Biochemistry of Iron Absorption

cellular level

Most dietary iron absorption occurs in the duodenum and proximal jejunum and depends largely on the physical state of the iron atoms. At physiological pH, iron exists in the oxidized ferric (Fe3+) state. To be absorbed, iron must be in the ferrous (Fe2+) state or bound by proteins such as heme. The low pH of gastric acid in the proximal duodenum allows the ferric reductase duodenal cytochrome B (Dcytb) to convert insoluble iron (Fe3+) into absorbable ferrous (Fe2+) ions at the brush border of enterocytes. . Gastric acid production plays a key role in plasma iron homeostasis. Iron absorption is greatly reduced when proton pump inhibitors such as omeprazole are used. Once ferric iron is reduced to ferrous iron in the intestinal lumen, a protein on the apical membrane of the enterocyte called divalent metal cation transporter 1 (DMT1) transports the iron across the apical membrane into the cell. Hypoxia-inducible factor 2 (HIF-2α) upregulates DMT1 and Dcytb levels in the hypoxic environment of the intestinal mucosa.

Certain dietary compounds inhibit or enhance the duodenal pH-dependent iron absorption process.

• Inhibitors of iron absorption include phytate, a compound found in plant-based diets that exhibits dose-dependent effects on iron absorption. Polyphenols are found in black and herbal teas, coffee, wine, legumes, grains, fruits and vegetables, and have been shown to inhibit iron absorption. Unlike other inhibitors, such as polyphenols and phytates, which only block non-heme iron absorption, calcium inhibits both heme and non-heme iron when initially absorbed by enterocytes. Animal proteins such as casein, whey, egg whites, and plant proteins have been shown to inhibit the body's absorption of iron. Oxalic acid, found in spinach, beets, legumes and nuts, binds and inhibits iron absorption.
• The enhancer of iron absorption is primarily the effect of vitamin C, which can overcome the effects of all dietary inhibitors when included in a diet high in non-heme iron (usually a diet high in vegetables). Ascorbic acid forms a chelate with ferric iron (Fe3+) in the low pH of the stomach, which persists and remains soluble in the alkaline environment of the duodenum.

molecular level

Once inside enterocytes, iron can be stored as ferritin or transported across the basolateral membrane into the circulation bound to ferroportin.

Ferritin is a hollow, globular protein composed of 24 subunits that enhances the storage and regulation of iron levels in the body. Iron is stored in the interior of the ferritin globules in the Fe3+ state by incorporation into a solid crystalline mineral called ferrihydrite [FeO(OH)]8[FeO(H2PO4)].

The monomer of the ferritin molecule has ferroxidase activity (Fe3+ ↔ Fe2+), which causes the Fe2+ ions to migrate out of the ferrihydrite lattice structure, allowing them to subsequently flow out of the intestinal epithelial cells through ferroportin and cross the basolateral membrane of the intestinal epithelial cells. Enter the loop. The transmembrane protein ferroportin is the only efflux pathway for cellular iron and is almost entirely regulated by hepcidin levels. High levels of iron, inflammatory cytokines, and oxygen lead to increased levels of the peptide hormone hepcidin. Hepcidin binds to ferroportin, causing its internalization and degradation, and effectively shunts cellular iron into ferritin stores and prevents its absorption into the blood. thereby,

If hepcidin levels are low and ferroportin is not downregulated, ferrous iron (Fe2+) can be released from the enterocyte, where it is again oxidized to ferric iron (Fe3+) to bind to transferrin, which is present in Carrier proteins in plasma. Two copper-containing enzymes, ceruloplasmin in plasma and hephaestin on the basolateral membrane of enterocytes, catalyze the oxidation of ferrous iron and subsequently bind to transferrin in plasma. The main function of transferrin is to chelate iron to make it soluble, prevent the formation of reactive oxygen species, and facilitate its transport into the cell.

clinical significance

Enterocyte DMT1 and Dcytb levels are upregulated in the setting of iron deficiency anemia, and mutations in DMT1 have been shown to cause microcytic anemia and hepatic iron overload.

Conditions that degrade the duodenal mucosa that reduce iron absorption include:

• Celiac disease
• tropical sprue
• Crohn's disease
• duodenal cancer
• duodenal ulcer
• familial adenomatous polyposis

Anemia of chronic disease is a normocytic, normocytic anemia characterized by elevated ferritin stores but reduced systemic iron levels. Inflammatory states increase cytokine release (IL-6), which stimulates hepcidin expression in the liver. Hepcidin degradation through ferroportin leads to reduced iron absorption and reduced iron release from macrophages. The iron accumulated in the cells of anemia of chronic disease is stored in the form of ferritin.

Iron deficiency anemia is a hypochromic microcytic anemia caused by bleeding, reduced dietary iron, or reduced iron absorption. Menstruating women of childbearing age need twice the amount of iron as men of the same age. Pregnancy and breastfeeding also significantly increase a woman's iron requirements, helping to make iron deficiency the most common dietary deficiency in the world.