The absorption of iron in the gastrointestinal tract is a tightly regulated process that depends on body iron requirements, erythropoietic activity, dietary factors, and hormonal control (particularly hepcidin). Iron absorption occurs mainly in the duodenum and upper jejunum and is influenced by both luminal factors and mucosal regulation.

The factors increasing and inhibiting iron absorption are as follows:

   Factors Increasing Iron Absorption

1. Conditions Associated with a Higher Apoferritin Level in Mucosal Cells of the Small Intestine:

This mechanism is based on the classical mucosal block theory, in which apoferritin in intestinal mucosal cells binds iron to form ferritin. When apoferritin levels are increased, iron uptake from the intestinal lumen is enhanced.

These include the following:

• After hemorrhage: Hemorrhage leads to increased erythropoiesis in the bone marrow due to loss of circulating red blood cells. This creates a strong demand for iron for hemoglobin synthesis. As a result, iron stored as ferritin in intestinal mucosal cells and other tissues is mobilized. The ferritin releases its iron, leading to increased formation of apoferritin in mucosal cells, thereby enhancing further iron absorption from the intestine.
• Iron deficiency anemia: In iron deficiency states, body iron stores are depleted, leading to low ferritin levels. The mucosal cells respond by increasing apoferritin availability, allowing maximal absorption of dietary iron.
• On going to high altitudes: At high altitude, reduced oxygen tension stimulates erythropoietin secretion from the kidneys, increasing red blood cell production. This increased erythropoietic activity enhances iron utilization, reduces ferritin stores, and increases apoferritin levels in intestinal mucosal cells, thereby increasing iron absorption.
• Repeated administration of iron: Repeated iron intake stimulates synthesis of apoferritin in mucosal cells, increasing their iron-binding capacity. However, prolonged and unnecessary iron supplementation may lead to iron overload due to continuous absorption beyond physiological needs.

In addition to mucosal regulation, increased erythropoietic activity (due to hemorrhage or hypoxia) suppresses hepatic production of hepcidin, a key regulatory hormone. Low hepcidin increases iron export from enterocytes into blood via ferroportin, thereby markedly increasing iron absorption.

2. Taking ascorbic acid, succinic acid, and sorbitol along with iron:

Ascorbic acid (vitamin C) enhances iron absorption by maintaining iron in its ferrous (Fe²⁺) state, which is the more soluble and absorbable form. It also prevents oxidation of Fe²⁺ to Fe³⁺ and facilitates reduction of dietary ferric iron in the intestinal lumen, thereby improving uptake.

Ascorbic acid also acts as a chelating agent, forming soluble iron complexes that prevent precipitation and improve transport across the intestinal mucosa.

3. Intake of inorganic iron:

Inorganic (non-heme) iron absorption is enhanced when dietary conditions favor its solubility and reduction. Compared to organic iron complexes, inorganic iron is more influenced by luminal chemical conditions and can be absorbed more readily when reducing agents are present.

4. Pathological conditions:

Hemochromatosis is a disorder characterized by excessive intestinal iron absorption due to defective regulation. The absorbed iron accumulates in tissues such as the liver, pancreas, heart, and skin, leading to organ dysfunction. Total body iron may increase up to 50 g compared to the normal 3–5 g.

In addition, increased iron absorption is observed in cirrhosis, portacaval shunts, and some forms of pancreatic insufficiency due to altered hepatic regulation of iron metabolism.

In hereditary hemochromatosis, mutations (commonly in the HFE gene) result in decreased hepcidin production. This leads to unregulated ferroportin activity and excessive intestinal iron absorption.

5. Administration of cobalt and erythropoietin and the later stages of pregnancy:

Cobalt and erythropoietin stimulate erythropoiesis. Increased red blood cell production increases iron demand, thereby enhancing intestinal iron absorption. During the later stages of pregnancy, iron absorption is increased due to elevated maternal blood volume, fetal iron requirements, and increased erythropoietin activity.

6. Low body iron stores and decreased hepcidin (modern mechanism):

When body iron stores are reduced, hepatic synthesis of hepcidin decreases. Low hepcidin levels increase the activity of ferroportin, the iron exporter on enterocytes, allowing more iron to enter circulation. This is the central regulatory mechanism of iron homeostasis in modern physiology.

7. Physiological states of increased demand:

States such as growth, adolescence, and recovery from blood loss or anemia are associated with increased erythropoietic activity. This increases iron requirement, suppresses hepcidin, and enhances intestinal iron absorption.

   Factors Inhibiting Iron Absorption

1. Malabsorption syndromes:

Conditions such as steatorrhea, sprue, and celiac disease damage intestinal mucosa and reduce absorptive surface area, thereby decreasing iron absorption.

2. Diarrheal diseases:

In diarrheal states, rapid intestinal transit time reduces contact between iron and absorptive surfaces, leading to decreased absorption.

3. An excess of phosphates, oxalates, or phytic acid:

These dietary components form insoluble complexes with iron, especially non-heme iron, making it unavailable for absorption. Plant-based foods rich in phytates significantly reduce iron bioavailability.

4. Subtotal gastrectomy:

Removal of part of the stomach reduces gastric acid secretion. Since acidic pH is essential for converting ferric (Fe³⁺) to ferrous (Fe²⁺) iron, this impairs iron absorption.

5. Surgical removal of the upper small intestine:

The duodenum and proximal jejunum are the principal sites of iron absorption. Their removal results in significant reduction of iron uptake due to loss of absorptive surface.

6. Food intake along with iron:

Simultaneous ingestion of food reduces iron absorption because dietary components such as phosphates, phytates, and proteins (especially eggs) bind iron and form insoluble complexes.

7. Antacid therapy:

Antacids increase gastric pH, reducing the conversion of Fe³⁺ to Fe²⁺. Achlorhydria produces a similar effect by eliminating gastric acid, both leading to reduced iron absorption.

8. Chronic infections:

Chronic infections and inflammatory states reduce iron absorption and availability due to increased production of hepcidin, which inhibits intestinal iron transport and traps iron in macrophages.

9. Increased hepcidin in inflammation (modern concept):

In chronic infections and inflammatory diseases, cytokines (especially IL-6) stimulate hepatic hepcidin synthesis. Hepcidin inhibits ferroportin, reducing iron absorption from the intestine and causing functional iron deficiency (anemia of chronic disease).

10. Calcium:

Calcium, particularly from dairy products or supplements, inhibits both heme and non-heme iron absorption. It interferes with iron transport mechanisms at the intestinal mucosa and reduces iron bioavailability when consumed simultaneously.