From the Guidelines
For elevated ferritin levels below 1000 ng/mL, a systematic workup should begin with a thorough history and physical examination, focusing on alcohol use, obesity, metabolic syndrome, and inflammatory conditions. The initial step in evaluating hyperferritinemia is to identify common causes of elevated ferritin levels, such as chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD) and/or the metabolic syndrome 1.
Initial Evaluation
Initial laboratory testing should include:
- Complete blood count
- Comprehensive metabolic panel
- Iron studies (serum iron, total iron binding capacity, transferrin saturation)
- Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) If transferrin saturation is greater than 45%, genetic testing for HFE mutations (C282Y, H63D) should be performed to evaluate for hereditary hemochromatosis 1.
Further Testing
For patients with normal transferrin saturation, consider evaluating for metabolic dysfunction-associated steatotic liver disease with liver ultrasound, particularly if metabolic risk factors are present. Additional testing may include:
- Hepatitis serologies
- Autoimmune markers
- Thyroid function tests depending on clinical suspicion.
Management
Management depends on the underlying cause - lifestyle modifications for metabolic causes, phlebotomy for hemochromatosis, and treating the underlying condition for secondary causes. In the absence of indicators suggestive of significant liver disease, C282Y homozygotes who have an elevated ferritin (but <1000 lg/L) should proceed to phlebotomy without a liver biopsy 1. Repeat ferritin measurement in 3-6 months is reasonable to monitor response to interventions. This stepwise approach helps distinguish between iron overload conditions requiring specific treatment and inflammatory or metabolic causes of hyperferritinemia. In patients with end-organ damage due to iron overload, regular phlebotomy to the same endpoints as indicated above should be performed 1. During treatment for HH, dietary adjustments are unnecessary, and vitamin C supplements and iron supplements should be avoided 1.
From the Research
Workup for Elevated Ferritin Levels
Elevated ferritin levels below 1000, indicating hyperferritinemia, require a thorough workup to determine the underlying cause. The following steps can be taken:
- Review patient history and clinical parameters, including transferrin saturation, serum concentrations of alanine, and aspartate aminotransferases (ALT, AST) 2
- Test for HFE mutations, as hereditary hemochromatosis can cause elevated ferritin levels 3
- Perform liver imaging and consider liver biopsy to assess liver iron concentration 2
- Evaluate for inflammatory and malignant diseases, as ferritin is an acute phase protein and can be elevated in these conditions 4, 5
- Consider other potential causes of hyperferritinemia, such as non-human immunodeficiency virus infection, solid tumor, liver dysfunction, renal failure, and hematological malignancy 5
Potential Causes of Hyperferritinemia
The following are potential causes of hyperferritinemia:
- Iron-overload syndromes, such as hereditary hemochromatosis 2, 3
- Inflammatory diseases, such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome 6
- Malignant diseases, such as solid tumors and hematological malignancies 6, 5
- Liver dysfunction and renal failure 5
- Non-human immunodeficiency virus infection 5
- Other conditions, such as anemia of chronic inflammation and seemingly indolent disease or levels of chronic inflammation 6