What are the next steps for a patient with hyperferritinemia and elevated iron levels without a known cause?

Management of Elevated Iron and Ferritin in a 40-Year-Old Female with Negative Hemochromatosis Gene

The next step for this 40-year-old female with elevated iron (173) and ferritin (255) but negative hemochromatosis gene testing should be a comprehensive evaluation for non-hereditary causes of hyperferritinemia, including metabolic syndrome, inflammation, liver disease, and other secondary causes of iron dysregulation. 1

Initial Assessment

Evaluate for Common Non-Iron Overload Causes of Hyperferritinemia:

• Metabolic syndrome components (check BMI, blood pressure, lipid panel, fasting glucose)
• Non-alcoholic fatty liver disease (NAFLD)
• Inflammatory conditions (check CRP, ESR)
• Alcohol consumption history
• Liver disease (check liver enzymes ALT, AST)
• Malignancy (consider age-appropriate cancer screening)
• Infections (acute or chronic)

Additional Laboratory Testing:

• Complete liver function tests
• Transferrin saturation calculation (crucial for distinguishing true iron overload from other causes)
• Complete blood count
• Fasting insulin and C-peptide levels (hyperferritinemia is significantly associated with insulin resistance) 2

Diagnostic Algorithm

1. Calculate transferrin saturation (TSAT):

   • If TSAT >45%: Suggests true iron overload despite negative HFE gene testing
   • If TSAT <45%: Suggests non-iron overload causes of hyperferritinemia 1

2. Based on TSAT results:

   • If TSAT >45%:

     • Consider rare non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) 3
     • Consider MRI for liver iron concentration assessment 3
     • Hepatology referral is appropriate

   • If TSAT <45%:

     • Focus on metabolic causes (most likely scenario)
     • Evaluate for NAFLD with ultrasound
     • Assess insulin resistance 2

Clinical Pearls and Pitfalls

• Key insight: 90% of elevated ferritin cases are due to non-iron overload conditions 4, with malignancy and inflammatory conditions being common causes 5

• Common pitfall: Assuming hyperferritinemia always indicates iron overload. In this patient with negative hemochromatosis gene testing, metabolic syndrome and NAFLD are more likely causes than rare forms of hemochromatosis 6

• Important consideration: Ferritin is an acute phase reactant and may be elevated in inflammatory conditions even when iron stores are normal or low 3

• Warning sign: If ferritin exceeds 1000 μg/L, this significantly increases risk of hepatic fibrosis and warrants prompt specialist referral regardless of cause 1

When to Refer

• Referral to a gastroenterologist or hematologist is appropriate if:
  • Ferritin continues to rise despite addressing metabolic factors
  • Ferritin exceeds 1000 μg/L
  • Liver enzymes are elevated
  • Transferrin saturation is >45% with negative HFE gene testing (suggesting rare hemochromatosis) 1, 4

Treatment Considerations

• If metabolic syndrome/NAFLD is identified as the cause:

  • Lifestyle modifications (weight loss, exercise, dietary changes)
  • Management of individual metabolic syndrome components
  • Avoid iron supplements and limit alcohol 1

• If true iron overload is confirmed despite negative HFE gene:

  • Consider therapeutic phlebotomy if iron overload is documented by MRI or liver biopsy 3
  • Monitor ferritin and hemoglobin during treatment

This patient's presentation with modestly elevated ferritin (255) and iron (173) but negative hemochromatosis gene is most consistent with dysmetabolic hyperferritinemia rather than a primary iron overload disorder, but a systematic evaluation is needed to confirm this and guide appropriate management.