron studies
  • Annual follow-up if parameters remain stable 1

Indications for Specialist Referral

• Ferritin levels >1000 μg/L
• Unclear cause of elevated ferritin after initial evaluation
• Suspicion of hereditary hemochromatosis
• Evidence of organ damage 1

Important Considerations and Pitfalls

• Avoid overchelation: Monitor serum ferritin monthly to prevent excessive iron removal, especially in patients with ferritin <1000 μg/L 6
• Be aware of medication side effects: Chelation therapy can cause serious adverse effects including renal impairment, hepatotoxicity, and bone marrow suppression 6
• Consider age-related risks: Elderly and pediatric patients may be more susceptible to toxicity from chelation therapy 6
• Remember non-iron overload causes: Malignancy is the most common cause of markedly elevated ferritin (>1000 μg/L), followed by iron-overload syndromes 3
• Interpret in clinical context: Extremely high ferritin levels can occur in seemingly indolent diseases or chronic inflammation 3