What causes elevated ferritin levels?

Causes of High Ferritin

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 Conditions:

  • Hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity, C282Y/H63D compound heterozygosity) 1
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1
  • Transfusional iron overload (patients with serum ferritin levels exceeding 7,500 ng/mL) 2, 3

• Inflammatory Conditions:

  • Systemic inflammatory response syndrome 1
  • Adult-onset Still's disease (AOSD) - often associated with extremely high ferritin levels (average 14,242 μg/L) 1, 4
  • Infections (bacterial, viral) 1

Secondary Causes of Hyperferritinemia

• Liver Disorders:

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

• Metabolic Conditions:

  • Metabolic syndrome 1
  • Obesity 5
  • Diabetes 5

• Other Causes:

  • Malignancies (solid tumors and lymphomas) 1, 4
  • Cell necrosis 1
  • Chronic kidney disease 2

Diagnostic Approach to Hyperferritinemia

Initial Assessment

• Check transferrin saturation (TS) and serum ferritin 1
• Morning blood samples for transferrin saturation are recommended (fasting not required) 2
• Consider that serum ferritin is an acute phase reactant that increases during inflammation 3

Evaluation Algorithm

1. Rule out common non-iron overload causes:

   • Alcohol consumption history 2, 5
   • Evaluate for metabolic syndrome, obesity, diabetes 1, 5
   • Check for signs of inflammation, infection, or malignancy 1
   • Assess liver function 2, 1

2. If common causes excluded, proceed with iron overload evaluation:

   • HFE genetic testing for C282Y and H63D mutations 2, 1
   • Consider liver biopsy or MRI for hepatic iron concentration assessment 1

3. For very high ferritin levels (>1000 μg/L):

   • Consider referral to specialist (gastroenterologist, hematologist) 5
   • Note that serum ferritin >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 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 with mild hyperferritinemia, iron overload is not the most common cause of elevated ferritin 6
• Post-test likelihood of finding C282Y homozygosity in patients with ferritin 200-1000 μg/L ranges from 0.3% to 30.4% depending on gender and ferritin level 6
• In hemodialysis patients with elevated ferritin due to inflammation, ferritin levels typically normalize within 4 months after resolving the inflammatory state 7
• Unexpected changes in serum ferritin levels should always be investigated, as significant fluctuations are not normal 7
• The association between increased ferritin levels and infections is due to infection causing increased ferritin levels, rather than iron overload causing increased risk of infection 2

Pitfalls to Avoid

• Don't assume that elevated ferritin automatically indicates iron overload - 90% of cases are due to non-iron overload conditions 5
• Don't overlook the possibility of multiple contributing factors to hyperferritinemia 2, 1
• Don't miss that serum ferritin concentrations are often elevated in conditions associated with fatty liver disease, which must be considered when investigating high ferritin 2
• Be aware that chronic alcohol excess can increase serum ferritin through multiple mechanisms including increased iron absorption and liver injury 2