What are the causes and management of hyperferritinemia?

Causes and Management 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 outpatient cases. 1

Primary Causes of Hyperferritinemia

• Iron Overload Disorders:

  • Hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity, C282Y/H63D compound heterozygosity) 2, 1
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1, 3
  • Ferroportin disease (autosomal dominant condition with iron overload) 4

• Genetic Disorders Without Iron Overload:

  • Hyperferritinemia-cataract syndrome 5

Secondary Causes of Hyperferritinemia

• Inflammatory Conditions:

  • Systemic inflammatory response syndrome 1
  • Adult-onset Still's disease (AOSD) 1
  • Rheumatic conditions 3
  • Chronic inflammatory disorders 6

• Liver Diseases:

  • Alcoholic liver disease 1
  • Non-alcoholic fatty liver disease (NAFLD) 1, 7
  • Viral hepatitis (B and C) 1
  • Acute hepatitis 1
  • Chronic liver disease 3

• Hematologic Disorders:

  • Hemolytic anemia 6
  • Thalassemia syndromes 3
  • Myelodysplastic syndrome 3
  • Myelofibrosis 3
  • Sideroblastic anemias 3
  • Sickle cell disease 3
  • Chronic transfusion 8

• Other Causes:

  • Malignancies (solid tumors and lymphomas) 1, 3, 8
  • Infections 1, 3
  • Metabolic syndrome 1, 7
  • Cell necrosis 1
  • Kidney failure 3
  • Hemophagocytic lymphohistiocytosis (HLH) 8

Diagnostic Approach to Hyperferritinemia

1. Initial Assessment:

   • Measure serum ferritin and transferrin saturation (TS) 1, 4
   • Check inflammatory markers (CRP, ESR) 4
   • Assess liver function tests 4

2. Interpretation of Initial Results:

   • TS <20% with ferritin >100 μg/L suggests anemia of chronic disease 4
   • TS ≥45% with elevated ferritin suggests potential iron overload 2
   • Normal TS with elevated ferritin suggests inflammation, liver disease, or other non-iron overload causes 6

3. Further Evaluation Based on Initial Results:

   • If TS ≥45% (suggesting iron overload):

     • Perform HFE genetic testing for C282Y and H63D mutations 2, 3
     • If C282Y homozygous: diagnosis of HFE-related hemochromatosis 2
     • If other genotypes or negative: consider secondary causes or non-HFE hemochromatosis 2, 5

   • If TS <45% (suggesting non-iron overload causes):

     • Evaluate for inflammation (check CRP) 2, 1
     • Assess for cell necrosis (check AST, ALT, CK) 2, 1
     • Screen for metabolic syndrome (check blood pressure, BMI, cholesterol, triglycerides, glucose) 2, 7
     • Consider malignancy evaluation (ESR, imaging) 1

4. Advanced Testing When Indicated:

   • Liver biopsy for hepatic iron concentration and histopathology in unclear cases 2
   • MRI for non-invasive assessment of hepatic iron 1, 5
   • Testing for non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) when iron overload is confirmed but HFE testing is negative 2, 1
   • Glycosylated ferritin measurement (≤20% suggests adult-onset Still's disease) 1

Management of Hyperferritinemia

1. Treatment of Underlying Cause:

   • Address primary etiology (inflammation, liver disease, etc.) 4

2. Management of Iron Overload:

   • Hereditary Hemochromatosis:

     • Therapeutic phlebotomy is the mainstay of treatment 2
     • Target serum ferritin <500 μg/L to prevent toxicity 4

   • Secondary Iron Overload:

     • Iron chelation therapy with:
       • Deferiprone: oral iron chelator for transfusional iron overload 9
       • Deferoxamine: for acute iron intoxication and chronic transfusional iron overload 10
     • Monitor for adverse effects of chelation therapy:
       • Auditory and ocular toxicity 10
       • Renal toxicity 10
       • Respiratory distress 10
       • Growth suppression in pediatric patients 10
       • Serious infections (mucormycosis, Yersinia) 10

   • NAFLD with Hyperferritinemia:

     • Lifestyle modifications are more effective than phlebotomy when hyperferritinemia is due to inflammation rather than iron overload 7
     • Phlebotomy is only effective with hepatocellular iron overload 7

3. Monitoring:

   • Regular assessment of serum ferritin and transferrin saturation 2
   • Liver function tests 2
   • Specific monitoring based on underlying cause 1

Important Clinical Pearls

• Serum ferritin <1000 μg/L has high negative predictive value for cirrhosis in hemochromatosis patients 2, 1
• Serum ferritin >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1
• In the general population, iron overload is not the most common cause of elevated ferritin 2
• Extreme hyperferritinemia (>10,000 ng/mL) is most commonly due to chronic transfusion (35%), liver disease (27%), and hematologic malignancy (16%) 8
• When using Vitamin C with iron chelation therapy, limit to 200 mg daily to avoid cardiac dysfunction 9, 10