From the Guidelines
Isolated elevated ferritin levels should be thoroughly investigated to rule out underlying causes such as hemochromatosis, inflammation, liver disease, or metabolic disorders, as elevated ferritin can lead to significant morbidity and mortality if left untreated. The initial workup should include transferrin saturation, complete blood count, liver function tests, and inflammatory markers, as recommended by the EASL clinical practice guidelines for HFE hemochromatosis 1.
Key Considerations
- If transferrin saturation is high (>45%), genetic testing for hereditary hemochromatosis is recommended, particularly for the C282Y and H63D polymorphisms 1.
- For confirmed iron overload, treatment may involve therapeutic phlebotomy, which has been shown to be effective in normalizing ferritin levels and preventing organ damage 1.
- Patients should avoid iron supplements and limit alcohol consumption to prevent further iron accumulation and liver damage.
- For non-iron overload causes, treating the underlying condition is essential, and metabolic-associated elevated ferritin may improve with lifestyle modifications including weight loss, exercise, and dietary changes.
Diagnostic Approach
- The diagnosis of HFE hemochromatosis should not be based on C282Y homozygosity alone, but requires evidence of increased iron stores, as stated in the EASL guidelines 1.
- C282Y/H63D compound heterozygotes and H63D homozygotes presenting with increased serum ferritin (>200 lg/L in females, >300 lg/L in males), increased transferrin saturation (>45% in females, >50% in males) or increased liver iron should first be investigated for other causes of hyperferritinemia 1.
- Genetic testing of ‘other hemochromatosis genes’ (TFR2, SLC40A1, HAMP, HJV) could be considered in patients with increased iron stores after exclusion of C282Y homozygosity, as suggested by the EASL guidelines 1.
Management and Monitoring
- Regular monitoring of ferritin levels is important regardless of cause, as chronic iron overload can damage multiple organs including the liver, heart, and endocrine glands, while inflammatory elevations may indicate serious underlying conditions requiring specific treatment.
- Elevated ferritin requires attention and prompt investigation to prevent long-term complications and improve quality of life, as emphasized by the EASL guidelines 1.
From the Research
Isolated Elevated Ferritin
- Isolated elevated ferritin can be caused by various conditions, including genetic and acquired disturbances in iron metabolism 2
- Hyperferritinemia may not always be reflective of elevated total body iron stores, and there are conditions in which ferritin levels are disproportionately elevated relative to iron status 3
- Ninety percent of elevated serum ferritin is due to non-iron overload conditions, where venesection therapy is not the treatment of choice 4
Differential Diagnoses
- Marked hyperferritinemia can indicate severe underlying conditions, including infections, cardiovascular diseases, endocrinological, autoimmune, and malignancies 5
- Hyperferritinemia can be caused by acute phase reactions and reactive increases in ferritin due to underlying conditions, and differentiation of the presence or absence of an associated iron overload is essential 6
- Conditions such as adult-onset Still's disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH) can present with hyperferritinemia, and a thorough diagnostic workup is necessary to identify the underlying cause 5
Diagnostic Approach
- Investigation of elevated serum ferritin involves identifying alcohol consumption, metabolic syndrome, obesity, diabetes, liver disease, malignancy, infection, or inflammation as causative factors 4
- An algorithm for the diagnostic workup and management of hyperferritinemia can be proposed, including the assessment of iron status, liver function, and inflammatory markers 6
- Referral to a specialist, such as a gastroenterologist, hematologist, or physician with an interest in iron overload, is appropriate if serum ferritin is >1000 µg/L or if the cause of elevated serum ferritin is still unclear 4