What is the significance of elevated Ferritin (Ferritin) levels with normal Iron and Total Iron-Binding Capacity (TIBC)?

From the Guidelines

High ferritin levels with normal iron and TIBC typically indicate a condition called iron overload syndrome or secondary hyperferritinemia, rather than true iron excess. This pattern suggests inflammation, liver disease, alcohol consumption, metabolic syndrome, or certain genetic conditions like hemochromatosis in early stages. The recommended approach is to first identify the underlying cause through additional testing, including liver function tests, inflammatory markers (CRP, ESR), hemoglobin A1C, and possibly genetic testing for hemochromatosis (HFE gene mutations) 1. No specific medication is typically prescribed initially, as treatment depends on the underlying cause. For inflammation-related elevation, addressing the inflammatory condition is key. For metabolic syndrome, lifestyle modifications including weight loss, exercise, and reduced alcohol consumption often help reduce ferritin levels. If hemochromatosis is confirmed, therapeutic phlebotomy may be necessary 1. It's essential to monitor ferritin levels over time, as persistently high levels without treatment can lead to organ damage, particularly in the liver. The disconnect between ferritin and other iron markers occurs because ferritin is an acute phase reactant that increases during inflammation independent of actual iron stores. Some key points to consider in the diagnosis and management of haemochromatosis include:

• Individuals with clinical and biochemical signs of haemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained 1.
• Patients with increased liver iron evident on liver biopsy or MRI should be clinically assessed and biochemically tested for haemochromatosis (serum ferritin and transferrin saturation) 1.
• Adult individuals with a positive family history of first-degree relatives with haemochromatosis should be genetically tested for haemochromatosis after informed consent for genetic testing has been obtained 1. The most recent guidelines from 2022 suggest that genotyping for p.C282Y in HFE should be carried out in individuals of European origin with biochemical evidence of iron overload, with or without clinical signs or symptoms suggestive of haemochromatosis 1. In patients with an unclear cause of hyperferritinemia, biochemical iron overload, or positive liver iron staining, MRI should be used to quantify hepatic iron concentrations and to assess extrahepatic organ involvement 1. Cardiac MRI can be performed in patients with haemochromatosis and signs of heart disease, and in juvenile forms of haemochromatosis 1. MRI is helpful for detection, non-invasive quantification of iron, and to study the distribution of iron in the liver, spleen, pancreas, heart, and brain in patients with suspicion or diagnosis of iron overload disorder 1.

From the Research

High Ferritin with Normal Iron and TIBC

• High ferritin levels with normal iron and Total Iron Binding Capacity (TIBC) can be indicative of an inflammatory condition, as ferritin is an acute phase reactant that increases in response to inflammation 2.
• A study published in 2020 found that patients with chronic alcoholic liver disease had higher serum ferritin levels, but lower transferrin and TIBC values, compared to controls 3.
• Another study published in 2021 suggested that optimal serum ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng/mL, and that levels above 194 ng/mL are associated with all-cause mortality 4.
• It is also important to note that ferritin levels can be affected by inflammation, and adjusting for inflammation can impact the interpretation of ferritin levels 5.
• In terms of diagnostic accuracy, a study published in 2016 found that serum iron and TIBC are not reliable markers for iron deficiency, and that ferritin is a more accurate indicator of iron status 6.

Possible Causes

• Inflammation or infection, as ferritin is an acute phase reactant that increases in response to inflammation 2.
• Liver disease, such as chronic alcoholic liver disease, which can cause elevated ferritin levels 3.
• Other conditions that can cause elevated ferritin levels, such as cancer or autoimmune disorders.

Clinical Implications

• High ferritin levels with normal iron and TIBC should be interpreted with caution, and in the context of the patient's overall clinical presentation 4.
• Inflammatory conditions should be considered as a possible cause of elevated ferritin levels, and further testing may be necessary to determine the underlying cause 2.
• Ferritin levels should be adjusted for inflammation when interpreting iron status, particularly in populations with high prevalence of inflammation 5.