Excerpt from Iron Deficiency Anemia

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Background

Iron deficiency is defined as a decreased total iron body content. Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. It is important economically because it diminishes the capability of individuals who are affected to perform physical labor, and it diminishes both growth and learning in children.

In healthy people, the body concentration of iron (approximately 60 parts per million [ppm]) is regulated carefully by absorptive cells in the proximal small intestine, which alter iron absorption to match body losses of iron (see Image 3 and Image 6). Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

Posthemorrhagic anemia is discussed in this section because it is an important cause of iron deficiency. The acute and potentially catastrophic problems of hypoxia and shock that can occur from significant hemorrhage or severe iron deficiency are discussed elsewhere in the textbook; however, daily blood losses can be small and may be overlooked. Occasionally, patients with severe iron deficiency anemia from slow but persistent gastrointestinal bleeding have repeatedly negative testing of stool for hemoglobin. Therefore, it is important for the clinician to be aware of characteristics of the anemia at all intervals after the onset of bleeding.

Pathophysiology

Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport. Iron equilibrium in the body is regulated carefully to ensure that sufficient iron is absorbed in order to compensate for body losses of iron.

While body loss of iron quantitatively is as important as absorption in terms of maintaining iron equilibrium, it is a more passive process than absorption. Consistent errors in maintaining this equilibrium lead to either iron deficiency or iron overload.

Iron balance is achieved largely by regulation of iron absorption in the proximal small intestine. Either diminished absorbable dietary iron or excessive loss of body iron can cause iron deficiency. Diminished absorption usually is due to an insufficient intake of dietary iron in an absorbable form.

Hemorrhage is the most common cause of excessive loss of body iron, but it can occur with hemoglobinuria from intravascular hemolysis. Malabsorption of iron is relatively uncommon in the absence of small bowel disease (sprue, celiac disease, regional enteritis) or previous gastrointestinal surgery.

Iron uptake in the proximal small bowel occurs by 3 separate pathways (see Image 8). These are the heme pathway and separate pathways for ferric and ferrous iron.

In North America and Europe, one third of dietary iron is heme iron, but two thirds of body iron is derived from dietary myoglobin and hemoglobin. Heme iron is not chelated and precipitated by numerous constituents of the diet that renders nonheme iron nonabsorbable (see Image 4). Examples are phytates, phosphates, tannates, oxalates, and carbonates. Heme is maintained soluble and available for absorption by globin degradation products produced by pancreatic enzymes. Heme iron and nonheme iron are absorbed into the enterocyte noncompetitively.

Heme enters the cell as an intact metalloporphyrin, presumably by a vesicular mechanism. Heme is degraded within the enterocyte by heme oxygenase with release of iron so that it traverses the basolateral cell membrane in competition with nonheme iron to bind transferrin in the plasma.

Ferric iron utilizes a different pathway to enter cells than ferrous iron. This was shown by competitive inhibition studies, the use of blocking antibodies against divalent metal transporter-1 (DMT-1) and beta3-integrin, and transfection experiments using DMT-1 DNA. This indicated that ferric iron utilizes beta3-integrin and mobilferrin, while ferrous iron uses DMT-1 to enter cells.

Which pathway transports most nonheme iron in humans is not known. Most nonheme dietary iron is ferric iron. Iron absorption in mice and rats may involve more ferrous iron because they excrete moderate quantities of ascorbate in intestinal secretions. Contrariwise, humans are a scorbutic species and are unable to synthesize ascorbate to reduce ferric iron.

Other proteins are described that appear related to iron absorption. These are stimulators of iron transport (SFT), which are reported to increase the absorption of both ferric and ferrous iron, and hephaestin, which is postulated to be important in the transfer of iron from enterocytes into the plasma. The relationship and interactions between the newly described proteins is not known at this time and is being explored in a number of laboratories.

The iron concentration within enterocytes varies directly with the body's requirement for iron. Absorptive cells in iron-deficient humans and animals contain little stainable iron, whereas this is increased significantly in subjects who are replete in iron. Untreated phenotypic hemochromatosis creates little stainable iron in the enterocyte, similar to iron deficiency. Iron within the enterocyte may operate by up-regulation of a receptor, saturation of an iron-binding protein, or both. In contrast to findings in iron deficiency, enhanced erythropoiesis, or hypoxia, endotoxin rapidly diminishes iron absorption without altering enterocyte iron concentration. This suggests that endotoxin and, perhaps, cytokines alter iron absorption by a different mechanism.

Most iron delivered to nonintestinal cells is bound to transferrin. Transferrin iron is delivered into nonintestinal cells via 2 pathways, the classical transferrin receptor pathway (high affinity, low capacity) and the pathway independent of the transferrin receptor (low affinity, high capacity). Otherwise, the nonsaturability of transferrin binding to cells cannot be explained.

In the classical transferrin pathway, the transferrin iron complex enters the cell within an endosome. Acidification of the endosome releases the iron from transferrin so that it can enter the cell. The apotransferrin is delivered by the endosome to the plasma for reutilization. The method by which the transferrin receptor–independent pathway delivers iron to the cell is not known.

Nonintestinal cells also possess the mobilferrin integrin and DMT-1 pathways. Their function in the absence of an iron-saturated transferrin is uncertain; however, their presence in nonintestinal cells suggests they may participate in intracellular functions in addition to their capability to facilitate cellular uptake of iron.

Frequency

United States

In North America and Europe, iron deficiency is most common in women of childbearing age and as a manifestation of hemorrhage. Iron deficiency caused solely by diet is uncommon in adults in countries where meat is an important part of the diet. Depending upon the criteria used for the diagnosis of iron deficiency, approximately 4-8% of premenopausal women are iron deficient. In men and postmenopausal women, iron deficiency is uncommon in the absence of bleeding.

International

In countries where little meat is in the diet, iron deficiency anemia is 6-8 times more prevalent than in North America and Europe. This occurs despite consumption of a diet that contains an equivalent amount of total dietary iron because heme iron is absorbed better from the diet than nonheme iron. In certain geographic areas, intestinal parasites, particularly hookworm, worsen the iron deficiency because of blood loss from the gastrointestinal tract. Anemia is more profound among children and premenopausal women in these environs.

Mortality/Morbidity

Chronic iron deficiency anemia is seldom a direct cause of death; however, moderate or severe iron deficiency anemia can produce sufficient hypoxia to aggravate underlying pulmonary and cardiovascular disorders.

• Hypoxic deaths have been observed in patients who refuse blood transfusions for religious reasons. Obviously, with brisk hemorrhage, patients may die from hypoxia due to posthemorrhagic anemia.
• While a number of symptoms, such as ice chewing and leg cramps, occur with iron deficiency, the major debility of moderately severe iron deficiency is fatigue and muscular dysfunction that impairs muscular work performance.
• In children, the growth rate may be slowed, and a decreased capability to learn is reported. In young children, severe iron deficiency anemia is associated with a lower IQ, a diminished capability to learn, and a suboptimal growth rate.

Race

Race probably has no significant effect upon the occurrence of iron deficiency anemia; however, because diet and socioeconomic factors play a role in the prevalence of iron deficiency, it more frequently is observed in people of various racial backgrounds living in poorer areas of the world.

Sex

An adult male absorbs and loses about 1 mg of iron from a diet containing 10-20 mg daily. During childbearing years, an adult female loses an average of 2 mg of iron daily and must absorb a similar quantity of iron in order to maintain equilibrium. Because the average woman eats less than the average man does, she must be more than twice as efficient in absorbing dietary iron in order to maintain equilibrium and avoid developing iron deficiency anemia.

• Healthy males lose body iron in sloughed epithelium, in secretions from the skin and gut lining, and from small daily losses of blood from the gastrointestinal tract (0.7 mL of blood daily). Cumulatively, this amounts to 1 mg of iron. Males with severe siderosis from blood transfusions can lose a maximum of 4 mg daily via these routes without additional blood loss.
• A woman loses about 500 mg of iron with each pregnancy. Menstrual losses are highly variable, ranging from 10-250 mL (4-100 mg of iron) per period. These iron losses in women double their need to absorb iron in comparison to males.

Age

Healthy newborn infants have a total body iron of 250 mg (80 ppm), which is obtained from maternal sources. This decreases to approximately 60 ppm in the first 6 months of life, while the baby consumes an iron-deficient milk diet. Infants consuming cow milk have a greater incidence of iron deficiency because bovine milk has a higher concentration of calcium, which competes with iron for absorption. Subsequently, growing children must obtain approximately 0.5 mg more iron daily than is lost in order to maintain a normal body concentration of 60 ppm.

• During adult life, equilibrium between body loss and gain is maintained. Children are more likely to develop iron deficiency anemia. In certain geographic areas, hookworm adds to the problem. Children are more likely to walk in soil without shoes and develop heavy infestations.
• During childbearing years, women have a high incidence of iron deficiency anemia because of iron losses sustained with pregnancies and menses.
• Gastrointestinal neoplasms become increasingly more prevalent with each decade of life. They frequently present with gastrointestinal bleeding that may remain occult for long intervals before it is detected. Usually, bleeding from neoplasms in other organs is not occult, prompting the patient to seek medical attention before developing severe iron depletion.

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