Introduction

Iron is an essential element of various metabolic processes in humans, including DNA synthesis, electron transport, and oxygen transport. Unlike other minerals, iron levels in the human body are controlled only by absorption. The mechanism of iron excretion is an unregulated process arrived at through loss in sweat, menstruation, shedding of hair and skin cells, and rapid turnover and excretion of enterocytes. In the human body, iron exists mainly in erythrocytes as the heme compound hemoglobin (approximately 2 g of iron in men and 1.5 g in women), to a lesser extent in storage compounds (ferritin and hemosiderin) and in muscle cells as myoglobin. Iron is also found bound to proteins (hemoprotein) and non-heme enzymes involved in oxidation-reduction reactions and the transfer of electrons (cytochromes and catalase).[1][2][3]

Additionally, approximately 2.2% of total body iron is found in the so-called labile pool, a poorly defined and reactive pool of iron that forms reactive oxygen species via the Fenton Reaction, which forms complexes with a drug class known as chelators. Iron chelators treat iron overload, a condition often caused by transfusion therapies used to treat thalassemias and other anemias.[4][5]

Fundamentals

There are two types of absorbable dietary iron: heme and non-heme iron.

• Heme iron, derived from hemoglobin and myoglobin of animal food sources (meat, seafood, poultry), is the most easily absorbable form (15% to 35%) and contributes 10% or more of our total absorbed iron.
• Non-heme iron is derived from plants and iron-fortified foods and is less well absorbed.

Despite its relative abundance in the environment and the relatively low daily iron requirements (10 mg ingested/1 mg absorbed) of humans, iron is often a growth-limiting nutrient in the human diet. Low intake of iron accounts for most anemia in developed countries and is responsible for nearly half of the anemias in non-industrialized nations. One reason for the lack of adequate iron absorption is that upon exposure to oxygen, iron forms highly insoluble oxides, which are unavailable for absorption in the human gastrointestinal tract. Human enterocytes contain apical membrane-bound enzymes whose activity can be regulated and which function to reduce insoluble ferric (Fe3+) to absorbable ferrous (Fe2+) ions. 

Although iron deficiency is a relatively common problem, it is not the only extreme of the iron-balance spectrum that must be avoided. Iron overload can be particularly damaging to the heart, liver, and endocrine organs. Excess ferrous iron forms free hydroxyl radicals via the Fenton reaction that cause damage to tissues through oxidative reactions with lipids, proteins, and nucleic acids. Thus, dietary iron absorption and factors affecting bioavailability in the body are tightly regulated where possible.

Cellular Level

The absorption of most dietary iron occurs in the duodenum and proximal jejunum and depends heavily on the physical state of the iron atom. 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+) to absorbable ferrous (Fe2+) ions. Gastric acid production plays a key role in plasma iron homeostasis. When proton-pump inhibiting drugs such as omeprazole are used, iron absorption is greatly reduced. Once ferric iron is reduced to 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 include 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. Unlike other inhibitors such as polyphenols and phytates, which prevent only non-heme 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. Oxalic acid is found in spinach, chard, beans, and nuts and acts to bind and inhibit iron absorption.  
• Enhancers of iron absorption are dominated by the effect of 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.

Molecular Level

Once inside the enterocyte, iron can be 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 to 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+), allowing 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, resulting in its internalization and degradation and effectively shunting cellular iron into ferritin stores and 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 feces and out of the body.

If hepcidin levels are low and ferroportin is not downregulated, ferrous iron (Fe2+) can be released from the enterocyte, where it is oxidized once again into ferric iron (Fe3+) for binding to transferrin, which is its carrier protein present in the plasma. Two copper-containing enzymes, ceruloplasmin in the plasma and hephaestin on the basolateral membrane of the enterocyte, catalyze the oxidation of and subsequent binding of ferrous iron to transferrin in the plasma. The principal role of transferrin is to chelate iron to be rendered soluble, prevent the formation of reactive oxygen species, and facilitate its transport into cells.   

Clinical Significance

Enterocyte DMT1 and Dcytb levels are upregulated in cases of iron deficiency anemia, and mutations in DMT1 have been shown to give rise to microcytic anemias and liver iron overload.[6][7]

Conditions that degrade the mucosa of the duodenum will decrease absorption of iron and include:

• Celiac disease
• Tropical sprue
• Crohn’s disease
• Duodenal cancer
• Duodenal ulcers
• Familial adenomatous polyposis

Anemia of chronic disease is a normochromic, normocytic anemia that shows characteristically elevated ferritin stores but lower total body iron. Inflammatory states increase cytokine release (IL-6), which stimulates hepcidin expression in the liver. Hepcidin causes decreased iron absorption through ferroportin degradation and decreases the release of iron from macrophages. The iron that accumulates in cells in anemia of chronic disease is stored as ferritin. 

Iron-deficiency anemia is a hypochromic, microcytic anemia caused by hemorrhage (most commonly through trauma or gastrointestinal lesions), decreased dietary iron, or decreased iron absorption. Menstruating women of reproductive age require twice the amount of iron as similarly-aged men. Pregnancy and breastfeeding also significantly increase the iron requirements of women, helping to make iron deficiency the most common dietary deficiency in the world.[8][9]