Physiology

Iron Absorption

The gastric acid production plays a key role in plasma iron homeostasis.  To be absorbed, iron must be in the ferrous (Fe2+) state or bound by a protein such as heme. 

Iron absorption-

  • The absorption of most dietary iron -> duodenum and proximal jejunum.
  • 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 a protein such as heme. 
  • The low pH of gastric acid in the proximal duodenum allows a ferric reductase enzyme, duodenal cytochrome B (Dcytb), on the brush border of the enterocytes to convert the insoluble ferric (Fe3+) -> ferrous (Fe2+) ions.  
  • The gastric acid production plays a key role in plasma iron homeostasis
  • once ferric iron -> ferrous iron in the intestinal lumen, a protein on the apical membrane of enterocytes called divalent metal cation transporter 1 (DMT1) transports iron across the apical membrane and into the cell. 
  • Levels of DMT1 and Dcytb are upregulated in the hypoxic environment of the intestinal mucosa by hypoxia-inducible factor-2 (HIF-2α).

The duodenal pH-dependent process of iron absorption is inhibited or enhanced by certain dietary compounds.  

  • Inhibitors of iron absorption 
    • Phytate which is a compound found in plant-based diets that demonstrate a dose-dependent effect on iron absorption. 
    • Polyphenols are found in black and herbal tea, coffee, wine, legumes, cereals, fruit, and vegetables and have been demonstrated to inhibit iron absorption.
    • Calcium inhibits both heme and non-heme iron at the point of initial uptake into enterocytes. 
    • Animal proteins such as casein, whey, egg whites, and proteins from plants (soy protein) have been shown to inhibit iron absorption in humans as well. 
    • Oxalic acid is found in spinach, chard, beans, and nuts and acts to bind and inhibit iron absorption.  
  • Enhancers of iron absorption 
    • ascorbic acid (vitamin C) which can overcome the effects of all dietary inhibitors when it is included in a diet with high non-heme iron availability (usually a meal heavy in vegetables).  Ascorbic acid forms a chelate with ferric (Fe3+) iron in the low pH of the stomach which persists and remains soluble in the alkaline environment of the duodenum.

Once inside the enterocyte- 

  • Iron is stored as ferritin or transported through the basolateral membrane and into circulation bound to ferroportin
  • (Ferritin that is not bound to iron is called apoferritin, which has an intrinsic catalytic activity that oxidizes ferrous iron into ferric iron so that it can be bound and stored as ferritin.)
  • Ferritin is a hollow, spherical protein consisting of 24 subunits that potentiate the storage and regulation of iron levels within the body. 
  • Iron is stored in the Fe3+ state on the inside of the ferritin sphere through incorporation into a solid crystalline mineral called ferrihydrite [FeO(OH)]8[FeO(H2PO4)].  
  • Monomers of the ferritin molecule have ferroxidase activity (Fe3+ ↔ Fe2+) which allows the mobilization of Fe2+ ions out of the ferrihydrite mineral lattice structure, enabling its subsequent efflux out of the enterocyte via ferroportin, and into circulation across the basolateral membrane of the enterocyte. 
  • The transmembrane protein ferroportin is the only efflux route of cellular iron and is regulated almost exclusively by hepcidin levels.
  • High levels of iron, inflammatory cytokines, and oxygen lead to increased levels of the peptide hormone hepcidin. 
  • Hepcidin binds ferroportin  internalization and degradation  effectively shunting cellular iron into ferritin stores  preventing its absorption into the blood. Thereby, hepcidin also potentiates the excretion of iron through the sloughing of enterocytes (and their ferritin stores) into the faeces and out of the body.
  • If hepcidin levels are low and ferroportin is not downregulated  ferrous (Fe2+) iron can be released from the enterocyte, where it is oxidized once again into ferric (Fe3+) iron for binding to transferrin, it’s carrier protein which is present in the plasma. 
  • Two copper-containing enzymes, ceruloplasmin in the plasma and hephaestin on the basolateral membrane of the enterocyte catalyse the oxidation of and subsequent binding of ferrous iron to transferrin in the plasma. 
  • The principal role of transferrin -> chelate iron so that it can be rendered soluble, prevent the formation of reactive oxygen species, and facilitate its transport into cells.   

ref- stat-pearls, UptoDate.

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