What is the relationship between Ferritin, iron stores, and Total Iron-Binding Capacity (TIBC)?

From the Guidelines

Ferritin is the most accurate indicator of iron stores, and its levels should be prioritized when assessing iron status, with a goal ferritin level of 50 ng/mL, regardless of sex at birth, as recommended by the most recent guidelines 1. When evaluating iron status, it is essential to consider ferritin, iron stores, and TIBC (Total Iron Binding Capacity) together, as they provide different information.

• Ferritin reflects the amount of iron stored in the body's tissues, with normal levels ranging from 20-250 ng/mL for men and 10-120 ng/mL for women.
• Iron stores refer to the actual iron reserves in the body, primarily in the liver, spleen, and bone marrow, which ferritin measurements help quantify.
• TIBC measures the blood's capacity to bind iron with transferrin, with normal values ranging from 250-450 μg/dL, and increases in iron deficiency as the body tries to compensate for low iron levels by producing more transferrin. According to the latest expert consensus guidelines 1, laboratory evaluation following IV iron should include a CBC and iron parameters (ferritin, percent transferrin saturation (TSAT) calculated by dividing the serum iron by the total iron binding capacity (TIBC)) 4 to 8 weeks after the last infusion.
• The soluble transferrin receptor (sTfR) has been shown to be more sensitive in patients with inflammatory conditions where the ferritin (but not the TSAT) is unreliable for evaluation of ID and IDA 1.
• Reticulocyte Hb content is a direct assessment of the functional availability of iron to the erythropoietic tissue and can be measured by two methods, the reticulocyte hemoglobin content (CHr) or reticulocyte hemoglobin equivalent (RET-He) 1. It is crucial to note that 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 to diagnose and treat ID even in the absence of anemia 1.

From the FDA Drug Label

Following intravenous administration, Venofer is dissociated into iron and sucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with iron sucrose containing 100 mg of iron, three times weekly for three weeks, significant increases in serum iron and serum ferritin and significant decreases in total iron binding capacity occurred four weeks from the initiation of iron sucrose treatment.

The relationship between ferritin, iron stores, and TIBC (Total Iron Binding Capacity) is as follows:

• Ferritin is a protein that stores iron in the body.
• Iron stores refer to the amount of iron available in the body for use by the body's tissues.
• TIBC measures all proteins available for binding mobile iron, including both transferrin and other proteins. When iron stores are low, ferritin levels decrease, and TIBC increases, indicating that there is more transferrin available to bind iron. Conversely, when iron stores are high, ferritin levels increase, and TIBC decreases, indicating that there is less transferrin available to bind iron. In the context of the provided studies, administration of iron sucrose resulted in significant increases in serum iron and serum ferritin, and significant decreases in TIBC, indicating an increase in iron stores 2.

From the Research

Comparison of Ferritin, Iron Stores, and TIBC

• Ferritin is considered the investigation of choice in iron deficiency, but many laboratories also offer iron and TIBC/transferrin measurements 3.
• Transferrin or TIBC measurement outperforms iron and saturation in predicting iron deficiency, with a mean area under ROC curves of 0.94 compared to 0.77 for iron and 0.87 for saturation 3.
• Low baseline serum TIBC is associated with iron deficiency, protein-energy wasting, inflammation, poor quality of life, and mortality, and its decline over time is independently associated with increased death risk 4.

Diagnostic Accuracy of Serum Iron and TIBC

• Serum iron and TIBC have limited diagnostic accuracy in detecting iron deficiency, with sensitivity and specificity of 63.5% and 38.6% for serum iron, and 64.5% and 42.8% for TIBC, respectively 5.
• Ferritin shows poor correlation with iron, TIBC, and transferrin saturation, and is considered a more reliable indicator of iron status 5, 6.

Serum Ferritin as an Indicator of Iron Status

• Serum ferritin concentrations are the most commonly used indicator for determining iron deficiency, but there is considerable variation in ferritin cutoffs recommended by different expert groups 6.
• The commonly recommended ferritin cutoff of <15 μg/L is specific but not sensitive, and future studies are needed to define the appropriate ferritin cutoffs and compare this indicator with other established and emerging iron indexes 6.