What are the next steps in evaluating a patient with significantly elevated ferritin levels?

Evaluation of Elevated Ferritin (616 ng/mL)

For a patient with ferritin of 616 ng/mL, the next step should be complete iron studies including transferrin saturation (TSAT), serum iron, and total iron binding capacity (TIBC) to differentiate between true iron overload and non-iron-related causes of hyperferritinemia. 1

Initial Diagnostic Approach

1. Complete iron studies:

   • Transferrin saturation (TSAT)
   • Serum iron
   • Total iron binding capacity (TIBC)

2. Decision algorithm based on TSAT results:

   • TSAT >45%: Suggests true iron overload
     • Proceed with genetic testing for hemochromatosis
   • TSAT 20-45%: Intermediate range
     • Consider other causes of elevated ferritin
   • TSAT <20%: Suggests functional iron deficiency with inflammation
     • Evaluate for inflammatory conditions 1

3. Additional baseline testing:

   • Complete blood count
   • Liver function tests (ALT, AST, bilirubin)
   • Renal function tests (creatinine, eGFR)
   • Fasting glucose and HbA1c
   • Urinalysis 1

Common Causes of Elevated Ferritin to Evaluate

• Iron overload conditions:

  • Hereditary hemochromatosis
  • Transfusional iron overload
  • Ineffective erythropoiesis

• Non-iron overload conditions (90% of cases):

  • Alcohol consumption
  • Metabolic syndrome and obesity
  • Non-alcoholic fatty liver disease (NAFLD)
  • Inflammatory conditions
  • Malignancy
  • Infection
  • Liver disease 2

Follow-up Based on Initial Results

If TSAT >45% (Suggesting Iron Overload):

1. Perform genetic testing for HFE mutations (C282Y, H63D)
2. Consider liver function tests and imaging
3. Monitor ferritin levels monthly
4. Consider specialist referral if ferritin >1000 μg/L 1, 2

If TSAT <45% (Non-iron Overload Causes):

1. Evaluate for metabolic syndrome, alcohol use, liver disease
2. Check inflammatory markers (CRP, ESR)
3. Consider liver ultrasound if liver enzymes are elevated
4. Repeat iron studies in 3 months to assess trend 1

Special Considerations

• Ferritin >1000 μg/L:

  • Higher risk of cirrhosis (20-45%) if true iron overload exists
  • Specialist referral (gastroenterologist, hematologist) is recommended
  • Consider liver biopsy, especially if liver enzymes are elevated 1, 2

• Critically ill patients:

  • Very high ferritin (>9,000 μg/L) may suggest hemophagocytic lymphohistiocytosis
  • Evaluate for sepsis, which can also cause significant ferritin elevation 3

Management Based on Diagnosis

• If true iron overload is confirmed:

  • Consider therapeutic phlebotomy to reduce ferritin to 50-100 μg/L
  • Monitor ferritin, TSAT, CBC, and liver function monthly
  • Chelation therapy (deferasirox) may be considered if ferritin >1000 ng/mL and phlebotomy is contraindicated 1, 4

• If metabolic syndrome/NAFLD is the cause:

  • Lifestyle modifications (weight loss, regular physical activity)
  • Reduced red meat consumption
  • Limited alcohol intake
  • Avoidance of iron supplements 1

Monitoring and Follow-up

• Monitor ferritin levels and TSAT every 1-3 months during treatment
• For patients with true iron overload: monitor complete blood count, liver function, and renal function monthly
• For patients without iron overload: repeat iron studies in 3 months, then annually if stable 1

Important Cautions

• Tissue biopsy remains the gold standard for diagnosing iron overload but is not indicated for initial evaluation of mild hyperferritinemia
• Before starting chelation therapy with deferasirox (if needed), evaluate baseline renal function, liver function, and perform auditory and ophthalmic examinations 4
• Deferasirox is contraindicated in patients with eGFR <40 mL/min/1.73m² or severe hepatic impairment 4