Measuring iron toxicity

In the early course of iron overload, numerous homeostatic mechanisms prevent damage from accumulating iron. These include increased ferritin production needed to sequester the labile iron, and increment in individual antioxidants and/ or antioxidant enzymes to protect against radical damage promoted by iron. However, these mechanisms might fail as more iron accumulates.

Measurement of iron toxicity is crucial for diagnosis and management of patients with iron overload from such disorders as hereditary haemochromatosis, thalassemia major, sickle cell disease, aplastic anaemia and myelodysplasia. Body iron can be measured by several parameters including serum ferritin concentration and transferrin saturation. The normal range of serum ferritin is 18-300 ng/ml. A decreased value of serum ferritin is associated with iron deficiency, while an increased value may indicate an increase of total body iron. However, it is also elevated in liver diseases, inflammatory conditions and malignant neoplasm. Another simple measure but insufficiently indicating total body iron (Beaton et al. 1989; Cook et al. 1976) is transferrin iron saturation, which is calculated as the concentration of serum iron divided by TIBC. Estimation of total body iron using this measure is less conclusive owing to high individual variation and strong influence of inflammation. The normal range of transferrin saturation is 15-55 per cent and the value increases in haemochromatosis. Furthermore, when moderate to severe iron overload is suspected, liver biopsy is necessary to be performed.

Magnetic resonance imaging (MRI) potentially provides the best available technique for examining the three-dimensional distribution of excess iron in the body; however, measurements and techniques must be calibrated for each individual machine. Biomagnetic susceptometry such as superconducting quantum interference device (SQUID) susceptometry (Brittenham et al. 1982) or, potentially, magnetic resonance susceptometry (Brittenham et al. 2001) provides the only noninvasive method to measure tissue iron stores that has been calibrated, validated and used in clinical studies, but the complexity, cost and technical demands of the liquid-helium-cooled superconducting instruments required have restricted clinical access to the method.

As previously mentioned, iron in the circulation is normally attached to transferrin. However in the case of iron-overload, NTBI is present (de Valk et al. 2000). Some species of NTBI may be safely bound to endogenous chelators; other species, however, may be catalytically active and capable of generating oxygen radicals, which is the major source of iron toxicity. This active NTBI is termed labile plasma iron (LPI) (Esposito et al. 2003). This iron species can also accumulate inside the cell and is termed labile iron pool (LIP). LIP may become catalytically active and is crucial for regulating the expression of many iron-related proteins. The findings mentioned above stress the need to identify the potentially toxic species of iron in both plasma and cells. Different means for small- and large-scale estimation of NTBI, LPI and LIP should be available with reliable and inexpensive methods to detect subjects at risk. Providentially, one of them is being developed (Breuer & Cabantchik 2001).

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