What are the causes of elevated ferritin levels?

Causes of Elevated Ferritin Levels

Elevated ferritin levels are most commonly caused by inflammatory conditions, malignancy, and iron overload disorders, with specific diagnostic thresholds being >300 ng/mL for men and >200 ng/mL for women according to American College of Physicians guidelines. 1

Common Causes of Elevated Ferritin

Ferritin elevations can be broadly categorized into iron overload and non-iron overload conditions:

Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations - C282Y homozygous or C282Y/H63D compound heterozygous) 2
• Secondary iron overload:
  • Hematologic disorders (thalassemia, myelodysplastic syndrome, myelofibrosis, sideroblastic anemia) 2
  • Multiple blood transfusions 3
  • Excessive iron supplementation 1

Non-Iron Overload Conditions (90% of cases) 4

• Inflammatory conditions:
  • Adult-onset Still's disease
  • Systemic juvenile idiopathic arthritis
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 5
• Liver diseases:
  • Non-alcoholic fatty liver disease (NAFLD)
  • Alcoholic liver disease
  • Viral hepatitis 1, 2
• Metabolic conditions:
  • Metabolic syndrome
  • Obesity
  • Diabetes 4
• Malignancies (most frequent cause of markedly elevated ferritin >1000 μg/L) 5
• Infections 2
• Kidney failure 2

Diagnostic Approach

Step 1: Assess Ferritin Level and Clinical Context

• Interpret ferritin based on established thresholds:

  Ferritin Level	Interpretation
  <10 μg/L	Severe iron deficiency
  <30 μg/L	Iron deficiency without inflammation
  30-100 μg/L	Possible iron deficiency or anemia of chronic disease
  50-100 μg/L	Target maintenance range
  >100 μg/L	Possible anemia of chronic disease or iron overload
  >1000 μg/L	High risk of cirrhosis (20-45%) if true iron overload 1

Step 2: Complete Iron Studies

• Measure transferrin saturation (TSAT), serum iron, and total iron binding capacity (TIBC) 1
• TSAT >45% suggests iron overload
• TSAT <20% indicates functional iron deficiency with inflammation 1

Step 3: Evaluate for Common Causes

• If TSAT >45%: Consider hereditary hemochromatosis and order HFE genetic testing 2
• If TSAT <45%: Focus on non-iron overload causes:
  • Check liver function tests for liver disease
  • Screen for metabolic syndrome, diabetes
  • Evaluate for inflammatory conditions (CRP, ESR)
  • Consider malignancy workup if clinically indicated 1, 4

Management Considerations

• For true iron overload (confirmed hemochromatosis): Therapeutic phlebotomy to reduce ferritin to 50-100 μg/L 1
• For non-iron overload conditions: Treat the underlying cause 4
• Specialist referral is recommended when:
  • Ferritin >1000 μg/L
  • Unclear cause after initial evaluation
  • Evidence of organ damage 1

Clinical Pearls and Pitfalls

• Key Pitfall: Initiating phlebotomy without confirming true iron overload can be harmful for patients with non-iron overload causes of hyperferritinemia 4
• Important Note: Extremely high ferritin levels (>10,000 μg/L) are most commonly associated with malignancy, multiple blood transfusions, and inflammatory conditions like Still's disease 5, 3
• Caution: Ferritin >1000 μg/L with true iron overload carries a 20-45% risk of cirrhosis and warrants consideration of liver biopsy, especially with elevated liver enzymes 1
• Remember: While hereditary hemochromatosis is common genetically, 90% of elevated ferritin cases are due to non-iron overload conditions 4