What are the causes of hyperferritinemia?

Causes of Hyperferritinemia

The most common causes of hyperferritinemia 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 (Iron Overload Related)

• Hereditary Hemochromatosis (HH)

  • HFE gene mutations (C282Y homozygosity, C282Y/H63D compound heterozygosity) 1
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1
  • Ferroportin disease 2

• Secondary Iron Overload

  • Chronic transfusion therapy (35% of extreme hyperferritinemia cases) 3
  • Hematologic disorders:
    • Thalassemia syndromes
    • Myelodysplastic syndrome
    • Myelofibrosis
    • Sideroblastic anemias
    • Sickle cell disease
    • Pyruvate kinase deficiency 4

Secondary Causes (Non-Iron Overload Related)

• Liver Disease (27% of extreme hyperferritinemia cases) 3

  • Alcoholic liver disease
  • Viral hepatitis (B and C)
  • Non-alcoholic fatty liver disease (NAFLD) 1, 5
  • Acute hepatitis 1

• Inflammatory Conditions

  • Systemic inflammatory response syndrome
  • Adult-onset Still's disease (AOSD) 1
  • Rheumatic conditions 4
  • Hemophagocytic lymphohistiocytosis (HLH) 3
  • Macrophage activation syndrome 3

• Malignancies

  • Hematologic malignancies (16% of extreme hyperferritinemia cases) 3
  • Solid tumors 1, 3
  • Lymphomas 1

• Infections 1, 3

• Metabolic Conditions

  • Metabolic syndrome 1
  • Dysmetabolic iron overload syndrome (DIOS) - hyperferritinemia with mild reticuloendothelial iron accumulation 5

• Genetic Disorders Without Iron Overload

  • Hyperferritinemia-cataract syndrome 2

• Other Conditions

  • Chronic kidney disease 4
  • Cell necrosis (check AST, ALT, CK) 1

Diagnostic Approach to Hyperferritinemia

1. Initial Assessment

   • Check transferrin saturation (TS) and serum ferritin 1
   • If either is abnormal (TS ≥45% or elevated ferritin), proceed with further evaluation 1

2. Rule Out Common Causes of Hyperferritinemia

   • Inflammation (check CRP)
   • Cell necrosis (check AST, ALT, CK)
   • Chronic alcohol consumption
   • Metabolic syndrome (check blood pressure, BMI, cholesterol, triglycerides, glucose)
   • Tumors (check ESR, consider imaging) 1

3. If Common Causes Are Excluded

   • Perform HFE genetic testing for C282Y and H63D mutations 1
   • If C282Y homozygous: Diagnosis of HFE-HC can be established
   • For other genotypes (C282Y/H63D compound heterozygotes, H63D homozygotes): Investigate for other causes of hyperferritinemia 1

4. Further Evaluation When Needed

   • Consider liver biopsy or MRI for hepatic iron concentration assessment 1
   • Consider testing for non-HFE hemochromatosis genes if iron overload is confirmed but C282Y homozygosity is excluded 1

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 1
• A serum ferritin <1000 μg/L has a high negative predictive value for cirrhosis in hemochromatosis patients 1
• A serum ferritin >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1
• Glycosylated ferritin ≤20% has been used as a diagnostic marker for adult-onset Still's disease 1
• Extreme hyperferritinemia (>10,000 ng/mL) is most commonly associated with chronic transfusion, liver disease, and hematologic malignancy rather than HLH 3