Can cancer cause hyperferritinemia (elevated iron levels)?

Can Cancer Cause High Iron Levels?

Yes, cancer can cause elevated ferritin levels (hyperferritinemia) through multiple mechanisms, particularly through inflammation-driven processes that alter iron homeostasis.

Mechanisms of Cancer-Related Hyperferritinemia

• Cancer can trigger an inflammatory state that increases ferritin production as an acute-phase reactant, potentially falsely elevating serum ferritin levels even when iron stores are normal or low 1
• Malignancies can disrupt iron metabolism through the upregulation of hepcidin, the main regulator of iron uptake and release, leading to iron sequestration in macrophages and altered iron homeostasis 1
• Tumoral tissues themselves can produce significantly higher amounts of ferritin (up to 4.5 times more) than normal tissues, contributing to elevated serum levels 2
• Inflammatory cytokines released in cancer (particularly IL-1, IL-6, and tumor necrosis factor) stimulate hepatic synthesis of hepcidin, which binds to ferroportin in reticuloendothelial cells and prevents iron export into circulation 1

Clinical Manifestations and Patterns

• While only about 10% of patients with localized cancer present with hyperferritinemia, approximately 95% of patients with metastatic disease (particularly to liver, bone, or lung) demonstrate elevated ferritin levels 2
• Cancer-related functional iron deficiency can paradoxically present with high ferritin levels but low transferrin saturation (<20%), creating a diagnostic challenge 1
• Iron studies in cancer patients often show increased storage iron in bone marrow aspirates yet reduced-to-absent stainable iron in erythroid precursors, reflecting the dysregulation of iron metabolism 1

Diagnostic Considerations

• In cancer patients, the standard ferritin cutoff for iron deficiency should be raised from <30 ng/mL to <100 ng/mL due to the inflammatory state that falsely elevates ferritin 1
• Transferrin saturation (TSAT) <20% with elevated ferritin indicates functional iron deficiency, a common finding in cancer patients 1
• A comprehensive iron panel including serum iron, total iron binding capacity, and serum ferritin is necessary to distinguish between absolute iron deficiency, functional iron deficiency, and iron overload in cancer patients 1
• Other markers like reticulocyte hemoglobin content (CHr <28 pg) and percentage of hypochromic RBCs (%HYPO >5%) may help identify functional iron deficiency in cancer patients 1

Clinical Implications

• Hyperferritinemia in cancer patients can mask underlying functional iron deficiency, potentially leading to inadequate treatment of anemia 1
• Iron overload is associated with increased risk of liver cancer specifically (HR 4.49,95% CI 2.71-7.43), though not with overall cancer risk 3
• The combination of high ferritin and low hepcidin levels in plasma has been particularly associated with increased liver cancer risk 3
• Both iron deficiency and iron overload can coexist in cancer patients and may synergistically contribute to tumor progression 4

Management Considerations

• When evaluating iron status in cancer patients, clinicians should be aware that chronic inflammation may falsely elevate serum ferritin 1
• Intravenous iron supplementation should be considered for cancer patients with functional iron deficiency (ferritin <800 ng/mL and transferrin saturation <20%) who are receiving erythropoiesis-stimulating agents 1
• Iron status should be carefully assessed before initiating iron therapy in cancer patients to avoid potential harm from inappropriate iron administration 5, 4

Understanding the complex relationship between cancer and iron metabolism is crucial for proper diagnosis and management of anemia in cancer patients, as both iron deficiency and iron overload can negatively impact patient outcomes.