What are the causes of elevated ferritin levels?

Causes of Elevated Ferritin Levels

The most common causes of elevated ferritin levels include chronic alcohol consumption, inflammation, 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

• Iron Overload Disorders:

  • Hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity being most common) 2
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1
  • Secondary iron overload from transfusions or dyserythropoiesis 2

• Inflammatory Conditions:

  • Systemic inflammatory response syndrome 1
  • Adult-onset Still's disease - associated with extremely high ferritin levels (average 14,242 μg/L) 3
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3

Secondary Causes of Hyperferritinemia

• Liver Diseases:

  • Alcoholic liver disease 2, 1
  • Viral hepatitis (B and C) 1
  • Non-alcoholic fatty liver disease (NAFLD) 2, 1
  • Acute hepatitis 1

• Metabolic Conditions:

  • Metabolic syndrome - insulin resistance is significantly related to ferritin levels 4
  • Obesity 5
  • Diabetes 5

• Other Conditions:

  • Malignancies (most frequent cause in one study of markedly elevated ferritin) 3
  • Lymphomas 2
  • Infections 1
  • Cell necrosis (releasing ferritin from damaged cells) 2, 1
  • Chronic kidney disease 5

Diagnostic Approach to Elevated Ferritin

1. Initial Assessment:

   • Check transferrin saturation (TS) along with serum ferritin 2
   • Morning blood samples are recommended (fasting not required) 2

2. Interpretation of Results:

   • If TS ≥45% and ferritin elevated: Suspect iron overload 2, 6
   • If TS normal but ferritin elevated: More likely non-iron overload causes 2

3. Further Evaluation:

   • Rule out common causes: inflammation (check CRP), cell necrosis (check AST, ALT, CK), alcohol consumption, metabolic syndrome, tumors 2
   • If ferritin >1000 μg/L with elevated liver enzymes: Consider liver biopsy to assess for fibrosis/cirrhosis 2, 6
   • HFE genetic testing for C282Y and H63D mutations if iron overload suspected 2, 7

Important Clinical Pearls

• Serum ferritin has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions 1
• In the general population, iron overload is not the most common cause of elevated ferritin 2
• A serum ferritin <1000 μg/L has a high negative predictive value for cirrhosis in hemochromatosis patients 2
• A serum ferritin >1000 μg/L with elevated aminotransferases and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 6
• Referral to a specialist (gastroenterologist, hematologist) is appropriate if serum ferritin is >1000 μg/L or if the cause remains unclear after initial evaluation 5
• Markedly elevated ferritin levels (>1000 μg/L) are most commonly associated with malignancy and iron overload syndromes, but can also occur in seemingly indolent conditions 3

When to Consider Hereditary Hemochromatosis

• European ancestry with biochemical evidence of iron overload (females with TS >45% and ferritin >200 μg/L; males with TS >50% and ferritin >300 μg/L) 2
• Adult first-degree relatives of patients with confirmed C282Y homozygous hemochromatosis 2
• Unexplained elevated transferrin saturation with clinical signs suggestive of hemochromatosis 2