What is the test for transferrin saturation in an adult patient with elevated ferritin levels?

Transferrin Saturation Testing

Transferrin saturation is calculated as the ratio of serum iron concentration divided by total iron-binding capacity (TIBC), expressed as a percentage. 1

How the Test is Performed

The transferrin saturation test requires measurement of two components 1:

• Serum iron: Measured using a colorimetric reaction with a chromagen (such as ferrozine) that forms a color complex with iron 1
• TIBC or transferrin: Can be measured either directly as transferrin concentration or calculated as total iron-binding capacity 1

The calculation is: Transferrin saturation (%) = (Serum iron ÷ TIBC) × 100 1

Alternatively, when using direct transferrin measurement: (Serum iron mg/dL ÷ Transferrin mg/dL) × 71.24 1

Reference Ranges and Interpretation

Normal Values

• Normal transferrin saturation: 20-50% 1
• Values >45% in females or >50% in males with elevated ferritin warrant further evaluation for hemochromatosis 1

Clinical Thresholds for Iron Overload Evaluation

According to EASL guidelines, genetic testing for hemochromatosis should be considered in individuals of European origin with 1:

• Females: Transferrin saturation >45% AND serum ferritin >200 μg/L
• Males: Transferrin saturation >50% AND serum ferritin >300 μg/L

Important Pre-Analytical Considerations

Timing and Sample Collection

Fasting samples are strongly preferred because 2:

• Serum iron increases after meals, affecting accuracy
• Diurnal variation causes iron levels to be higher in morning and lower at night
• These fluctuations directly impact transferrin saturation calculations

Factors That Affect Results

Inflammation significantly impacts interpretation 1:

• All iron parameters including transferrin saturation are influenced by inflammatory states
• Ferritin acts as an acute-phase reactant and can be falsely elevated, potentially masking true iron deficiency
• In inflammatory conditions, transferrin saturation <20% with ferritin >300 ng/mL creates diagnostic confusion 3

Physiological factors that can alter TIBC (and thus transferrin saturation) 2:

• Oral contraceptive use raises TIBC readings
• Pregnancy elevates TIBC
• Chronic infection, malignancies, liver disease, nephrotic syndrome, and malnutrition lower TIBC

Clinical Application in Your Patient

For an adult patient with elevated ferritin, transferrin saturation is essential for distinguishing iron overload from inflammatory hyperferritinemia. 1

The diagnostic approach should include 1:

• Transferrin saturation (calculated from serum iron + TIBC or transferrin)
• Serum ferritin
• Complete blood count with reticulocytes to exclude anemia and red cell disorders

If transferrin saturation is elevated (>45-50%) along with high ferritin, proceed with HFE genetic testing for hemochromatosis. 1 If transferrin saturation is normal or low despite elevated ferritin, this suggests inflammatory hyperferritinemia rather than true iron overload. 1

Common Pitfalls to Avoid

• Do not rely on a single measurement: Persistently elevated transferrin saturation on repeat testing is more clinically significant than an isolated elevated value 1
• Do not order transferrin saturation in isolation: It must be interpreted alongside ferritin and clinical context 1
• Do not ignore sample timing: Non-fasting or afternoon samples may give misleadingly low results 2
• In iron-saturated plasma, standard colorimetric methods may overestimate serum iron due to nontransferrin-bound iron, leading to falsely elevated transferrin saturation 4