Iron and Transferrin Metabolism

Iron, Transferrin & Alternative Measurements

• Iron absorption is a process occurring in the duodenum and proximal jejunum
• Iron must be in the ferrous state (Fe2+) or bound to a protein like haem to be absorbed
• The acidic environment in the proximal duodenum allows the enzyme cytochrome B (Dcytb) to convert insoluble Fe3+ to absorbable Fe2+
• Iron is absorbed by the enterocyte via DMT1, stored as ferritin, or exported into the plasma by ferroportin
• Upon exit, Fe2+ is oxidised by hephaestin or ceruloplasmin, binding to apotransferrin to form holotransferrin
• Holotransferrin is internalised by target cells, and Fe3+ dissociates and is reduced by STEAP3
• Fe2+ is incorporated into protoporphyrin IX by ferrochelatase

Transferrin Cycle

• Apotransferrin (iron-free transferrin) is in the plasma, and binds Fe3+ to form holotransferrin
• Holotransferrin delivers iron to cells
• Transferrin receptors on cell membranes bind onto holotransferrin
• H+ ions lead to iron release into the cell via a H+ ATPase
• Iron is then incorporated into protoporphyrin

Key Measurements

• Serum Iron: Measures Fe3+ bound to transferrin, not a valuable measurement by itself. Free iron is not measured and so doesn't indicate bioavailability. Subject to daily variation but is often low in iron deficiency. Used for calculating Transferrin Saturation.
• Transferrin Saturation (TSAT): The ratio of serum iron to transferrin. Represents proportion of transferrin binding sites occupied by iron.
• Diurnal fluctuations can be significant. Malnutrition and chronic disease decrease transferrin synthesis, while TSAT <16% suggest anaemia. TSAT increases in inflammation if iron levels are constant. This can be useful measurement for equivocal Ferritin levels due to inflammation.

Other Parameters (not recommended)

• Total Iron Binding Capacity (TIBC): The maximum amount of iron that can bind to transferrin (increases when iron is deficient). Derived from transferrin levels
• Unsaturated Iron-Binding Capacity (UIBC): The concentration of free sites on transferrin
• Soluble Transferrin Receptor: Membrane-bound transferrin receptor levels increase in iron deficiency. Released into plasma. Raised levels may indicate advanced iron deficiency.
• Zinc Protoporphyrin: Outdated test.
• Hepcidin: Decreased in iron deficiency, increased in inflammation. Expensive test, no advantages over alternatives.

Summary

• Iron is not recommended as a standalone measure to assess iron deficiency
• Transferrin delivers iron to tissues, is a useful measure of iron availability when with other markers (like ferritin or FBC/reticulocyte parameters).
• Don't substitute Transferrin Saturation for other transferrin-based measurements
• Current guidelines do not recommend extensive tests due to limited clinical value.