What causes elevated ferritin levels?

Causes of High Ferritin Levels

Elevated ferritin levels are most commonly caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome, which account for over 90% of cases in outpatients. 1

Primary Causes of Hyperferritinemia

• Inflammatory conditions are among the most frequent causes of elevated ferritin, as ferritin acts as an acute phase reactant 2, 1
• Chronic alcohol consumption increases ferritin by increasing iron absorption and causing liver injury 2, 1
• Metabolic syndrome and NAFLD are major causes of hyperferritinemia in approximately 30% of NAFLD patients 1, 3
• Cell necrosis leads to ferritin release from damaged cells 2, 1
• Malignancies (solid tumors and lymphomas) are significant causes of elevated ferritin 1, 4

Secondary Causes of Hyperferritinemia

• Liver diseases including viral hepatitis B and C, alcoholic liver disease, and acute hepatitis 2, 1
• Systemic inflammatory response syndrome and infections 1
• Adult-onset Still's disease can cause extremely high ferritin levels (>10,000 μg/L) 1, 4
• Chronic kidney disease may present with elevated ferritin levels 5
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome can cause markedly elevated ferritin 1, 4

Iron Overload Disorders

• Hereditary hemochromatosis (HFE gene mutations, particularly p.C282Y homozygosity) is characterized by increased iron absorption and tissue deposition 2
• Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1
• Transfusional iron overload in conditions requiring regular blood transfusions 6
• Hematological disorders with ineffective erythropoiesis (thalassemia, myelodysplastic syndrome, sideroblastic anemia) 6

Diagnostic Approach to Elevated Ferritin

• Always measure both serum ferritin and transferrin saturation (TS) together for proper evaluation 5
• If TS ≥45% with elevated ferritin, consider iron overload disorders and proceed with HFE genetic testing 2
• If TS <45% with elevated ferritin, focus on non-iron overload causes like inflammation, liver disease, or malignancy 5
• Check inflammatory markers (CRP, ESR) and liver enzymes to identify underlying causes 5, 7
• Consider liver biopsy or MRI for hepatic iron concentration assessment in cases of suspected iron overload 1, 6

Clinical Pearls and Pitfalls

• Serum ferritin >1000 μg/L with elevated liver enzymes and platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1
• Extremely high ferritin levels (>10,000 μg/L) should raise suspicion for adult-onset Still's disease or hemophagocytic lymphohistiocytosis 5, 4
• Ferritin alone has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions 1, 8
• In patients with chronic kidney disease and anemia, intravenous iron may still be beneficial despite elevated ferritin (500-1200 μg/L) if transferrin saturation is low (<25%) 5
• In most NAFLD patients with hyperferritinemia, the elevation is due to inflammation rather than true iron overload, and phlebotomy is not indicated 3

Understanding the diverse causes of elevated ferritin is essential for appropriate management, as treatment should target the underlying condition rather than the ferritin level itself 5, 8.