From the Guidelines
When evaluating isolated elevated ferritin with normal liver function tests (LFTs), a thorough history and physical examination should be performed to rule out common causes, and additional laboratory tests such as complete blood count, transferrin saturation, and iron studies should be ordered to guide further management. The evaluation of isolated elevated ferritin is crucial to distinguish between true iron overload and inflammatory conditions. According to the most recent guidelines, if serum ferritin is lower than 1,000 lg/L, the risk of severe liver fibrosis is negligible 1.
Key Considerations
- A serum ferritin <1,000 lg/L, in the absence of hepatomegaly, thrombocytopenia, and abnormal transaminases, has a negative predictive value of 94% for advanced liver fibrosis 1
- Liver biopsy may be considered if serum ferritin is higher than 1,000 lg/L, taking into account the iron burden, other cofactors for liver disease, and the interpretation of non-invasive tests 1
- Phlebotomy remains the mainstay of treatment for hemochromatosis, and the decision to treat should be based on the presence of liver disease or other end-organ manifestations, as well as the patient's tolerance and adherence to the regimen 1
Management Approach
- Begin with a thorough history and physical examination, focusing on alcohol intake, family history, and symptoms of liver disease
- Order additional laboratory tests including complete blood count, transferrin saturation, iron studies, HFE gene testing (for hereditary hemochromatosis), inflammatory markers (CRP, ESR), and glycated hemoglobin (HbA1c)
- If transferrin saturation is elevated (>45%), genetic testing for hemochromatosis is warranted
- With normal transferrin saturation, consider metabolic syndrome, inflammation, or malignancy
- For persistent unexplained elevation, consider liver imaging (ultrasound or MRI) to assess for steatosis or iron overload
- Lifestyle modifications are important, including limiting alcohol, weight loss if overweight, and dietary changes
- Phlebotomy may be recommended for confirmed hemochromatosis, with the goal of reducing tissue iron stores to normal and improving survival, sense of well-being, and cardiac function 1
From the Research
Evaluating Isolated Elevated Ferritin
To evaluate isolated elevated ferritin in someone with normal LFTs, several steps can be taken:
- Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D mutations should be pursued to rule out hereditary hemochromatosis 2
- Magnetic resonance imaging with quantitative assessment of iron content or liver biopsy can be used to assess iron overload, especially if liver disease is suspected 2
- A secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations 2
- Differential diagnosis of secondary iron overload includes hematologic disorders, iatrogenic causes, or chronic liver diseases 2
Causes of Hyperferritinemia
Causes of hyperferritinemia include:
- Chronic liver disease
- Malignancy
- Infections
- Kidney failure
- Rheumatic conditions, such as adult-onset Still's disease or hemophagocytic lymphohistiocytosis 2
- Hematologic disorders, such as thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency 2
Diagnostic Approach
A diagnostic approach to hyperferritinemia can involve:
- Measuring serum glycosylated ferritin, which may be elevated in cases of iron overload 3
- Assessing transferrin saturation, which can indicate iron overload 3
- Evaluating for underlying conditions, such as chronic inflammatory conditions, that may cause reactive increases in ferritin 4
- Using an algorithm for the diagnostic workup and management of hyperferritinemia, as proposed in the literature 4
Unexplained Isolated Hyperferritinemia
In some cases, isolated hyperferritinemia may remain unexplained, and the cause may be attributed to increased cellular ferritin secretion and/or decreased serum ferritin clearance 5