Liver iron homeostasis

One of the most notable features of this inherited defect of iron homeostasis (Chapter 9) is the ability of individuals to accumulate large amounts of iron over many years and yet show no apparent adverse effects. This may in part be due to the ability of tissues, notably the liver, to increase their iron stores gradually over a long period of time, successfully sequestrating excess iron into ferritin and, predominantly, haemosiderin. However with time the excessive deposition of iron will cause a variety of toxic effects including diabetes and arthritis which are caused by deposition of iron in these tissues. Removal of this iron by venesection can often reduce these iron-induced symptoms. 

Finally, the hairpin-like peptides, hepcidins, isolated from human urine and liver [120], and from the gill of hybrid striped bass [121], are more complex, with eight cysteine residues forming four disulphide bridges. They form an unusual distorted P-sheet. Interestingly, besides their antimicrobial activity, hepcidins are the principal hormonal-regulators of iron homeostasis in humans [124]. 

While the bulk of literature on iron chelation concerns P-thalassemia, in patients with thalassemia intermedia abnormal regulation of iron homeostasis may lead to iron overload, even in the absence of transfusions. In an open study in 11 patients with thalassemia intermedia, deferasirox 10-20 mg/kg/day for 24 months was associated with significant reductions in liver iron content and serum ferritin concentrations in the first 12 months, which continued during the second part of the study no serious adverse events were recorded [9 ]. 

Wilson s disease is a pathological accumulation of copper in tissue which is later released into the bloodstream, leading to anaemia, and final accumulation of copper in liver and brain. It is the result of a mutation in the Wilson s disease gene in chromosome 13 which ordinarily codes for a cation transporting ATPase so that copper can be incorporated into ceruloplasmin prior to excretion. Also known as ferroxi-dase, in acknowledgement of its primary function as an oxidoreductase responsible for electron transfer, this enzyme contains iron and, more importantly, six copper atoms. It accounts for the transport of 90% of copper in the plasma so any impairment in its production or efficacy has a major impact on copper homeostasis. The greatly reduced concentration of ceruloplasmin in the blood of Wilson s disease sufferers correlates with their inability to metabolize copper effectively. It leads to chronic liver disease, for which the only real cure is a liver transplant,... 

Copper, zinc and iron are essential cationic trace elements. They are transferred and utilized as inorganic ions and transported by specific carriers across membranes. They also require carriers to maintain their solubility within the intra- and extracellular compartments. Their homeostasis is controlled primarily by the gastrointestinal tract and the liver. Each of these elements has its own specific function and metabolic control [1]. The diagnosis of deficiencies or excesses of copper and zinc can be difficult, since no single test reliably indicates whether an individual is at risk. The clinical state, homeostatic mechanisms, metabolism and tissue distribution all have to be considered for the interpretation of data [1]. 

---