In general, the digestive system is set up to maximize absorption; there is no regulation in the amount of substances absorbed into the body. A notable exception is iron, in which daily dietary absorption is regulated so that it matches daily iron loss. The reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism for regularly eliminating iron from the body. Iron is a necessary component of various enzymes, but its major role is in oxygen-binding as a component of hemoglobin in red blood cells. Iron deficiency leads to anemia, a decrease in the oxygen carrying capacity of blood. However, too much iron in the body can be extremely toxic to tissues because it promotes the formation of free radicals.
The majority of the body's iron is found in hemoglobin of developing and mature red blood cells. Of the remaining iron, a significant portion is stored in the liver, both in the hepatocytes, and in the Kupffer cells (also known as reticuloendothelial cells), a type of macrophage found in the liver. Kupffer cells play an important role in recycling body iron. They ingest aged red blood cells, liberating iron for reuse by breaking down hemoglobin.
The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron. The important players in the dietary absorption of iron are diagrammed in the figure. (Note that this is a simplified scheme; not all the details are included).
Iron is brought into the cell through an active transport process
involving the protein DMT-1 (divalent metal
transporter-1), which is expressed on the apical surface of
enterocytes in the initial part of the duodenum. DMT-1 is
not specific to iron, and can transport other metal ions such as
zinc, copper, cobalt, manganese, cadmium or lead.
Enterocytes also absorb heme iron through a mechanism that has not
yet been characterized.
Once inside the enterocyte, there are two fates for iron:
Iron that enters the internal environment of the body from the basolateral surface of the enterocyte is rapidly bound to transferrin, an iron-binding protein of the blood. Transferrin delivers iron to red blood cell precursors, that take up iron bound to transferrin via receptor-mediated endocytosis.
Normally, the capacity of transferrin to bind iron in the plasma greatly exceeds the amount of circulating iron. The transferrin saturation (percent of transferrin occupied by iron) is measured to determine if an individual has an excessive load of iron in the body. The normal transferrin saturation is in the range of 20-45%.
Iron absorption by the enterocyte is programmed to match the body's needs. There are two major signals that affect iron absorption.
1. One signal reflects the need for iron due to erythropoiesis (red blood cell generation). The hormone erythropoietin (produced by the kidneys) stimulates red blood cell production, but it is NOT the signal regulating iron absorption. Rather, once erythropoiesis is stimulated, another signal is generated that promotes increased iron absorption.
2. A second signal depends upon the amount of iron in body stores. Iron absorption is stimulated if the level in body stores is low.
These signals (and others) regulate iron absorption in the proximal duodenum, where iron is absorbed. An important player in this regulation is the recently discovered hormone hepcidin. Hepcidin is produced by hepatocytes when iron stores are full. Inflammation can also stimulate hepcidin production.
The figure shows the model for how hepcidin acts on duodenal enterocytes to decrease the amount of iron absorbed into the body. Experiments have shown that hepcidin binds to the basolateral iron transporter ferroportin. This causes ferroportin to be internalized and degraded. As a result, more iron remains within the enterocyte. This stimulates ferritin synthesis, so that the iron that enters the enterocyte gets bound to ferritin. This iron is mostly lost from the body when the enterocyte dies.
Hemochromatosis arises when there is an excess of iron in the body. Excessive iron forms deposits in tissues, promoting free-radical formation and damage to cells. Particular tissues that are affected are the joints, liver, pancreas, heart and pituitary gland. The most prevalent form of hereditary hemochromatosis is caused by a mutation in a gene known as HFE. The mutation in HFE that causes hemochromatosis is quite common in the Caucasian population, however, only some homozygotes will develop hemochromatosis later in life (after middle age). Women with mutations in HFE are to some degree protected from developing iron overload because of regular blood loss through menstrual bleeding. A very rare, severe juvenile form of hemochromatosis is due to a homozygous deletion of the gene for hepcidin.
The exact function of the HFE protein is still being determined, but it is thought that HFE functions in the process of sensing body iron levels and regulating hepcidin secretion. Genetic experiments in mice have shown that HFE function is required in hepatocytes to trigger normal levels of hepcidin secretion in response to increased iron in the body. Individuals with hereditary hemochromatosis have deficient secretion of hepcidin, and so iron absorption by duodenal enterocytes continues even when body iron stores are full.
Hemochromatosis is treated by reducing the load of iron in the body. This is effectively accomplished by periodic phlebotomy (blood withdrawal). Half a liter of blood contains approximately 200-250 mg of iron.