What is the significance of low Total Iron Binding Capacity (TIBC) with normal genetic markers?

From the Guidelines

Low TIBC with normal genetic markers suggests iron overload that is not due to hereditary hemochromatosis, and the most recent guidelines recommend consulting with a hematologist for proper evaluation and treatment. This condition occurs when the body's ability to bind and transport iron is reduced, while excess iron accumulates in tissues. Common causes include chronic liver disease, chronic inflammation, malnutrition, or acquired iron overload from multiple blood transfusions.

Key Considerations

• The evaluation should include additional blood tests such as serum ferritin, transferrin saturation, and complete blood count, as recommended by the EASL clinical practice guidelines on haemochromatosis 1.
• If iron overload is confirmed, treatment may involve therapeutic phlebotomy (blood removal) to reduce iron levels, dietary modifications to limit iron intake, and addressing any underlying conditions.
• The frequency of phlebotomy depends on the severity of iron overload, typically starting weekly until iron levels normalize, then transitioning to maintenance therapy every few months.

Diagnostic Approach

• The initial approach to diagnosis is by indirect markers of iron stores, namely TS or unsaturated iron-binding capacity and serum ferritin, as stated in the diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases 1.
• Serum ferritin has less biological variability than TS, but it has a significant false positive rate because of elevations related to inflammation.
• A recent study suggests that a serum ferritin >250 lg/L in men and >200 lg/L in women was positive in 77% and 56%, respectively, of C282Y homozygotes, as seen in the HEIRS study 1.

Treatment and Management

• The goal of treatment is to reduce iron levels and prevent complications such as liver damage, heart problems, and diabetes.
• The expert consensus guidelines: intravenous iron uses, formulations, administration, and management of reactions recommend laboratory evaluation following IV iron, including a CBC and iron parameters, 4 to 8 weeks after the last infusion 1.
• The frequency with which lab monitoring is required post-IV iron infusion is dependent on the cause of the ID, and those with recurrent blood loss will require more frequent and aggressive laboratory monitoring.

From the Research

Low TIBC and Normal Genetic Markers

• A low Total Iron Binding Capacity (TIBC) can be an indicator of iron overload, as seen in studies such as 2, where abnormal TIBC saturation was found in 1.7% of samples, with 11.5% of these cases being due to parenchymal iron overload.
• However, the relationship between TIBC and iron overload is not always straightforward, as noted in 3, where the correlation between serum ferritin levels and total iron burden was found to be greater in patients homozygous for the C282Y mutation than in those who were not.
• In terms of genetic markers, normal results do not necessarily rule out iron overload or other conditions, as genetic testing may not detect all cases of iron overload or other diseases, as seen in 4, where serum ferritin levels showed a clear relationship to liver iron concentration (LIC) for all disease groups.
• The use of TIBC and other markers, such as transferrin saturation and labile plasma iron, can be useful in assessing iron overload, especially in patients with underlying anemias, as seen in 4, where trends were evaluated between LIC, transferrin saturation, and labile plasma iron in patients with thalassemia major, myelodysplastic syndromes, and sickle-cell disease.
• It is also important to note that TIBC can be affected by various factors, including inflammation and liver disease, which can lead to false positives or false negatives, as seen in 5, where transferrin or TIBC measurement outperformed iron measurement and saturation index in predicting iron deficiency.