Iron accumulation liver

The progression of human immunodeficiency virus (HIV) towards its more advanced stages is accompanied by increasing body stores of iron. Iron accumulates in macrophages as well as microglia, endothelial cells and myocytes. The iron burden is especially intense in the bone marrow, brain white matter, muscle and liver. Such excesses of iron will enhance oxidative stress, impair several already compromised immune defence mechanisms and directly promote the growth of microbes (Boelaert et ah, 1996). 

Without a mechanism for its excretion, iron accumulates in vital organs (Pietrangelo, 2002). Because the liver binds both circulating nontransferrin and transferrin-bound iron, the liver is at particular risk for iron overload. Excess iron causes damage to hepatocytes primarily through induction of oxidative stress (Parkilla et al., 2001). 

Table I. Iron Complexes Used in the Study of Mitochondrial Iron Accumulation by Heart and Liver Mitochondria...

Table II. Properties of the Iron Accumulation by Isolated Rat Liver Mitochondria Using 59Fe(III)— Sucrose as Iron Donor0...

Figure 2. Effect of Ca2+ on the energy-dependent (respiratory chain linked) (A) and the energy-independent (B) iron accumulation hy rat liver mitochondria. The concentrations of iron were 250 pM (%) and 83 fiM (O) (27).

The parenchymatous liver cells (hepatocytes) hold a key position in the overall metabolism of iron (57, 58, 59, 60), and since functionally intact liver mitochondria can be conveniently prepared at high yield, these mitochondria have been most extensively studied so far. The iron transporting system discussed above for liver mitochondria is present also in mitochondria from other tissues and animal species (Table III). Quantitatively, erythroid cells of the bone marrow play the most important role in the overall metabolism of iron (61), and it was therefore not unexpected to find that the energized uptake of iron by isolated reticulocyte mitochondria exceeds that of mitochondria isolated from, for example, liver, kidney, and heart (Table IV). Thus, a relationship appears to exist between the rate and extent of heme protein turnover in mitochondria isolated from different tissues and their energized iron accumulation (30). Thus, it is evident that cellular differentiation is expressed at the mitochondrial level by modulation of the activity of essential functions related to iron transport and heme biosynthesis. 

Shiono Y, Wakusawa S, Hayashi H, Takikawa T, Yano M, Okada T, Mabuchi H, Kono S, Miyajima H. Iron accumulation in the liver of male patients with Wilson s disease. Am J Gastroenterol 2001 96(11) 3147-51. 

A dominantly inherited form of iron storage disease results from mutations in ferroportin (SLCllAS). Here iron storage occurs primarily in macrophages, not in liver parenchyma. Iron accumulation appears to be more common in Africans than Europeans, and although diet may play a major role, it is thought that there is also a genetic predisposition that may account for the increased iron burden. ... 

Aceruloplasminemia is an autosomal recessive disease, which is caused by mutations in the ceruloplasmin (Cp) gene and results in a total absence of Cp in the blood. It is an iron accumulation disorder causing clinical problems in the brain and liver. Cp is a ferroxidase, necessary to convert Fe to Fe so that the iron can be bound to transferrin and mobilized from cells. 

Exacerbation of hemochromatosis (an inherited disease in which excessive iron accumulates in the body) was reported in a 68-year-old woman with a history of type 2 diabetes, asthma, hypothyroidism, borderline hypertension, borderline diastolic dysfunction, and a fatty liver. The women had been taking 200 mg of milk thistle daily for over a year, along with two extra-strength acetaminophen pills every 2 to 3 days, and a can of cola (presumably a diet cola) every day (Whittington 2007). A letter regarding this case noted that elevated liver enzymes, reported as a sign of hemochromatosis exacerbation, may occur with regular acetaminophen use (Kidd 2008). 

Isolated Wistar rat liver mitochondria accumulated Fe(III) partly by an energy-dependent and partly by an energy independent mechanism (Romslo and Flatmark 1973). When the iron-loaded mitochondria were disrupted mechanically and the mitochondrial subfractions isolated by density gradient centrifugation, the iron accumulated by the energy-dependent mechanism was recovered mainly in the soluble matrix and intermembrane space (approx. 50 % of the total activity) and the inner membrane (approx. 30% Romslo and Flat-mark 1974). On the other hand, most of the energy-independent iron accumulation was confined to the outer and inner membranes (approx. 35 % of the total activity in each). 

The molecular pattern of iron deposition in tissues determines its accessibility to chelation, and depends upon the source of iron. Excessive intestinal absorption increases circulating levels of diferric transferrin, which deposits iron in hepatocytes and the parenchymal cells of other organs. Deposition in the reticuloendothelial system (RES) occurs only in advanced disease. On the other hand, transfused red cells are turned over in the RES and iron accumulates initially in the bone marrow, spleen, and Kupffer cells of the liver. In patients with aplastic anemia, loading is purely transfusional. However, in thalassemics with ineffective erythropoiesis there is a compensatory increase in intestinal iron absorption, and iron overload can occur even in the absence of transfusion (Ellis et al. 1954 Olivieri et al. 1992b). Therefore, even initial iron deposition in transfused thalassemics affects both RES and parenchymal cells, for example both the Kupffer cells and hepatocytes of the liver. 

If iron accumulates in large amounts it is deposited in the liver as insoluble intracellular granules of haemosiderin. Haemosiderin is less active metabolically than ferritin and serves as a longer term reserve. Excessive accumulation leads to siderosis in which there may be severe liver damage. 

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. 

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