Iron Overload Haemochromatosis

Iron overload is known to be toxic and potentially fatal. The major pathological effects of hepatic iron overload are fibrosis and cirrhosis, and hepatocellular carcinoma (Bonkovsky, 1991). The role of free radicals in the pathology of hepatic iron overload has been the subject of a detailed review recently (Bacon and Britton, 1990). 

There is very little data on ROM production in haemochromatosis in humans. Increases in thiobarbituric acid reactants in plasma were associated with increases in non-transferrin-bound free iron. However, other indices of lipid peroxidation were no different from controls (Peters eta/., 1985). There are no studies of in vivo lipid peroxidation in humans. It is also of interest that levels of antioxidant defences in liver biopsies from patients with haemochromatosis are normal (Selden et /., 1980). 

Isolated hepatocytes incubated with ionic iron rapidly undergo lipid peroxidation. Some studies have not shown a consequent decrease in viability (as indicated by uptake of trypan blue or release of enzymes). This is probably a result of short incubation times, as changes in viability lag behind increases in lipid peroxidation, and may not occur for more than 2 h after lipid peroxidation begins (Bacon and Britton, 1990). Recent studies have shown strong correlations between increased lipid peroxidation [production of thiobarbituric acid (TBA) reactants] and loss of cell viability (trypan blue staining) (Bacon and Britton, 1989). The significance of the lag between lipid peroxidation and decreases in cell viability is as yet uncertain. 

The effects of ROMs on liver have already been discussed. That iron is involved in such effects is indicated by the prevention of cell damage by t-butyl hydroperoxide by 

Treatment with iron chelators and a-tocopherol protect against lipid p eroxidation and hepatocellular injury in iron-overloaded rats (Sharma etal., 1990). When hepatocytes are isolated from rats, which have been pretreated with a-tocopherol, there is a significant reduction in iron-induced lipid peroxidation and improvement in cell viability in vitro (Poli et al., 1985). Similar effects were seen when hepatocytes were incubated with iron chelators (Bacon and Britton, 1990). Treatment of moderately, but not heavily, iron-loaded rats with desferrioxamine in vivo inhibits the pro-oxidant activity of hepatic ultrafiltrates (Britton et al., 1990b). 

---

Retinopathy of prematurity Dietary iron overload (red wine, beer brewed in iron pots) Idiopathic haemochromatosis... 

Transferrin receptor-2 Iron transport into hepatocytes Hereditary haemochromatosis (Camaschella et ah, 2000) increased iron absorption parenchymal iron overload... 

Haemochromatosis associated with insulin resistance Secondary iron overload, with increased iron absorption... 

The aim of treatment of iron overload is to remove all potentially toxic iron from the body. In hereditary haemochromatosis this can be achieved by weekly phlebotomies of 500 ml until the desired serum ferritin concentration (mostly <50 gg/1) or a normal transferrin iron saturation is reached (Brissot et ah, 2000). 

Among the genetic diseases that cause iron overload, rank several entities that were discussed in the previous section, such as haemochromatosis, thalassaemias and... 

Clearly, in the normal individual, iron levels are under extremely tight control and there is little opportunity for iron-catalysed free radical generating reactions to occur. However, there are situations when the iron status can change, either locally, as in ischaemic tissue, or systematically, as with idiopathic haemochromatosis or transfusion-induced iron overload. In such circumstances, abnormal levels of iron can induce toxic symptoms. 

There are several inherited diseases which are associated with the gradual excess accumulation of iron via the gut. Hereditary haemochromatosis is a relatively rare condition in which iron absorption is increased through an unidentified mechanism. This condition usually presents in the fourth or fifth decade of life with the secondary effects of iron overload such as heart failure, liver cirrhosis or sugar diabetes. As the production of red cells is unaffected, the excess iron can be removed slowly by venesecting a unit of blood every week for up to two years. However, in the acute situation, iron chelation may be used to remove toxic low-molecular-weight iron until sufficient negative iron balance has been obtained by venesection. 

Hereditary haemochromatosis Usuahy with family history of cirrhosis, skin hyperpigmentation, diabetes melhtus, pseudo-gout and/or cardiomyopathy, all due to iron overload. 

Transferrin A high-affinity serum iron transport protein Transferrin is synthesised in the liver and its levels are diminished in cirrhosis Iron overload i.e haemochromatosis/haemosiderosis may lead to cirrhosis. A transferrin saturation >55% in males (and postmenopausal women) or >50% in premenopausal women requires investigation to exclude a diagnosis of hereditary haemochromatosis... 

Hiibscher, S.G. Iron overload, inflammation and fibrosis in genetic haemochromatosis. (editorial) J. Hepatol. 2003 38 521 -525... 

Macfarlane, J.D., Vreugdenhil, G.R., Doornbos, J., van der Voet, G.B. Idiopathic haemochromatosis magnetic resonance signal intensity ratios permit non-invasive diagnosis of low levels of iron overload. Netherl. J. Med. 1995 47 49-53... 

McCune C, Al-Jader L, May A, Hayes S, Jackson H, Worwood M. Hereditary haemochromatosis Only 1% of adult HFEC282Y homozygotes in South Wales have a cMnical diagnosis of iron overload. Hum Genet 2002 111 538-43. 

As has already been mentioned, therapies designed to remove a contaminating metal often have a side effect of essential ion removal. However, this generally unwanted feature can be turned to good advantage in cases of severe overload of an essential metal, for example, in the iron overload of haemochromatosis. 

McNamaea L, MacPhail AP, Goedeuk VR, Has-STEDT SJ and Rouault T (1998) Is there a link between African iron overload and the described mutations of the hereditary haemochromatosis gene Br J Haematol 102 1176-1178. 

Walker, R.J. Williams, R. "Haemochromatosis and Iron Overload" in "Iron in Biochemistry and Medicine", Jacobs, A Worwood, M. Eds., Academic Press, New York, 1974. 

Excessive iron intake by diet or dietary supplements (> 1000 mg/day) and particularly in the event of a disorder of iron resorption regulation may cause accumulation of haemosiderin in the hver and other unwanted effects. This phenomenon is known as haemosiderosis and can lead to severe hver damage. The disorder of iron resorption known as hereditary haemochromatosis is a genetic disease. Transfusional iron overload can be the result of repeated blood transfusion. 

In haemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 ng/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was five folds greater in probands with serum levels of ferritin greater than 1000 ng/L... 

Fluxes of iron from the plasma towards BM and other tissues can be quantified by ferrokinetic studies, using 59Fe and sophisticated computer models (Ricketts et ah, 1975 Ricketts and Cavill, 1978 Barosi et ah, 1978 Stefanelli et ah, 1980). Plasma iron turnover (PIT), erythroid iron turnover (EIT), non-erythroid iron turnover (NEIT), marrow iron turnover (MIT), and tissue iron turnover (TIT) could be calculated in many disorders of iron metabolism and in all kinds of anaemias. Iron is rapidly cleared from the plasma in iron deficiency and in haemolytic anaemias. If more iron is needed for erythropoiesis, more transferrin receptors (TfR) are expressed on erythroblasts, resulting in an increased flux of iron from intestinal mucosal cells towards the plasma. In haemolytic anaemias MPS, and subsequently hepatocytes, are overloaded. In hereditary haemochromatosis too much iron is absorbed by an intrinsic defect of gut mucosal cells. As this iron is not needed for erythropoiesis,... 

---