Hemocromatosis dan Hemosiderosis

Hemocromatosis dan Hemosiderosis

Iron is a component that is close to the environment of all living things. Iron has an important role in metabolism, especially in electron transfer reactions. Storage of iron in the body is stored in circulating hemoglobin in red blood cells, containing about 1 mg/1ml red blood cells. A small amount of iron is stored in myoglobin and various enzymes. Iron is stored in cells in the form of ferritin and circulates in the plasma bound to transferrin. Absorption of inorganic iron includes ferrireductase and the divalent iron transporter, DMT-1, on the enterocyte apical membrane of the gastrointestinal lumen and ferroportin and heapahestin, which are located on the basolateral enterocyte membrane.

Systemic iron homeostasis is regulated by the hepatic peptide hormone hepcidin, which regulates plasma iron concentration, absorption and release of iron from macrophages as well as recycling and storage in hepatocytes. Cellular iron is exported via ferroportin which is a hepcidin receptor and is destroyed when the complex is formed. This affects the transport of the intestinal tract mucosa, from macrophages and from hepatocytes into the plasma, and causes a decrease in absorption and release from storage. 1.2

Iron distribution
Hemoglobin
Hemoglobin contains about 0.45% iron by weight. Each milliliter of red blood cells contains about 1 mg of iron. Due to the age of red blood cells 120 days, every 1/120 of the iron contained in hemoglobin every day is recycled by macrophages and returned to plasma where most of it is sent to bone marrow erythroblasts to be re-synthesized into new hemoglobin.

iron storage
Iron is stored in the form of ferritin or hemosiderin. The first form is soluble in water while the second form is insoluble in water. Ferritin is commonly found in cells in the body and in tissue fluids. Except in inflammatory conditions, plasma ferritin concentrations are generally related to total body iron stores, measuring serum ferritin concentrations is very important in diagnosing disorders of iron metabolism.
Hemosiderin is found mainly in macrophages. Microscopically, the tissue and bone marrow look like granules with refractile gold pigment. In pathological conditions, it will accumulate in large quantities in every tissue of the body. Hemosiderin is chemically similar to the iron core of ferritin in that its protective protein has been digested by lysosomes.
Myoglobin is a structure similar to hemoglobin. Each myoglobin consists of several hemes surrounded by a polypeptide of 154 amino acids. Myoglobin is present in small amounts in all skeletal and cardiac muscles where it acts as an oxygen reservoir to protect cells from injury during oxygen deprivation.

Table 1. Iron content in the body

Table 1. Iron content in the body

Tissue iron (other than hemoglobin, ferritin, hemosiderin, myoglobin) has a normal level of 6 to 8 mg. these include cytochromes and iron-containing enzymes. Although this iron level is very low, it has a very vital role and is very sensitive to iron deficiency

Table 2. Daily requirement of iron

Table 2. Daily requirement of iron

Transferrin is a glycoprotein of blood plasma that binds iron which contains a gap to bind Fe3+. Normally about one in 3 transferrins binds to iron. Normal human plasma contains 25 to 45 M (200 – 300 mg/dL) of transferrin capable of binding 50 to 90 M iron but only about 10 – 30 M (50 – 180 mcg/dL) iron. Apotransferrin (transferrin without iron) is synthesized by hepatocytes and cells of the macrophage and monocyte system. 3.4

Iron absorption

Iron normally enters the body through the gastrointestinal system, namely via enterocytes from the duodenum. The amount of iron that is absorbed regularly is regulated based on the body’s iron needs. Active erythropoiesis and/or iron deficiency increase absorption, iron overload and systemic inflammation decrease iron absorption.
Mechanism of transport through the intestinal mucosa
Heme iron is captured by enterocytes and converted to inorganic iron. Ferric iron is reduced to ferrous ions by cytochrome b reductant in the duodenum. Ferrous iron is transported into intestinal villi cells via the divalent metal transporter (DMT)-1. How iron transits between enterocytes is not known with certainty. Basolateral export of ferrous iron is mediated by ferroportin which is associated with hephaestin and plasma cerulesmin to oxidize iron to ferric state. The ferrous iron is then captured by apotransferrin.

Systemic iron hemostasis
Mechanisms of systemic iron hemostasis such as intestinal iron absorption, plasma iron concentration and tissue iron distribution are regulated by an endocrine mechanism as in other nutrients such as glucose and calcium.
Hepcidin is an amino acid produced by liver cells and has a central role in the systemic metabolism of hepcidin. Hepcidin regulates plasma iron concentration by regulating iron absorption in the intestinal enterocyte epithelium and releasing iron which is recycled by macrophages and hepatocytes. Overexpression of hepcidin will cause iron deficiency anemia. Microorganisms require plasma iron to survive in the circulation, hepcidin can play a role in protection against microbes. Hepcidin regulates iron regulation by binding to ferroportin, which is an iron-secreting transmembrane protein expressed by enterocytes, macrophages and hepatocytes. Once hepcidin is bound to ferroportin, ferroportin will be internalized and undergo proteolysis so that iron cannot escape from enterocytes, macrophages and hepatocytes into plasma. Hepcidin production is stimulated by proinflammatory cytokines such as interleukin (IL)-6 and overproduction of hepcidin is a pathomechanism of anemia of chronic disease. 3.4

Figure 2. Iron homeostasis

Figure 2. Iron homeostasis

An increase in plasma iron concentration and an increase in iron stores in the liver will increase the transcription of hepcidin. Absorption is increased during bleeding or erythropoietin administration and is chronically increased in the presence of ineffective erythropoiesis. Erythropherone is a glycoprotein whose secretion is induced by erythroblasts that suppresses hepcidin production in liver cells.
Iron transport
The main function of the transferrin protein is to move iron from the intestinal villi, liver sinusoids and spleen to the erythroblasts in the bone marrow and other sites that use iron.

Iron in erythroblast
During erythroblast development, iron must be transported into the mitochondria where it combines to form heme or is taken up into ferritin between siderosomes. Mitochondria work together with the cytoplasm of the cell to supply the heme of each cell. Although heme synthesis is important for all cells, erythroblasts synthesize more heme than other cells. The final step of mitochondrial-mediated heme synthesis is when iron is incorporated into protophorphirin. When there is a disruption of heme synthesis, it will trigger poisoning or sideroblastic anemia occurs. Erythroblasts contain sideroblast granules, normally 20-50% of erythrocyte precursors are present in the bone marrow and are visualized by microscopy. In many cases, if there is excess iron, the number of granules will increase and may increase in size. 3.4

Iron excretion
Much of the iron is excreted by desquamation of intestinal cells in the feces and is normally excreted at about 1–2 mg/day. Exfoliation through the skin and perspiration circulate much less. Iron is excreted in the urine in very small amounts. The lactation process will deliver about 1 mg of iron per day. Menstruation contributes to the establishment of a negative iron balance. A person with iron overload status as in the case of hemochromatosis may lose about 4 mg/day. 3.4

 

 

 

 

 

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