What are the implications of elevated ferritin (iron storage protein) levels?

From the Guidelines

Elevated ferritin levels are a significant indicator of excess iron storage in the body, requiring prompt medical evaluation to determine the underlying cause and prevent potential organ damage, particularly to the liver, heart, and pancreas. The most recent and highest quality study, 1, published in 2022, emphasizes the importance of non-invasive assessment of tissue iron overload using MRI, which can help determine the degree of iron overload and guide diagnosis and management.

Key Considerations

• Elevated ferritin levels can indicate increased tissue iron concentrations, but are also non-specific and can be caused by inflammatory and neoplastic conditions 1.
• Serum iron parameters, including transferrin saturation, are surrogates of body iron status, but alone are often insufficient to ascertain iron overload 1.
• MRI can be used to non-invasively quantify liver, spleen, pancreas, and cardiac iron, guiding diagnosis and management, especially in patients without homozygosity for p.C282Y and/or the presence of additional risk factors for hepatic iron overload 1.

Treatment and Management

• Therapeutic phlebotomy is a recommended treatment for conditions like hemochromatosis, with sessions typically removing 500ml of blood every 1-2 weeks until iron levels normalize, as suggested by the 2011 practice guideline by the American Association for the Study of Liver Diseases 1.
• Dietary modifications, such as limiting alcohol and reducing consumption of red meat and iron-fortified foods, can help manage iron levels, but are considered unnecessary during treatment for HH, and vitamin C supplements and iron supplements should be avoided 1.
• Regular monitoring through blood tests is essential to track progress and adjust treatment as needed, with target ferritin levels ranging from 50-100 lg/L, as recommended by the 2011 practice guideline 1.

Important Notes

• The 2022 EASL clinical practice guidelines on haemochromatosis 1 provide the most recent and highest quality evidence, superseding previous guidelines and studies, such as the 2011 practice guideline by the American Association for the Study of Liver Diseases 1 and the 2011 study on the diagnosis and management of hemochromatosis 1.
• Untreated high ferritin can lead to organ damage, and common causes include inflammation, liver disease, metabolic syndrome, and genetic disorders, emphasizing the need for prompt medical evaluation and treatment.

From the FDA Drug Label

Monitor serum ferritin concentration every two to three months to assess the effect of deferiprone on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting deferiprone therapy until serum ferritin rises above 500 mcg/L.

The implications of elevated ferritin levels are not explicitly stated in the drug label. However, the label does provide guidance on monitoring ferritin levels to assess the effect of deferiprone on body iron stores.

• Elevated ferritin levels are not directly addressed in the label.
• The label discusses monitoring serum ferritin concentration every two to three months.
• It provides guidance on temporarily interrupting deferiprone therapy if serum ferritin is consistently below 500 mcg/L, but does not discuss the implications of elevated levels 2 2.

From the Research

Implications of Elevated Ferritin Levels

Elevated ferritin levels can have various implications, including:

• Inflammatory conditions such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3
• Malignancy, which is the most frequent condition associated with elevated ferritin levels 3
• Iron-overload syndromes, which are the second most common condition associated with elevated ferritin levels 3
• Anemia of chronic inflammation 3
• Infections, such as SARS-CoV-2 infection 4
• Chronic liver disease, which can cause hyperferritinemia 5, 6
• Rheumatic conditions, such as adult-onset Still's disease or hemophagocytic lymphohistiocytosis 5, 6
• Kidney failure, which can cause hyperferritinemia 5

Diagnostic Approach

When evaluating a patient with elevated serum ferritin levels, the following steps can be taken:

• Exclude hereditary hemochromatosis by performing HFE genetic testing 5, 7
• Investigate the presence of iron overload by measuring transferrin-iron saturation and performing magnetic resonance imaging or liver biopsy 5
• Identify potential causes of hyperferritinemia, such as chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions 5, 6, 7
• Refer the patient to a specialist, such as a gastroenterologist, haematologist, or physician with an interest in iron overload, if the cause of elevated serum ferritin is unclear or if serum ferritin is >1000 µg/L 7

Prognostic Implications

Elevated ferritin levels can have prognostic implications, including:

• Increased mortality risk, particularly at ferritin levels >100 ng/mL 4
• Association with disease severity and outcomes, such as in SARS-CoV-2 infection 4
• Potential benefit of lowering serum ferritin levels to reduce cardiovascular mortality risk, with optimal levels suggested to be between 20-100 ng/mL 4