What causes elevated ferritin levels above 2000?

Causes of Ferritin Levels Above 2000 ng/mL

Markedly elevated ferritin levels above 2000 ng/mL are most commonly caused by hepatocellular injury, infections, malignancies, and iron overload syndromes, with hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) having the highest mean ferritin values. 1

Common Causes of Extreme Hyperferritinemia (>2000 ng/mL)

• Hepatocellular injury/liver disease: The most prevalent cause of markedly elevated ferritin, accounting for approximately 23-38% of cases with extreme hyperferritinemia 1, 2
• Infections: The second most common cause, representing about 21-29% of cases with ferritin >2000 ng/mL 1, 3
• Malignancies: Particularly hematologic malignancies, accounting for 10-24% of cases with extreme hyperferritinemia 2, 3
• Iron overload syndromes: Including hemochromatosis and transfusional iron overload, representing about 22-35% of cases 2, 3
• Chronic renal failure: Associated with approximately 18% of cases with ferritin >2000 ng/mL 4
• Systemic inflammatory diseases: Including adult-onset Still's disease, which can present with extremely high ferritin levels (mean >11,000 ng/mL) 4

Inflammatory Conditions with Extreme Hyperferritinemia

• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS): Though relatively rare (3-5% of cases), these conditions are associated with the highest median ferritin values, often >14,000 ng/mL 1, 2
• Adult-onset Still's disease: Presents with dramatically elevated ferritin levels, with mean values >11,000 ng/mL 4
• Systemic juvenile idiopathic arthritis: Associated with extremely high ferritin levels similar to adult-onset Still's disease 2

Ferritin as an Acute Phase Reactant

• Ferritin is an acute phase reactant that increases during inflammation, making it less reliable as a sole indicator of iron status in chronic disease states 5
• In inflammatory conditions, ferritin levels can be markedly elevated despite normal or low iron stores 5
• Serum ferritin levels between 100-700 ng/mL in the presence of inflammation can indicate functional iron deficiency or inflammatory iron block 5

Clinical Significance and Evaluation

• Unexplained extreme hyperferritinemia is associated with significantly higher mortality (up to 80% in some studies) 3
• Multiple underlying conditions often coexist in patients with extreme hyperferritinemia, with 41-70% of patients having more than one cause 3, 6
• When evaluating a patient with ferritin >2000 ng/mL, consider:
  • Liver function tests to assess for hepatocellular injury 1
  • Evaluation for infections, including uncommon pathogens such as HIV, dengue, syphilis, and murine typhus 3
  • Screening for malignancies, particularly hematologic malignancies 2
  • Assessment of iron overload with transferrin saturation (TSAT) 7
  • Evaluation for HLH/MAS, especially with extremely high ferritin levels (>10,000 ng/mL) 1

Iron Overload Considerations

• Iron overload therapy should only be considered when there is evidence of chronic transfusional iron overload, including transfusion of at least 100 mL/kg of packed red blood cells and serum ferritin consistently greater than 1000 ng/mL 7
• Liver cell damage has been noted in patients with transfusional hemosiderosis who had serum ferritin levels exceeding 7,500 ng/mL and transferrin saturation greater than 88% 8
• Iron deposition in proximal muscle has been demonstrated in iron-overloaded hemodialysis patients with ferritin levels between 1,030 to 5,000 ng/mL, particularly in those who inherited hemochromatosis alleles 8

Pitfalls and Caveats

• Extreme hyperferritinemia as an isolated finding is not specific for any single diagnosis, including HLH/MAS 1
• The number of underlying causes correlates with the degree of ferritin elevation - patients with multiple etiologies tend to have higher ferritin levels 6
• In 3-5% of cases with extreme hyperferritinemia, no clear cause may be identified despite thorough evaluation 2, 3
• When evaluating ferritin levels in patients with chronic kidney disease, consider that inflammatory states may mask underlying iron deficiency despite elevated ferritin values 5