Causes and Management of Elevated Ferritin Levels
Elevated ferritin levels are most commonly caused by inflammation, malignancy, and liver disease (90% of cases), while true iron overload conditions account for only about 10% of cases. 1, 2
Common Causes of Elevated Ferritin
Iron Overload Conditions
- Hereditary hemochromatosis - characterized by elevated ferritin with high transferrin saturation (>45%), particularly in C282Y homozygotes 3
- Transfusional iron overload - requires evidence of chronic transfusion of packed red blood cells and consistently elevated ferritin >1000 μg/L 4
- Iron overload due to ineffective erythropoiesis (thalassemia, myelodysplastic syndromes) 5
Non-Iron Overload Conditions
- Inflammatory conditions - ferritin acts as an acute phase reactant 2
- Malignancy - most frequent cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 6
- Liver disease - particularly with alcohol consumption and fatty liver disease 7
- Metabolic syndrome and obesity 1
- COVID-19 and other severe infections - hyperferritinemia correlates with disease severity 8
- Adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis - associated with extremely high ferritin levels (average 14,242 μg/L) 6
Diagnostic Approach
Initial Laboratory Evaluation
- Complete blood count - to assess for anemia 7
- Serum iron and total iron binding capacity - to calculate transferrin saturation 7
- Liver function tests - to assess for liver disease 7
- Inflammatory markers (CRP, ESR) - to identify inflammatory conditions 2
When to Suspect Iron Overload
- Ferritin >1000 μg/L with transferrin saturation >45% strongly suggests iron overload 3
- Consider genetic testing for HFE mutations (C282Y, H63D) when iron overload is suspected 3
- MRI is helpful for non-invasive quantification of iron in the liver, spleen, pancreas, heart, and brain 7
- Liver biopsy may be indicated in selected cases to assess for fibrosis/cirrhosis when ferritin >1000 μg/L with elevated liver enzymes 3
When to Suspect Other Causes
- Normal or low transferrin saturation with elevated ferritin suggests inflammation, malignancy, or liver disease 2
- In patients with pruritus and elevated ferritin, consider both iron deficiency and iron overload as potential causes 7
- In patients with chronic kidney disease, elevated ferritin may be due to inflammation rather than iron overload 7
Management Strategies
Iron Overload Conditions
- Therapeutic phlebotomy is the cornerstone of treatment for confirmed hemochromatosis 3
- Target ferritin level should be <500 μg/L to avoid toxicity of iron overload 3
- For transfusional iron overload, iron chelation therapy with agents like deferasirox may be indicated 4
- Initial deferasirox dose is 14 mg/kg/day for patients with eGFR >60 ml/min/1.73m² 4
- Monitor serum ferritin monthly and adjust dose every 3-6 months based on trends 4
Non-Iron Overload Conditions
- Treat the underlying cause (inflammation, infection, malignancy) 2
- For metabolic syndrome and fatty liver disease, weight loss through dietary modification and increased physical activity is recommended 7
- In patients with excessive alcohol consumption, reducing intake is crucial as the combination with elevated iron parameters increases risk of fibrosis and hepatocellular malignancy 7
- For patients with iron deficiency and elevated ferritin due to inflammation, iron replacement therapy may be beneficial 7
Special Considerations
Hyperferritinemia with Low Transferrin Saturation
- May indicate functional iron deficiency in inflammatory states 7
- Intravenous iron may be beneficial in selected patients with elevated ferritin but low transferrin saturation, particularly in chronic kidney disease 7
- Safety concerns exist with IV iron administration in patients with very high ferritin levels (>800 ng/ml) 7
When to Refer
- Referral to a gastroenterologist, hematologist, or physician with interest in iron overload is appropriate if serum ferritin is >1000 μg/L or if the cause remains unclear 1
- Patients with suspected hereditary hemochromatosis should have family screening with serum ferritin, transferrin saturation, and HFE genetic testing 3
Monitoring
- Regular monitoring of ferritin levels during treatment is essential 3
- For iron overload conditions, once target ferritin is reached, maintenance phlebotomies are typically needed 3-4 times per year 3
- Ongoing surveillance for complications (diabetes, arthropathy, cardiac issues) is recommended in patients with iron overload 3