What is the management approach for elevated ferritin levels?

Management of Elevated Ferritin Levels

The first step in managing elevated ferritin is to measure transferrin saturation (TS) alongside ferritin to distinguish true iron overload (TS ≥45%) from secondary causes, then proceed with HFE genotype testing if iron overload is suspected, while ferritin >1000 μg/L warrants specialist referral regardless of cause. 1, 2

Initial Diagnostic Workup

Always measure both ferritin and transferrin saturation together - using ferritin alone is a critical pitfall that leads to misdiagnosis. 1

Interpret the combination:

• If TS ≥45% with elevated ferritin: Suspect hereditary hemochromatosis and proceed to HFE genotype testing for C282Y and H63D mutations 1, 2

• If TS <45% with elevated ferritin: Evaluate for secondary causes by checking:

  • Inflammatory markers (CRP, ESR) 1
  • Liver enzymes (ALT, AST) 1
  • Consider malignancy, infection, liver disease, metabolic syndrome, or chronic inflammatory conditions 1, 3, 4

• If TS <45% and normal ferritin: No further evaluation needed 1

Critical Ferritin Thresholds

Ferritin >1000 μg/L:

• Refer to gastroenterologist, hematologist, or iron overload specialist 1, 5
• Indicates 20-45% prevalence of cirrhosis in C282Y homozygotes 1
• Consider liver biopsy if accompanied by:
  • Elevated liver enzymes, OR
  • Platelet count <200,000/μL 1
• Below this threshold with normal transaminases and no hepatomegaly, risk of advanced liver fibrosis is very low (94% negative predictive value) 1

Ferritin >10,000 μg/L:

• Suggests life-threatening conditions requiring urgent specialist referral: adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 3
• Average ferritin in these syndromes is 14,242 μg/L 3

Management Based on Underlying Cause

Hereditary Hemochromatosis (Confirmed by HFE Testing):

Therapeutic phlebotomy is the cornerstone of treatment 2

• Initial regimen: Weekly removal of one unit of blood (450-500 mL, containing 200-250 mg iron) 2
• Target ferritin: 50-100 μg/L 1, 2
• Maintenance: 3-4 phlebotomies per year once target reached 2
• For ferritin <1000 μg/L: C282Y homozygotes with normal transaminases and age <40 can proceed with phlebotomy without liver biopsy 1
• For ferritin >1000 μg/L: Evaluate for liver disease and strongly consider liver biopsy if elevated enzymes or low platelets present 1

Secondary Causes (Inflammation, Liver Disease, Malignancy):

Treat the underlying condition, not the elevated ferritin 1

• Most common causes in hospitalized patients: malignancy (24%), infection (15%), hepatocellular injury (38%) 3, 4
• Do not perform phlebotomy - 90% of elevated ferritin is due to non-iron overload conditions 5
• Monitor ferritin based on the underlying disease activity 1

Chronic Kidney Disease with Anemia:

Intravenous iron may be beneficial despite ferritin 500-1200 μg/L if TS <25%, especially with erythropoietin therapy (functional iron deficiency) 1, 2

• Withhold iron therapy when:
  • Ferritin exceeds 1000 μg/L, OR
  • TS exceeds 50% 1, 2

Transfusion-Dependent Iron Overload:

Consider iron chelation therapy (deferasirox) when:

• Serum ferritin ≥1000 μg/L consistently, AND

• Transfusion of ≥100 mL/kg packed RBCs (≥20 units for 40 kg person) 2, 6

• Starting dose: 14 mg/kg/day orally once daily 6

• Monitor monthly: Ferritin, renal function, liver function, blood counts 6

• Adjust dose every 3-6 months in 3.5-7 mg/kg increments based on ferritin trends 6

• Maximum dose: 28 mg/kg/day 6

Monitoring Strategy

• During phlebotomy: Monitor ferritin monthly and adjust frequency every 3-6 months 1, 6
• If ferritin falls below 1000 μg/L: Consider dose reduction if on chelation >17.5 mg/kg/day 1
• If ferritin falls below 500 μg/L: Interrupt therapy and continue monthly monitoring 1

Family Screening for Hemochromatosis

Screen first-degree relatives with:

• Serum ferritin
• Transferrin saturation
• HFE genetic testing 2

Siblings have 25% chance of being affected if proband has hereditary hemochromatosis 2

Advanced Imaging When Indicated

MRI with T2/T2 relaxometry* is the standard non-invasive method to quantify hepatic iron concentration 1, 7

• Shows 84-91% sensitivity and 80-100% specificity 1
• Useful for monitoring chelation therapy effectiveness 1, 7
• Cardiac T2* mapping assesses cardiac iron loading 1

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 1
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1
• Do not delay treatment while awaiting cardiac MRI in severe hemochromatosis with heart disease signs 1
• Do not give iron supplementation to patients with elevated ferritin from secondary causes 1