Chapter 431. Iron Deficiency

Matthew M. Heeney

Iron Deficiency: Introduction

Despite being the most abundant metal on earth, iron is the most prevalent single nutrient deficiency worldwide. The term newborn possesses about 75 mg of elemental iron/kg (0.25–0.5 g of total body iron) and must absorb about 4.5 g of iron during childhood, or about 1 mg/d, to achieve the nearly 5.0 g of body iron in the average adult. An additional 0.2 to 0.5 mg/day of absorbed iron is required to balance physiologic losses (eg, desquamation of epithelial cells in the gastrointestinal tract). During periods of maximal growth—infancy and adolescence—the iron requirements for expanding blood volume and muscle mass may exceed the rate of dietary iron accrual.

Epidemiology

Iron deficiency is the most common global nutritional deficiency with an estimated 2 billion affected persons.1 Iron deficiency affects all age groups, but is particularly common in infants, young children, and women of childbearing age. Iron-deficiency anemia is the most common hematologic disease of infancy and childhood.2

In industrialized nations, the most common etiology of iron deficiency is insufficient dietary iron. The availability of iron-fortified formula, in conjunction with initiatives such as the US federal Special Supplemental Nutrition Program for Women, Infants and Children (WIC) and the American Academy of Pediatrics’ promotion of formula in place of cow’s milk, have greatly reduced the prevalence of iron deficiency in developed countries. According to the Fourth National Health and Nutrition Examination Survey (NHANES-IV), iron deficiency without anemia exists in 7% of toddlers ages 1 to 2 years, 9% of adolescent girls, and 16% of women of childbearing age.3 Low income, minority ethnicity, and poor maternal iron status are recognized socioeconomic risk factors for iron-deficiency anemia.4-7 In developing countries, the higher prevalence of iron-deficiency anemia related to nutritional deficiency is compounded by the contribution of chronic blood loss related to parasitic infections.

Pathophysiology and Genetics

The majority of body iron is incorporated into the hemoglobin of circulating erythrocytes and their marrow precursors. Only a small fraction of the average daily requirement to support erythropoiesis is absorbed from the diet. The majority of the daily erythroid iron requirement is supplied by recovery of heme iron through the phagocytosis of senescent erythrocytes by reticuloendothelial macrophages and degradation of hemoglobin. This recycled iron is then made available to the developing erythroid precursors in the bone marrow.

Because only about 10% of dietary iron is absorbed, the child’s diet must contain 10 to 15 mg of iron to maintain a positive iron balance. During infancy, when only small amounts of iron-rich foods may be consumed, this level of iron intake is difficult to attain unless iron-fortified foods are provided. Infants and children from low-income families continue to have iron deficiency, despite a decline in the incidence of the condition over the past 30 years.

Iron Absorption

Nonheme dietary iron, primarily in the ferric (Fe3+) state, is reduced to the ferrous (Fe2+) state in the acidic environment of the proximal duodenum by a brush border ferrireductase. Gastric acidity may assist conversion to the absorbable ferrous (Fe2+) form, and the use of histamine H2 blockers or proton pump inhibitors to treat peptic gastroesophageal reflux can impair iron absorption (see Chapter 394). In addition, many plant products contain iron, but absorption is limited both by low solubility and by dietary chelators, such as phytates, that bind ambient iron. Fe2+ iron is then cotransported with protons through the apical membrane of the enterocyte by divalent metal transporter 1 (DMT1),8,9 whose expression is significantly increased in iron deficiency. DMT1 is also capable of transporting other divalent metals such as Cu2+ and Zn2+.8 Heme or organic iron present in animal food products is the most readily absorbed form of iron, and its absorption occurs by a different mechanism that is independent of gastric pH and incompletely understood. Some imported iron remains stored within the enterocyte cytoplasm as ferritin; the remainder is exported through the enterocyte basolateral membrane by another transporter protein, ferroportin.10-12 This basolateral transport of iron is believed to be facilitated by the ferrioxidase activity of hephaestin or ceruloplasmin,13 which returns the iron to its Fe3+ state and allows binding to transferrin, the predominant iron-binding protein in plasma.

Only a small fraction of dietary iron is imported by the enterocyte, and only a fraction again is exported from the enterocyte into the plasma. Iron remaining within enterocytes is lost from the body through the physiologic sloughing of these cells into the gut lumen.

The regulation of intestinal iron absorption is the primary mechanism for determining overall iron status in the body. This intestinal control is mediated primarily through hepcidin (discussed later in this chapter).

Some disorders disrupt the integrity of the enteric mucosa and hinder iron absorption. Inflammatory bowel disease, particularly Crohn disease and celiac sprue, can damage the duodenum, where most iron absorption occurs, and gastrointestinal bleeding may exacerbate the problem. An oral iron challenge can assess iron absorption by obtaining a serum iron level immediately prior to and 1 to 2 hours after an oral dose of 1 to 2 mg/kg of elemental iron. Failure to observe a significant increase over baseline level is consistent with iron malabsorption. Rarely, malabsorption of iron without a structurally defective intestine occurs as an autosomally recessive inherited syndrome related to the inappropriate expression of hepcidin.14

Iron Recycling

Virtually all plasma iron exists bound to the abundant, circulating, glycoprotein transferrin (Tf). In the normal physiologic state, Tf iron-binding sites are approximately 30% saturated. Each Tf molecule binds two atoms of Fe3+ iron with high affinity, serving three major functions. First, transferrin allows Fe3+ to remain soluble in the aqueous and pH-neutral plasma environment. Second, it renders iron nonreactive, thus allowing it to circulate in a safe form. Third, Tf facilitates the cellular import of iron through the transferrin cycle. The transferrin cycle commences with iron-loaded plasma Tf (holotransferrin) binding with high affinity to transferrin receptors (TfR) on the cell surface (reviewed in ref. 15). The Tf/TfR receptor complex is endocytosed. Proton pumps then acidify the resultant endosome,16 prompting iron release from transferrin.17 The unbound iron is reduced and is transported out of the endosome into the cytoplasm in a proton-dependent process involving DMT1.18 Empty Tf (apotransferrin) and TfR return to the cell surface, where they dissociate at neutral pH and become available to repeat the importation process.

In the macrophage, phagocytosed erythrocytes are lysed, hemoglobin is degraded, and iron is liberated from heme within the phagolysosome with the aid of heme oxygenase. Macrophages store some iron in ferritin and hemosiderin, and similar to enterocytes, export the remainder through ferroportin.19

Regulation of Iron Homeostasis

Iron homeostasis requires carefully coordinated regulation of intestinal iron absorption, cellular iron import/export, and iron storage. Humans have no physiologic iron excretion mechanism; therefore, the control of iron balance must occur at the level of intestinal absorption. More recent discoveries of molecular modulators of these processes are allowing greater understanding of the molecular regulation of these processes.

Hepcidin is a small peptide hormone that plays a central role in the regulation of iron homeostasis as a negative regulator of intestinal iron absorption and macrophage iron release. Hepcidin is synthesized by the liver, secreted into the serum, and excreted into the urine.20 Hepcidin acts as a negative regulator of iron export from cells21-23 by acting directly on ferroportin, causing its internalization and degradation, and thus limiting iron availability to the plasma. As a negative molecular regulator, decreased hepcidin leads to increased ferroportin-mediated cellular iron export and to elevated plasma iron levels.

Intestinal iron absorption appears to be mediated by at least five physiologic “regulators”—dietary iron load, body iron stores, erythropoietic demand, hypoxia, and inflammation. The latter four appear to have hepcidin as their common effector molecule (reviewed in ref. 15). Large oral iron loads result in an observed “mucosal block” of subsequent dietary iron, even in the setting of iron deficiency, by an unclear mechanism.24 Iron replete or overload states result in increased hepcidin expression, whereas the converse occurs in iron deficiency.21,25 The “stores regulator”26 can modulate intestinal absorption severalfold through an unclear mechanism that may detect the degree of transferrin saturation. The “erythroid regulator” increases intestinal absorption in response to increased erythropoietic iron demand, regardless of the current body iron stores26 and is associated with depressed hepcidin levels, resulting in increased intestinal iron absorption and reticuloendothelial iron release. At times, as seen in diseases of ineffective erythropoiesis such as thalassemia intermedia and congenital dyserythropoietic anemia, this may lead to iron overload. The expression of hepcidin is also decreased in hypoxic states,21 yet the “hypoxia regulator” appears to be distinct from the erythroid regulator.26 Finally, an “inflammatory regulator,” likely mediated through IL-6,27 induces increased hepcidin expression21,28,29 results in cellular iron sequestration, decreased serum iron, iron-restricted erythropoiesis, and, if persistent, the development of the anemia of chronic inflammation. Elevation of hepcidin in response to inflammation may have evolved as an element of host defense against invading pathogens and neoplastic cells requiring iron for proliferation.30 Inappropriately high hepcidin levels can also occur as a paraneoplastic phenomenon,28 or an inherited disorder14 can lead to an iron-resistant iron-deficiency anemia (IRIDA) phenotype.

The regulation of hepcidin in response to these regulators appears to be at the level of hepcidin gene transcription; however, the exact molecular mechanism remains incompletely understood.

Blood Loss

Chronic blood loss, particularly menstrual and gastrointestinal tract bleeding, commonly causes iron deficiency. Gastroesophageal reflux, peptic ulcer disease, or Meckel diverticulum can result in chronic blood loss that may present as iron-deficiency anemia. Other structural defects such as hereditary hemorrhagic telangiectasia (the Osler-Weber-Rendu syndrome) are much less frequent. Cow’s milk contains proteins that can irritate the lining of the gastrointestinal tract in some infants, resulting in chronic blood loss and iron deficiency. The leading cause of gastrointestinal blood loss worldwide is hookworm infection, caused by Necator americanus or Ancylostoma duodenale, which is endemic in much of the world. Trichuriasis, or whipworm infection, and schistosomiasis, very common in tropical areas, may be associated with chronic blood loss and iron-deficiency anemia in children.

Menorrhagia may lead to iron-deficiency anemia. Anovulatory dysfunctional uterine bleeding is a relatively common phenomenon that can often be ameliorated by oral contraceptives. Disorders of hemostasis, particularly von Willebrand disease, and pelvic anatomic abnormalities may also contribute to blood loss.

Occasionally, bleeding into the urinary tract causes iron deficiency, but gross urinary blood is usually sufficiently alarming that patients seek medical attention before iron deficiency develops. Patients with chronic intravascular hemolysis, such as occurs with intracardiac prostheses and paroxysmal nocturnal hemoglobinuria, may develop iron deficiency as consequence of hemoglobinuria. Pulmonary blood loss sufficiently severe to produce iron deficiency is rare but can occur in idiopathic pulmonary hemosiderosis (see Chapter 517).

Clinical Features and Differential Diagnosis

Careful inquiry into dietary intake and blood loss must always be undertaken.

The anemia impairs tissue oxygenation, producing the symptoms of pallor, weakness, fatigue, and lightheadedness. Pica—the compulsion to eat nonfood substances—occurs variably in patients with iron-deficiency anemia; the ingested substances may include soil, laundry starch, and clay, which can bind iron in the gastrointestinal tract, thereby exacerbating the deficiency. Iron deficiency increases the gastrointestinal absorption not only of iron, but also of a number of divalent metals, including lead, that share the same absorption pathways. Risk factors for chronic lead exposure should be explored because it can exacerbate iron deficiency by competitive inhibition of iron absorption.

On physical examination, pallor, tachycardia, and systolic murmur are more prevalent as the microcytic, hypochromic anemia worsens. Epithelial changes such as atrophy of the papillae of the tongue and spooning of the fingernails can be seen in adults with iron-deficiency anemia but are unusual in children.

Given that iron is an essential metal in numerous biologic processes other than oxygen delivery by erythrocytes, it is not surprising that it can be associated with other significant morbidities. Iron deficiency, with or without anemia, may affect growth and cause potentially irreversible mental and psychomotor developmental abnormalities in children younger than 2 years,31,32 and thus prevention of iron deficiency during infancy is imperative.

Diagnostic Evaluation

Laboratory Diagnosis

The diagnosis of iron-deficiency anemia is not tenable if the red blood cell (RBC) indices are normal. Iron-deficiency anemia is associated with microcytic, hypochromic RBCs on peripheral blood smear (see Fig. 430-1), corresponding to low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Iron-restricted erythropoiesis also results in an uneven RBC size (anisocytosis), which is reflected by an increased RBC distribution width (RDW). The reticulocyte count may be low or inappropriately “normal” relative to the degree of anemia. Measurement of reticulocyte hemoglobin content (CHr) has been suggested for early detection of iron-restricted erythropoiesis because it measures the amount of hemoglobin in the most recently produced cells, rather than the entire population of cells of varying ages. Thrombocytosis is often present with platelet counts > 450 × 109/L, but rarely a significant thrombocytopenia may be present. Serum iron concentration is low, and serum iron-binding capacity is increased, resulting in low transferrin iron saturation (< 15%). When serum transferrin saturation is < 15%, iron availability begins to restrict erythropoiesis. Serum ferritin reflects the iron stores within both the liver and the reticuloendothelial system. Low ferritin concentrations (< 10–15 ng/mL) invariably indicate that iron stores are essentially absent. Greatly elevated ferritin (> 1000 ng/mL) occurs in iron overload states such as transfusional hemosiderosis. Serum ferritin is also an acute phase reactant that is increased during infection or inflammation, as well as in hepatocellular disease; therefore, its diagnostic value can be limited in these circumstances.

Another marker of iron status is the serum transferrin receptor (sTfR) (normal < 8.5 mg/L). A portion of the extracellular component of the transferrin receptor is cleaved from developing normoblasts, and the plasma level of sTfR reasonably reflects erythropoietic activity; sTfR is characteristically increased in iron deficiency and states of ineffective erythropoiesis and decreased in aplastic anemia. Although sTfR is not specific for iron deficiency, the ratio of sTfR to the log of ferritin (sTfR-F index) can help distinguish iron deficiency from the anemia of chronic inflammation. A sTfR-F index < 1.5 is characteristic of the anemia of chronic inflammation, whereas values > 1.5 suggests iron deficiency alone or in combination with an inflammatory condition.33

The ultimate step of heme formation is the insertion of an iron molecule into the porphyrin ring. If iron is not available to complete this step, there is an increase in the ratio of zinc protoporphyrins (ZPP) to heme. A ZPP-to-heme ration of > 80 mmol/mol is biochemical evidence of relative iron-deficient erythropoiesis attributable to any etiology, including lead poisoning (see Chapter 120).

Progressive iron deficiency has several stages that are defined by laboratory values (Table 431-1). Prelatent iron deficiency occurs when tissue iron stores are decreased, as indicated by a low (but still > 15 ng/mL) serum ferritin level, but normal transferrin saturation and no anemia. Latent iron deficiency is characterized by low serum ferritin and transferrin saturation (< 15%), but without anemia, decrease in MCV, or increased free erythrocyte protoporphyrin (FEP). In frank iron-deficiency anemia, all measures of iron status are abnormal, and significant microcytic anemia is present.

Table 431-1. Stages of Iron Deficiency

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Table 431-1. Stages of Iron Deficiency

Normal

Prelatent

Latent

Iron Deficiency Anemia

Iron stores

Present

Decreased

Absent

Serum ferritin (ng/mL)

> 40

< 20

< 10

Transferrin saturation (%)

< 16

Free erythrocyte protoporphyrin (ng/dL blood)

> 35

Hemoglobin (g/dL)

< 11

Mean corpuscular volume (fL)

< 70

The α- and β-thalassemia traits are often confused with iron deficiency because both are associated with microcytosis and hypochromia. The clinician can discern clues distinguishing these entities from the RBC indices and peripheral blood smear: The Mentzer Index (MCV/RBC) is usually > 12 in iron deficiency and < 11 in thalassemia. The RDW is usually normal in thalassemia trait, which produces uniformly small erythrocytes, but is increased in iron-deficiency anemia, which alters RBC size unevenly. Basophilic stippling and target cells are seen in thalassemia trait. Laboratory measures of iron status in thalassemia trait are usually normal, and the associated mild anemia/microcytosis is unresponsive to iron therapy.

Prevention and Treatment

To prevent iron deficiency in infancy, the Committee on Nutrition of the American Academy of Pediatrics has recommended the following:

1. Breast milk should be used for at least 6 months, when possible. Elemental iron supplementation of 1 mg/kg/day should be provided to infants who are exclusively fed breast milk beyond 6 months of age.
2. Infants weaned before 12 months of age should not receive cow’s milk but should receive iron-fortified infant formula. Whole cow’s milk should be avoided during the first year of life.
3. Infants who are not breast-fed should receive an iron-supplemented formula (4–12 mg of elemental iron per liter) for the first year of life.
4. Complementary foods rich in iron (eg, iron-enriched cereals) should be introduced gradually beginning around 6 months of age.

Premature infants are particularly susceptible to iron deficiency as a result of a reduced iron endowment at birth because the majority of iron is transferred during the third trimester. Iron supplementation or iron-fortified formulas should be started by 1 to 2 months of age and continued for at least 1 to 2 years.

The introduction of whole cow’s milk (prior to 12 months of age) and consumption of more than 16 ounces of whole cow’s milk per day in toddlerhood should be avoided because this increases the risk of iron deficiency. In addition to a poor iron source and interference with iron absorption, cow’s milk may cause occult gastrointestinal bleeding in some infants.

Treatment of iron deficiency should always be coupled with the identification and correction of an underlying cause when possible. Oral iron salts are inexpensive and almost always sufficient to correct anemia and replete iron stores. The treatment dose of oral iron is 2 to 6 mg of elemental ferrous iron per kilogram per day, given as a single or divided dose. The iron should not be mixed with milk or taken with food. Ascorbic acid supplementation can enhance iron absorption. Gastrointestinal intolerance and constipation related to iron therapy are unusual in children. Oral iron may cause staining of the teeth, but this is temporary and can be avoided by rinsing the mouth or brushing the teeth after the medication is given. Response to iron therapy is signaled by a rise in CHr and reticulocytosis beginning at 3 to 5 days and peaking 7 to 10 days after starting therapy. An increase in hemoglobin of at least 10 to 20 g/L after 1 month is diagnostic of iron deficiency. Lack of response usually indicates noncompliance with the medication or another diagnosis. Adequate replacement of storage iron in iron-deficiency anemia usually requires several months of therapy after the anemia has been corrected. With ongoing blood losses, oral replacement of storage iron can be futile. Parenteral iron is rarely indicated in children with nutritional iron deficiency unless oral iron is poorly tolerated, duodenal absorption is compromised, or rapid replacement of iron stores is required. In addition to iron dextran, which can be administered intravenously or intramuscularly, there are newer intravenous formulations, including iron gluconate and iron sucrose, that are primarily used for iron replacement in the setting of hemodialysis.

Transfusion of packed red blood cells (PRBCs) for iron-deficiency anemia is indicated only in the most severe cases (eg, heart failure or hemoglobin < 5 g/dL) and/or when ongoing losses are expected to exceed or equal bone marrow production after appropriate iron therapy. Correction of severe chronically developed iron-deficiency anemia with transfusion must be performed slowly and requires special care to prevent fluid overload due to the relatively expanded plasma volume in such patients.

Anemia of Chronic Inflammation

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The anemia of chronic inflammation (also known as anemia of chronic disease) is associated with a number of pediatric diseases such as juvenile rheumatoid arthritis, chronic infections, and inflammatory bowel disease. Chronic disorders that lack an inflammatory component generally do not produce this type of anemia. The cause of the anemia of chronic inflammation is multifactorial, but the characteristic features are impaired iron mobilization from reticuloendothelial stores and poor intestinal absorption of dietary iron. This impairment of iron absorption and recycling is the result of elevated hepcidin expression induced by the inflammatory cytokine interleukin-6, through a direct effect on the hepcidin promoter.

The laboratory diagnosis of anemia of chronic inflammation can be difficult. The associated anemia is usually mild to moderate (Hb 80–110 g/L), normochromic, normocytic, and with a slightly increased RDW. The reticulocyte count is not appropriately increased. Serum iron level is low, but the increased total iron-binding capacity (TIBC) characteristic of iron deficiency does not occur; therefore, transferrin saturation can be normal. Plasma ferritin concentration, an acute phase reactant, is almost uniformly elevated (400–800 ng/mL). A low serum iron level in the face of an elevated plasma ferritin can distinguish the anemia of chronic inflammation from iron deficiency, where both values are low. Inappropriately low/normal levels of serum ferritin (20–50 ng/mL) in a patient with active inflammatory disease may indicate concomitant iron deficiency. Serum transferrin receptor is normal in the anemia of inflammation but elevated in iron deficiency. Bone marrow staining usually reveals reticuloendothelial iron, indicating defective mobilization from tissue stores. Impaired marrow response to erythropoietin (EPO) and inappropriately low plasma EPO levels, secondary to proinflammatory cytokines and hepcidin, also contribute to the pathophysiology of the anemia of chronic inflammation. Soon, a clinical assay to quantify hepcidin should clarify the diagnostic challenge.

Treatment of the anemia of chronic inflammation currently hinges on control of the underlying inflammatory or infectious process. Erythropoietin in very large doses can ameliorate the degree of anemia somewhat, but the improvement is usually modest, and thus EPO is rarely indicated. Despite the low levels of serum iron, iron supplementation is ineffective. Future therapy will likely focus on the manipulation of hepcidin production.

References

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