Iron, absorption overload

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

TfR is low in these patients, PIT is normal and most iron is stored in hepatocytes. In patients with hypoplastic anaemias and with transfusion iron overload, the BM cannot utilize iron, resulting in low TfR expression and decreased iron absorption. Quantitative analysis of all iron fluxes, which can be deduced from Figure 9.1, can assist in understanding the clinical expression of mutations of proteins involved in iron transport. 

Transferrin Iron transport in plasma and into cells hpx mice (Huggenvik et al, 1989 Bernstein, 1987 Craven et al, 1987 Goya et al, 1972) Hypotransferinemia (Goya et al., 1972) microcytic anaemia increased iron absorption parenchymal iron overload... 

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

Adaptive Response of Iron Absorption in Iron-overload Diseases... 

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

Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major). 

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. 

The paramount aim of treatment is to reach a negative iron balance. This must be achieved before complications due to the chronic iron overload have their effect on the predisposed organs. The extreme uncontrolled increase in iron absorption is treatable by adjuvant measures, albeit with limited success. 

In rural sub-Saharan Africa, there is a kind of beer which is traditionally brewed in iron vats. The daily iron overload can amount to as much as 200 mg with markedly increased iron absorption (T.H. Bothwell et at, 1965). Such a condition is also observed in South Africa among the black population. Their diet consists of porridge fermented in iron pots with an acid pH value (V.R. Gordeuk et al., 1986). In both conditions, absorption of iron is facilitated by various factors, e. g. protein or vitamin C deficiency, alcohol abuse, acidic diet. It has been suggested that such iron overload is triggered by genetic factors. (437)... 

Iron removal Increased iron and ferritin levels are found in approx. 30% of patients with chronic hepatitis B or C. Several studies have shown that the success rate of interferon therapy is reduced in the presence of elevated liver iron values. This is attributed to the fact that iron overload inhibits not only lymphocyte proliferation, but also the function of killer cells and B cells as well as the production of antibodies. Iron plays a role in the formation of free radicals and the occurrence of dangerous lipid peroxidations, (s. pp 68, 401) Furthermore, iron, like oxygen radicals, promotes fibrogenesis. Iron removal leads to an improvement in laboratory parameters and better response to interferon-a therapy. (217, 243) On the other hand, the iron level is reduced as a result of successful IFN therapy. In the case of a higher serum iron status before the initiation of interferon therapy, venesections at one week intervals should be considered, if necessary until normal laboratory values (iron, ferritin, transferrin saturation) have been restored. During interferon therapy, a low-iron diet is advisable, as is the consumption of 2 x 1 cup of black tea (in the morning and at noon) to reduce iron absorption through chelate formation ( cheap, free of side effects and useful )- (s. p. 625) Silymarin also leads to iron mobilization due to chelate formation. 

Iron-overload disease, or hemochromatosis, may occur as a consequence of an, as yet, undefined genetic defect, or as a secondary effect of another medical disorder, such as thalassemia. In the former condition, primary hemochromatosis, iron accumulates in various tissues because of a lack of control of iron absorption from the gut. In the latter, or secondary hemochromatosis, the accumulation of iron results from the breakdown of red blood cells and the consequent need for frequent blood transfusions, which lead to an increase in the levels of tissue iron. In both cases the predominant store for iron is hemosiderin (147). 

Hereditary Hemochromatosis. Hereditary hemochromatosis is the classical disorder of iron overload. It is due to an inborn error of iron absorption the precise mechanism remains unknown. Approximately 80% of whites of Northern European origin are homozygotes for a common mutation of the HFE gene. This mutation (845 G > A C282Y) is a common polymorphism in Northern Europe. 

The daily recommended dietary allowance for iron is 8 mg in adult males and postmenopausal females, and 18 mg in menstruating females. Children require more iron due to growth-related increases in blood volume, and pregnant women have an increased iron demand brought about by fetal development. However, iron overload does not occur, as only the amount of iron lost per day is absorbed. The amount of iron absorbed from food depends on the body stores, the rate of RBC production, the type of iron provided in the diet, and the presence of any substances that may enhance or inhibit iron absorption. 

The transmembrane transport of iron into eukaryotic cells was not well defined when these studies began. In fact, a eukaryotic iron transporter had not yet been identified. Even within the well-characterized manunalian transferrin-dependent iron transport system, the mechanism of transmembrane iron transport from the endosomal lumen into the cytosol was unknown [6]. It is important to characterize eukaryotic iron transport since disruption of iron homeostasis in humans results in disease. Anemia, due to iron deficiency is a serious health problem [7]. In addition, the common genetic disease hereditary hemochromatosis results, excess iron absorption from the gut which causes iron overload [8]. The excess iron accumulates... 

Model Iron absorption Lymphocytes Gene/mutation Overload... 

Figure 13-1 Free representation of some of the elements known to play a role in iron absorption, iron distribution and iron accumulation. The central circle indicates that in ways that are still not fully imderstood these various elements must be integrated into an overall protective function from tissue iron overload toxicity. GH, growth hormone CD8T, subpopulation of T lymphocytes CD8CD28, subpopulation of TCD8+ lymphocytes HFE, non-classical MHC class I gene C282Y and H63D, HFE mutations TfR, transferrin receptor pS61ck, kinase of importance in T cell activation, whose activity is diminished in CD8-I- cells in HH patients [36] DCTl, iron transporter gene.

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