What is the purpose and interpretation of a transferrin test in evaluating iron deficiency or overload in a patient?

Transferrin Test: Purpose and Interpretation

Transferrin saturation (TSAT) is a critical diagnostic test that identifies iron-deficient erythropoiesis by measuring the percentage of transferrin binding sites occupied by iron, with values <20% confirming iron deficiency in most clinical contexts and <16% diagnostic in healthy individuals without inflammation. 1, 2

Calculation and Measurement

• TSAT is calculated using the formula: (serum iron / TIBC) × 100, where TIBC represents total iron-binding capacity reflecting available transferrin binding sites 1
• Transferrin can be converted to TIBC using: TIBC (μmol/L) = Transferrin (g/L) × 25.1 1
• Normal TSAT range in adults is 20-50%, with transferrin normally not more than 50% saturated to prevent free iron availability for microbial growth 1

Diagnostic Thresholds for Iron Deficiency

In healthy individuals without inflammation, TSAT <16% confirms absolute iron deficiency with 93% specificity, though sensitivity is only 20%. 1

• In patients with chronic inflammatory conditions (heart failure, CKD, inflammatory bowel disease, cancer), TSAT <20% is the diagnostic threshold 1
• TSAT <20% combined with ferritin 100-300 ng/mL confirms functional iron deficiency despite seemingly "normal" ferritin levels 1
• TSAT <30% may help diagnose iron deficiency when ferritin is equivocal, though therapeutic response to oral iron or bone marrow aspiration remains definitive 3

Interpreting Results in Different Clinical Contexts

Absolute Iron Deficiency

• TSAT <16% with ferritin <30 ng/mL confirms absolute iron deficiency in non-inflammatory states 1, 2
• Low TSAT indicates a high proportion of vacant iron-binding sites on transferrin 2
• TIBC increases when serum iron and stored iron are low, further supporting the diagnosis 2

Functional Iron Deficiency (Chronic Disease States)

• TSAT <20% with ferritin 100-300 ng/mL indicates functional iron deficiency where iron stores are trapped and unavailable for erythropoiesis due to inflammation 1
• In inflammatory states, hepcidin blocks iron absorption and traps iron in storage sites, reflected by low TSAT despite elevated ferritin 1
• TSAT <20% indicates iron-deficient erythropoiesis regardless of ferritin levels, meaning bone marrow lacks sufficient available iron for hemoglobin production 1

Iron Overload

• TSAT >50% suggests iron overload conditions 1
• In iron overload, UIBC may be decreased or near zero as transferrin becomes saturated 2

Critical Factors Affecting TSAT Measurement

TSAT has greater day-to-day variation within individuals than hemoglobin, requiring awareness of confounding factors: 1

• Diurnal variation: TSAT rises in the morning and falls at night 1
• Recent meals: Serum iron increases after each meal, affecting TSAT 1
• Inflammation and infection: Decrease serum iron concentration and affect TSAT 1
• Timing after IV iron: Do not evaluate iron parameters within 4 weeks of total dose iron infusion as circulating iron interferes with assays 1

Clinical Application and Treatment Targets

• Laboratory evaluation following IV iron should include CBC and iron parameters (ferritin, TSAT) 4-8 weeks after the last infusion 1
• Target TSAT ≥20% after iron repletion to ensure adequate iron availability for erythropoiesis 1
• In hemodialysis patients receiving ESAs, maintain TSAT >20%, with targeting 30-50% resulting in lower ESA dose requirements 1
• Use IV iron in heart failure patients (NYHA class II-III) when ferritin <100 ng/mL or 100-300 ng/mL with TSAT <20% to improve functional status and quality of life 1

Common Pitfalls and How to Avoid Them

Relying solely on TSAT without considering ferritin levels leads to missed diagnoses—always interpret both together. 1

• Failing to account for inflammatory status when interpreting TSAT and ferritin causes inaccurate diagnoses: use TSAT <16% threshold in healthy individuals but <20% in inflammatory conditions 1
• Not recognizing functional iron deficiency can occur despite normal or elevated ferritin levels: TSAT <20% with ferritin 100-300 ng/mL requires treatment 1
• In chronic kidney disease, TIBC may be lower than in healthy individuals despite iron deficiency, making interpretation more challenging 1
• TSAT is less sensitive to changes in iron stores than serum ferritin concentration and indicates iron-deficient erythropoiesis rather than iron depletion 1

Superiority Over Hemoglobin Screening Alone

• TSAT detects iron deficiency earlier than hemoglobin screening, which has become increasingly inefficient with less than 50% of children and women with anemia by hemoglobin criteria actually having iron deficiency 1
• The cost of TSAT measurement is justified by preventing misdiagnosis and inappropriate treatment, as diagnostic accuracy is higher than hemoglobin alone 1