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 of Hyperferritinemia

• Iron Overload Disorders:

  • Hereditary hemochromatosis (HFE-related) - C282Y homozygosity or C282Y/H63D compound heterozygosity 2
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1
  • Ferroportin disease 3
  • Hyperferritinemia-cataract syndrome 3

• Hematologic Disorders:

  • Chronic transfusion therapy 4
  • Thalassemia syndromes 5
  • Myelodysplastic syndrome 5
  • Myelofibrosis 5
  • Sideroblastic anemias 5
  • Sickle cell disease 5
  • Pyruvate kinase deficiency 5

Secondary Causes of Hyperferritinemia

• Liver Diseases:

  • Alcoholic liver disease 1, 6
  • Viral hepatitis (B and C) 1, 6
  • Non-alcoholic fatty liver disease (NAFLD) 1, 6
  • Acute hepatitis 1

• Inflammatory Conditions:

  • Systemic inflammatory response syndrome 1
  • Adult-onset Still's disease (AOSD) - often with extremely high levels (>10,000 μg/L) 1, 7
  • Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome 7, 4
  • Rheumatic conditions 5

• Other Conditions:

  • Malignancies (both solid tumors and hematologic) 1, 7, 4
  • Infections 1
  • Metabolic syndrome 1
  • Cell necrosis 1
  • Chronic kidney disease 5
  • Anemia of chronic inflammation 2

Diagnostic Approach to Hyperferritinemia

1. Initial Assessment:

   • Measure both serum ferritin and transferrin saturation (TS) 2, 8
   • Check for common causes of hyperferritinemia:
     • Inflammation (check CRP, ESR) 2
     • Cell necrosis (check AST, ALT, CK) 2
     • Chronic alcohol consumption 2
     • Metabolic syndrome (check blood pressure, BMI, cholesterol, triglycerides, serum glucose) 2
     • Tumors (check ESR, consider CT scan) 2

2. Further Evaluation Based on Transferrin Saturation:

   • If TS ≥45% with elevated ferritin:
     • Consider iron overload disorders 8
     • Proceed with HFE genetic testing for C282Y and H63D mutations 2
   • If TS <45% with elevated ferritin:
     • Focus on inflammatory conditions, anemia of chronic disease, or liver disease 8

3. Additional Testing for Specific Scenarios:

   • For extremely high ferritin levels (>10,000 μg/L):
     • Consider adult-onset Still's disease, HLH, or macrophage activation syndrome 9, 4
   • For confirmed iron overload without C282Y homozygosity:
     • Consider testing for non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) 2
   • For liver disease evaluation:
     • Consider liver biopsy in C282Y homozygotes with serum ferritin >1000 μg/L, elevated AST, hepatomegaly, or age >40 years 2

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 liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 2
• Family screening is essential for siblings of patients with HFE-related hemochromatosis, as they have a 25% chance of being susceptible 2
• Using ferritin alone without transferrin saturation to diagnose iron overload is a common pitfall to avoid 9