What are the causes of elevated ferritin levels?

Causes of Elevated Ferritin Levels

Elevated ferritin levels are most commonly caused by inflammatory conditions, malignancy, liver disease, and metabolic syndrome, with hereditary hemochromatosis accounting for only a small percentage of cases in clinical practice. 1

Primary Categories of Hyperferritinemia

1. Inflammatory Conditions

• Acute and chronic inflammation (ferritin acts as an acute phase reactant) 2
• Autoimmune disorders:
  • Adult-onset Still's disease
  • Systemic juvenile idiopathic arthritis
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (can cause extremely high levels >10,000 μg/L) 1
• Infections (bacterial, viral)

2. Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity) 2
• Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 2
• Secondary iron overload:
  • Multiple blood transfusions
  • Chronic hemolytic anemias
  • Ineffective erythropoiesis (thalassemia, sideroblastic anemia)

3. Liver Disease

• Alcoholic liver disease 2
• Non-alcoholic fatty liver disease (NAFLD) 3
• Viral hepatitis 4
• Cirrhosis of any etiology

4. Metabolic Disorders

• Metabolic syndrome 3
• Insulin resistance 3
• Type 2 diabetes 2
• Obesity 3

5. Malignancies

• Most common cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 1
• Hematologic malignancies
• Solid tumors

6. Cell Damage/Necrosis

• Ferritin is released from damaged cells as a "leakage product" 5
• Acute liver injury
• Rhabdomyolysis
• Hemolysis

7. Other Causes

• Chronic kidney disease 2
• Hyperthyroidism
• Ferroportin disease (SLC40A1 mutations) 2

Clinical Approach to Elevated Ferritin

Step 1: Assess for Common Causes

• Check for inflammatory markers (CRP, ESR)
• Evaluate liver function (ALT, AST)
• Screen for metabolic syndrome (BMI, blood pressure, lipids, glucose)
• Consider alcohol consumption history

Step 2: Evaluate Iron Status

• Measure transferrin saturation (TSAT)
  • If TSAT >45% in women or >50% in men, consider iron overload 2
  • If TSAT is normal or low with high ferritin, consider inflammation, liver disease, or metabolic syndrome 2

Step 3: Genetic Testing (if iron overload suspected)

• HFE gene testing for C282Y and H63D mutations if TSAT elevated 2
• Consider non-HFE gene testing if iron overload confirmed but HFE testing negative 2

Important Clinical Pearls

1. Ferritin level correlation with disease severity:

   • Ferritin <1000 μg/L is rarely associated with cirrhosis in hemochromatosis 2
   • Extremely high ferritin (>10,000 μg/L) should raise suspicion for hemophagocytic syndromes 1

2. Diagnostic pitfalls:

   • Mild to moderate hyperferritinemia (200-1000 μg/L) is rarely due to hereditary hemochromatosis 6
   • Post-test likelihood of C282Y homozygosity with ferritin 200-1000 μg/L is only 0.3-30.4% 6
   • Metabolic syndrome and NAFLD are much more common causes of mild hyperferritinemia than genetic iron overload 3

3. Interpretation challenges:

   • Ferritin can be elevated due to both iron overload and inflammation simultaneously
   • In chronic kidney disease, ferritin levels may be elevated without true iron overload 2
   • Acute hepatitis can cause rapid rises in serum ferritin without corresponding increases in tissue iron 4

By systematically evaluating patients with elevated ferritin using this approach, clinicians can identify the underlying cause and determine appropriate management strategies to reduce morbidity and mortality associated with conditions causing hyperferritinemia.