Evaluation of iron overload

The effective management of iron overload requires frequent evaluation of body iron stores. Measurement of serum ferritin, although easy to perform, gives results that are too variable for the accurate prediction of total body iron. Determination of the liver iron concentration is still regarded as the best predictor of total body iron, but the procedure is invasive and has risks. Quantitative, non-invasive methods for measuring body iron are needed that are safe, accurate and readily available. At present, biomagnetic susceptometry [superconducting quantum interference device (SQUID)] is regarded as the most accurate non-invasive method for measuring liver iron, but its clinical availability is restricted. Magnetic resonance imaging (MRI) is widely available and, in principle, allows the evaluation of tissue iron in all organs that may be affected by iron overload. To date, only MRI methods for estimation of liver iron have been calibrated with tissue biopsies. Although the available methods may be improved further, clinically useful liver iron estimates can be achieved at present. Iron overload is caused by increased intestinal absorption or by parenteral iron administration as blood transfusions. Because iron excretion in humans is limited, iron accumulation from blood transfusions is predictable, providing 200–250 mg iron from each unit of blood. In contrast, iron loading caused by gastrointestinal iron absorption may be difficult to predict, and may even vary from patient to patient (Pippard, 1990). Increased intestinal absorption is caused either by augmented erythropoiesis, hypoxia (Raja et al, 1986), or by the presence of variant genes causing hereditary haemochromatosis (HH), as for example the HFE-variant (Feder et al, 1996). In the so-called iron-loading anaemias intestinal absorption may also be severely increased. In b-thalassaemia intermedia iron absorption can be up to 5–10 times normal (Pippard & Weatherall, 1984), because of an expanded, dyserythropoietic, ineffective erythropoiesis (Pippard & Weatherall, 1984; Pootrakul et al, 1988). In b-thalassaemia major hypertransfusion reduces the gastrointestinal iron absorption to 1–4 mg/d by decreasing hypoxia and the expansion of erythropoiesis (Pippard & Weatherall, 1984). Whereas excess iron caused by intestinal absorption is directed to parenchymal tissue and may cause organ damage, transfusional iron is primarily deposited in the reticuloendothelial macrophage system (RES), and is regarded as relatively harmless (Jacobs, 1977). However, iron-induced organ damage has also been reported in patients without expanded erythropoiesis, as in adult patients receiving blood transfusions for a variety of refractory, mainly hypoplastic anaemias (Schafer et al, 1981). Thus, absence of erythroid expansion is not a barrier to the redistribution of iron to parenchymal cells. The factors influencing this redistribution from the RES to parenchymal cells are not known in detail, and therefore, the associated risk of organ damage is poorly predictable. This circumstance highlights the need for a reliable estimate of the body iron content and its distribution for practical management of iron overload. Reliable measures of body iron content are especially needed in blood transfusiondependent anaemia patients on iron chelation, to maintain a balance between the chelator’s effectiveness and its toxicity, and owing to problems of compliance with iron chelation treatment (desferrioxamine) that arise frequently in the management of patients with thalassaemia (Olivieri & Brittenham, 1997). The iron status of patients with transfusional iron overload can be studied by several methods, none of which are completely satisfactory. The use of two or more indices of iron status will usually be needed to define the amount of iron and its distribution in different organs (Worwood, 1997). In general, two types of methods may be differentiated: the direct methods, based on the detection of iron within the tissue, performed either by biopsy or non-invasive methods, and the indirect tools, for example the serum ferritin concentration or iron saturation of serum transferrin. This article focuses primarily on the quantitative assessment of transfusional iron overload, but many of the conclusions may also be applied to other disorders with an increased body iron burden, e.g. HH.