What is the management approach for elevated ferritin levels?

Management of Elevated Ferritin Levels

Measure both serum ferritin and transferrin saturation together, then proceed with HFE genotype testing if transferrin saturation ≥45%, as this combination indicates true iron overload requiring therapeutic phlebotomy, while isolated ferritin elevation without elevated transferrin saturation typically reflects inflammation or secondary causes that should be treated by addressing the underlying condition rather than iron removal. 1

Initial Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Alongside Ferritin

• Always obtain fasting transferrin saturation (TS) with ferritin to distinguish iron overload from secondary causes 1
• 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 inflammatory conditions, liver disease, malignancy, or infection rather than iron overload 1

Step 2: Risk Stratification by Ferritin Level

• Ferritin <1000 μg/L: Low risk of advanced fibrosis (94% negative predictive value with normal transaminases) 1
• Ferritin >1000 μg/L: Critical threshold indicating 20-45% prevalence of cirrhosis in C282Y homozygotes; strongly consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL 1, 2
• Ferritin >10,000 μg/L: Life-threatening conditions requiring urgent specialist referral—consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 3, 4

Common Causes of Elevated Ferritin

Secondary Causes (90% of cases, TS <45%) 5

• Inflammatory conditions: chronic liver disease (alcohol, viral hepatitis, NAFLD), rheumatologic diseases 1
• Malignancy: most frequent cause in hospitalized patients 3, 4
• Infection: second most common after malignancy in acute settings 4, 6
• Metabolic syndrome, obesity, diabetes 5
• Chronic kidney disease 1, 2

Primary Iron Overload (TS ≥45%)

• Hereditary hemochromatosis (HFE gene mutations) 1, 2
• Transfusion-dependent disorders 7

Management Based on Cause

For Hereditary Hemochromatosis (Confirmed by HFE Testing)

Therapeutic Phlebotomy Protocol 2

• Initial schedule: 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 phlebotomy: 3-4 times per year once target reached 2
• C282Y homozygotes with ferritin <1000 μg/L, normal transaminases, and age <40 years can proceed without liver biopsy 1

When to Consider Liver Biopsy

• Ferritin >1000 μg/L with elevated liver enzymes 1, 2
• Platelet count <200,000/μL 1
• These factors indicate significant risk of cirrhosis requiring histologic assessment 1

For Secondary Causes (TS <45%)

Treat the underlying condition, not the ferritin 1

• Inflammatory conditions: address the primary disease (liver disease, rheumatologic conditions) 1
• Malignancy or infection: treat the underlying disorder 3, 4, 6
• Metabolic syndrome: lifestyle modification and metabolic management 5

For Transfusion-Dependent Iron Overload

Iron Chelation Therapy 2, 7

• Consider when serum ferritin ≥1000 ng/mL or transfusion need ≥2 units/month for >1 year 2
• Deferasirox starting dose: 14 mg/kg/day for patients ≥2 years with eGFR >60 mL/min/1.73 m² 7
• Monitor ferritin monthly and adjust dose every 3-6 months 7
• Critical safety threshold: If ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if dose >17.5 mg/kg/day 7
• Stop chelation: If ferritin falls below 500 mcg/L to avoid overchelation toxicity 7

Special Population: Chronic Kidney Disease

Functional Iron Deficiency Despite Elevated Ferritin 1, 2

• For dialysis patients with ferritin 500-1200 ng/mL but TS <25%: intravenous iron may still be beneficial, especially if receiving erythropoietin therapy 1, 2
• This represents functional iron deficiency despite elevated ferritin 2
• Withhold iron therapy when ferritin exceeds 1000 ng/mL or TS exceeds 50% 1, 2

Monitoring and Follow-Up

During Active Treatment

• Monitor ferritin monthly 2, 7
• Monitor blood counts, liver function, and renal function monthly 7
• Adjust phlebotomy or chelation dose every 3-6 months based on ferritin trends 7

Family Screening for Hereditary Hemochromatosis

• Screen first-degree relatives with serum ferritin, transferrin saturation, and HFE genetic testing 2
• Siblings have 25% chance of being affected 2

Critical Pitfalls to Avoid

Do not use ferritin alone without transferrin saturation to diagnose iron overload 1

• Ferritin is highly sensitive but poorly specific—elevated in inflammation, liver disease, malignancy 1
• Normal ferritin essentially rules out iron overload (excellent negative predictor) 1

Do not overlook liver biopsy in high-risk patients 1

• Ferritin >1000 μg/L with abnormal liver tests requires assessment for cirrhosis 1

Do not continue chelation therapy when ferritin approaches normal range 7

• Continued administration at 14-28 mg/kg/day when iron burden is normal can result in life-threatening adverse events 7
• Overchelation increases risk of renal adverse events, particularly in pediatric patients 7

Do not delay specialist referral for extremely elevated ferritin 1, 5

• Ferritin >1000 μg/L regardless of TS: refer to gastroenterologist, hematologist, or iron overload specialist 1, 5
• Ferritin >10,000 μg/L: urgent specialist referral for life-threatening conditions 1

Imaging Considerations

MRI for Iron Quantification 8

• T2/T2* relaxometry is standard non-invasive method to quantify hepatic iron concentration 1
• Excellent correlation with biochemical hepatic iron (correlation coefficient 0.74-0.98) 1
• Sensitivity 84-91%, specificity 80-100% 1
• Use same MRI technique in subsequent visits for comparable results 8