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

Relationship Between Iron, TIBC, and Percent Saturation

Transferrin saturation (TSAT) is calculated as serum iron divided by TIBC and multiplied by 100, representing the proportion of transferrin's iron-binding sites that are occupied by iron—this relationship is fundamental to assessing iron availability for red blood cell production. 1

The Mathematical Relationship

• TSAT (%) = (Serum Iron / TIBC) × 100 2, 1
• TIBC measures the total iron-binding capacity within serum and reflects the availability of iron-binding sites on transferrin, the primary iron transport protein 1, 3
• Transferrin contains two binding sites for transporting iron from storage sites to erythroid progenitor cells 2
• A TSAT of 50% indicates that half of the available binding sites are occupied by iron 2

Clinical Interpretation of the Relationship

Normal Values

• Normal TSAT range in adults is 20-50% 1
• When iron levels are adequate and TIBC is normal, TSAT falls within this physiologic range 1

Iron Deficiency Pattern

• Low TSAT (<20%) with high TIBC indicates iron deficiency—the body produces more transferrin (increasing TIBC) to capture whatever iron is available, but serum iron is low, resulting in many vacant binding sites 1, 3
• TSAT below 16% in healthy individuals without inflammation confirms absolute iron deficiency 1
• In chronic inflammatory conditions, TSAT below 20% is the diagnostic threshold 1

Iron Overload Pattern

• High TSAT (>50%) indicates iron overload—excessive iron saturates most transferrin binding sites 1
• This pattern suggests conditions like hemochromatosis where iron accumulates beyond physiologic needs 1

Absolute vs. Functional Iron Deficiency

This distinction is critical for understanding TSAT interpretation, particularly in patients receiving erythropoiesis-stimulating agents:

Absolute Iron Deficiency

• Depleted iron stores with impaired delivery to bone marrow 2
• Characterized by serum ferritin <100 ng/mL and TSAT <20% in chronic kidney disease patients 2
• In healthy subjects, ferritin <12 ng/mL and TSAT <16% indicate absolute deficiency 2

Functional Iron Deficiency

• Occurs when iron demand exceeds the rate of iron release from stores, despite adequate total body iron 2, 1
• TSAT decreases to deficiency levels (<20%) despite normal or elevated ferritin 2
• Common with pharmacological stimulation of erythropoiesis (e.g., epoetin therapy) where red blood cell production outpaces iron mobilization 2
• Patients may demonstrate increased hemoglobin when IV iron is administered, even though traditional criteria for absolute deficiency are not met 2

Important Clinical Caveats

Factors Affecting Measurements

• Diurnal variation: TSAT rises in the morning and falls at night due to fluctuations in serum iron 1
• Recent meals: Serum iron increases after each meal, artificially elevating TSAT 1
• Inflammation and infection: Decrease serum iron concentration, lowering TSAT even when iron stores are adequate 1
• Day-to-day variation: TSAT has greater within-individual variation than hemoglobin 1

Timing of Laboratory Assessment

• Do not evaluate iron parameters within 4 weeks of total dose iron infusion—circulating iron interferes with the assay 1
• Laboratory evaluation should occur 4-8 weeks after the last iron infusion 1, 3

Special Populations

• In chronic kidney disease patients, TIBC may be lower than in healthy individuals despite iron deficiency, making interpretation more challenging 1
• Malnourished dialysis patients may have decreased TIBC, which erroneously increases the transferrin saturation ratio, potentially masking true iron deficiency 4

Diagnostic Approach

• Always interpret TSAT alongside serum ferritin—relying on TSAT alone leads to missed diagnoses 1
• High TIBC + low iron + low TSAT strongly indicates iron deficiency requiring further evaluation 3
• Consider inflammatory markers (CRP, ESR) to distinguish absolute iron deficiency from anemia of chronic disease 3
• In inflammatory conditions, ferritin up to 100 ng/mL may still indicate iron deficiency despite seemingly elevated levels 1

Practical Measurement Considerations

• TIBC can be measured directly or calculated from transferrin concentration using: TIBC (μmol/L) = Transferrin (g/L) × 25.1 1
• Transferrin measurement outperforms isolated iron measurement and saturation indices in predicting iron deficiency 5
• TSAT is less sensitive to changes in iron stores than serum ferritin concentration 1
• TSAT indicates iron-deficient erythropoiesis rather than iron depletion per se 1