Explain the mechanism of iron absorption in the intestine. What are the factors regulating the process?

I. Digestion and Initial Processing of Iron

The journey of iron absorption begins in the stomach. Gastric acid (HCl) liberates iron from food complexes, converting ferric iron (Fe³⁺) to the more readily absorbed ferrous iron (Fe²⁺). Vitamin C (ascorbic acid) further enhances this conversion. The acidic environment also solubilizes iron salts. Heme iron, however, is directly absorbed without requiring this initial reduction step.

II. Absorption Mechanisms at the Enterocyte Level

The duodenum is the primary site of iron absorption. The process involves several key players:

• Dcytb (Duodenal Cytochrome b): This brush border enzyme, located on the apical membrane of enterocytes, reduces Fe³⁺ to Fe²⁺, facilitating its uptake.
• DMT1 (Divalent Metal Transporter 1): Fe²⁺ is transported across the apical membrane into the enterocyte via DMT1. This transporter also handles other divalent metals like zinc and manganese, leading to competition for absorption.
• Heme Carrier Protein 1 (HCP1): Heme iron is absorbed via HCP1, a specific transporter for heme. Once inside the enterocyte, heme oxygenase breaks down heme, releasing Fe²⁺.
• Ferroportin: Fe²⁺ is then transported across the basolateral membrane of the enterocyte into the circulation by ferroportin, the only known iron exporter.
• Hephaestin: This copper-containing ferroxidase oxidizes Fe²⁺ to Fe³⁺ on the basolateral side, enabling binding to transferrin.
• Transferrin: Fe³⁺ binds to transferrin, the primary iron transport protein in the blood, and is delivered to storage sites (liver, spleen, bone marrow) or utilized for erythropoiesis.

III. Factors Regulating Iron Absorption

Iron absorption is a highly regulated process, influenced by both physiological and dietary factors:

A. Enhancing Factors:

• Iron Status: Low iron stores increase DMT1 expression and ferroportin activity, enhancing absorption.
• Vitamin C: As mentioned earlier, vitamin C promotes the reduction of Fe³⁺ to Fe²⁺.
• Acidic Environment: Gastric acid aids in iron solubilization.
• Heme Iron: Heme iron is absorbed more efficiently than non-heme iron.
• Hypoxia: Low oxygen levels can increase iron absorption to support increased erythropoiesis.

B. Inhibiting Factors:

• Hepcidin: This hormone, produced by the liver, is the central regulator of iron homeostasis. Hepcidin binds to ferroportin, causing its internalization and degradation, thereby blocking iron export from enterocytes and macrophages. Inflammation, infection, and high iron stores stimulate hepcidin production.
• Phytates: Found in plant-based foods, phytates bind to iron, forming insoluble complexes that are poorly absorbed.
• Polyphenols: Present in tea, coffee, and red wine, polyphenols inhibit iron absorption by forming complexes with iron.
• Calcium: High calcium intake can interfere with iron absorption.
• Zinc & Other Divalent Metals: Competition for DMT1 can reduce iron absorption.

IV. Iron Recycling

It's important to note that the majority of iron used by the body is not derived from dietary absorption, but from the recycling of iron from senescent red blood cells by macrophages. This recycled iron is then stored in the liver or released back into circulation via ferroportin, again regulated by hepcidin.