Fig. 12.9 Regulationofironabsorption.Duodenalepithelialcelluptakeofhemeandnonhemeirondiscussedinthetextisdepicted.Whenthestoragesitesofthebodyarerepletewithironanderythropoieticactivityisnormal,plasmahepcidinbalancesironuptakeandlosstomaintainironhemeostasisbydown-regulatingferroportinandlimitingironuptake(middlepanel).Hepcidinrisesinthesettingofsystemicinflammationorwhenironlevelsarehigh,decreasingironuptakeandincreasingironlossbythesheddingofduodenocytes(rightpanel),anditfallsinthesettingoflowplasmaironorprimaryhemochromatosis,resultinginincreasedironuptake(leftpanel)withreducedshedding.DMT1, Divalentmetaltransporter-1.
http://ebooksmedicine.net iron (Fe2+) is transported across the apical membrane by divalent metal transporter-1 (DMT1). A second transporter, ferroportin, then moves iron from the cytoplasm to the plasma across the basolateral membrane. The newly absorbed iron is next oxidized by hephaestin and ceruloplasmin to ferric iron (Fe3+), the form of iron that binds to transferrin. Both DMT1 and ferroportin are widely distributed in the body and are involved in iron transport in other tissues as well. As depicted in
Fig. 12.9 (middle panel), part of the iron that enters enterocytes is delivered to transferrin by ferroportin, whereas the remainder is incorporated into cytoplasmic ferritin and is lost through the exfoliation of mucosal cells.
The fraction of iron that is absorbed is regulated by hepcidin, a small peptide that is synthesized and secreted from the liver in an iron-dependent fashion. In general, high iron levels in the plasma enhance hepcidin production, whereas low iron levels suppress it. However, hepcidin production also is sensitive to inflammation and to factors released from erythroblasts in the bone marrow. Specifically, hepcidin levels rise in the face of systemic inflammation because of the direct effects of inflammatory mediators such as IL-6 on hepatocytes, and in the setting of ineffective hematopoiesis, which is marked by increased numbers of erythroblasts in the bone marrow. Hepcidin circulates to the duodenum, where it binds ferroportin and induces its internalization and degradation. Thus, when hepcidin concentrations are elevated (
Fig. 12.9 , right panel), such as when serum iron levels are high or there is systemic inflammation, ferroportin levels fall and more iron is incorporated into cytoplasmic ferritin and is lost by excretion. Conversely, when hepcidin levels are low (
Fig. 12.9 , left panel), such as when there is iron deficiency, ineffective hematopoiesis, or the genetic defects that lead to primary hemochromatosis (Chapter 16), the basolateral transport of iron is increased. In iron deficiency, the suppression of hepcidin is beneficial as it serves to help to correct the deficiency, but inappropriately low levels of hepcidin, as in primary hemochromatosis, eventually lead to systemic iron overload.
Iron deficiency arises in a variety of settings:
Chronic blood loss is the most important cause of iron deficiency anemia in the Western world. The most common sources of bleeding are the gastrointestinal tract (e.g., peptic ulcers, colon cancer, hemorrhoids) and the female genital tract (e.g., menorrhagia, metrorrhagia, endometrial cancer).
In the developing world, low intake and poor bioavailability because of predominantly vegetarian diets are the most common causes of iron deficiency.
In the United States, low dietary intake is an infrequent culprit but is sometimes culpable in infants fed exclusively milk, in the impoverished, in the elderly, and in teenagers subsisting predominantly on junk food.