Transferrin saturation

Transferrin saturation (TSAT) is the percentage of iron-binding sites on transferrin — the main iron-transport protein in blood — occupied by iron, calculated as (serum iron ÷ total iron-binding capacity) × 100. Physiologically, transferrin is 20–35% saturated, leaving reserve capacity to buffer free iron; the normal range is approximately 15–50% in adults, with values below 20% typical of iron deficiency. When TSAT exceeds 45–50%, non-transferrin-bound iron (NTBI) — a redox-active labile pool — appears in plasma and accumulates in hepatocytes, cardiomyocytes, and endocrine tissue, driving Fenton-reaction hydroxyl-radical generation, lipid peroxidation, and ferroptosis. Chronically elevated TSAT is associated with greater all-cause mortality. A NHANES I follow-up cohort (n = 10,714; Mainous et al., 2004) found HR 1.60 (95% CI 1.17–2.21) for TSAT > 55%; a NHANES II analysis by the same group showed elevated TSAT combined with high dietary iron roughly tripled mortality risk (HR 2.90; 95% CI 1.39–6.04). A fasting TSAT > 45% is the standard first-line screening threshold for hereditary hemochromatosis (HFE-related, most often C282Y homozygosity); EASL 2022 Clinical Practice Guidelines define iron overload as TSAT > 45% plus ferritin > 200 µg/L in women, or TSAT > 50% plus ferritin > 300 µg/L in men, with HFE genotyping indicated once either criterion is reproducibly exceeded. Because TSAT reflects iron flux rather than total stores, it complements ferritin and can detect preclinical iron excess before organ damage is measurable.