Iron deficiency is the most common nutritional cause of anemia in humans. It can result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy. When severe, it results in a characteristic microcytic, hypochromic anemia. However, the impact of iron deficiency is not limited to the erythron (Dallman, 1982). Iron also is an essential component of myoglobin; heme enzymes such as the cytochromes, catalase, and peroxidase; and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme α-glycerophosphate oxidase. Iron deficiency can affect metabolism in muscle independently of the effect of anemia on oxygen delivery. This may reflect a reduction in the activity of iron-dependent mitochondrial enzymes. Iron deficiency also has been associated with behavioral and learning problems in children, abnormalities in catecholamine metabolism, and possibly, impaired heat production. Awareness of the ubiquitous role of iron has stimulated considerable interest in the early and accurate detection of iron deficiency and in its prevention.
History. The modern understanding of iron metabolism began in 1937 with the work of McCance and Widdowson on iron absorption and excretion and Heilmeyer and Plotner's measurement of iron in plasma (Beutler, 2002). In 1947, Laurell described a plasma iron transport protein that he called transferrin (Laurell, 1951). Hahn and coworkers first used radioactive isotopes to measure iron absorption and define the role of the intestinal mucosa to regulate this function (Hahn, 1948). In the next decade, Huff and associates initiated isotopic studies of internal iron metabolism. The subsequent development of practical clinical measurements of serum iron, transferrin saturation, plasma ferritin, and red-cell protoporphyrin permitted the definition and detection of the body's iron store status and iron-deficient erythropoiesis. In 1994, Feder and colleagues identified the HFE gene, which is mutated in type 1 hemochromatosis, on the short arm of chromosome 6 at 6p21.3 (Feder et al., 1996). In 2000, Ganz and colleagues discovered a peptide produced by the liver, which was termed hepcidin (Park et al., 2001). Soon thereafter hepcidin was found to be the master regulator of iron homeostasis and to play a role in anemia of chronic disease (Ganz, 2003; Ganz and Nemeth, 2009).
Iron and the Environment. Iron exists in the environment largely as ferric oxide or hydroxide or as polymers. In this state, its biological availability is limited unless solubilized by acid or chelating agents. For example, bacteria and some plants produce high-affinity chelating agents that extract iron from the surrounding environment. Most mammals have little difficulty in acquiring iron; this is explained by an ample iron intake and perhaps also by a greater efficiency in absorbing iron. Humans, however, appear to be an exception. Although total dietary intake of elemental iron in humans usually exceeds requirements, the bioavailability of the iron in the diet is limited.
Metabolism of Iron. The body store of iron is divided between essential iron-containing compounds and excess iron, which is held in storage. Quantitatively, hemoglobin dominates the essential fraction (Table 37–2). This protein, with a molecular weight of 64,500 Da, contains four atoms of iron per molecule, amounting to 1.1 mg (20 μmol) of iron per milliliter of red blood cells. Other forms of essential iron include myoglobin and a variety of heme and nonheme iron-dependent enzymes. Ferritin is a protein-iron storage complex that exists as individual molecules or as aggregates. Apoferritin has a molecular weight of ∼450,000 and is composed of 24 polypeptide subunits that form an outer shell, within which resides a storage cavity for polynuclear hydrous ferric oxide phosphate. More than 30% of the weight of ferritin may be iron (4000 atoms of iron per ferritin molecule). Ferritin aggregates, referred to as hemosiderin and visible by light microscopy, constitute about one-third of normal stores, a fraction that increases as stores enlarge. The two predominant sites of iron storage are the reticuloendothelial system and the hepatocytes, although some storage also occurs in muscle.
Table 37-2The Body Content of Iron ||Download (.pdf) Table 37-2 The Body Content of Iron
| ||MG/KG OF BODY WEIGHT |
| ||MALE ||FEMALE |
|Essential iron || || |
| Hemoglobin ||31 ||28 |
| Myoglobin and enzymes ||6 ||5 |
|Storage iron ||13 ||4 |
|Total ||50 ||37 |
Internal exchange of iron is accomplished by the plasma protein transferrin (Garrick and Garrick, 2009). This 76-kDa β1-glycoprotein has two binding sites for ferric iron. Iron is delivered from transferrin to intracellular sites by means of specific transferrin receptors in the plasma membrane. The iron-transferrin complex binds to the receptor, and the ternary complex is internalized through clathrin-coated pits by receptor-mediated endocytosis. A proton-pumping ATPase lowers the pH of the intracellular vesicular compartment (the endosomes) to ∼5.5. Iron subsequently dissociates and the receptor returns the apotransferrin to the cell surface, where it is released into the extracellular environment.
Cells regulate their expression of transferrin receptors and intracellular ferritin in response to the iron supply (De Domenico et al., 2008). The synthesis of apoferritin and transferrin receptors is regulated post-transcriptionally by two iron-regulatory proteins 1 and 2 (IRP1 and IRP2). Double knockout of the genes encoding these proteins is embryonic lethal, and conditional double knockout of these genes in the intestine results in cellular iron depletion and death of intestinal epithelial cells (Galy et al., 2008). These IRPs are cytosolic RNA-binding proteins that bind to iron regulating elements (IREs) present in the 5′ or 3′ untranslated regions of mRNA encoding apoferritin or the transferrin receptors, respectively. Binding of these IRPs to the 5′ IRE of apoferritin mRNA represses translation, whereas binding to the 3′ IRE of mRNA encoding the transferrin receptors enhances transcript stability, thereby increasing protein production. When iron is abundant, IRP2 undergoes rapid proteolysis and IRP1 is converted from a RNA-binding protein into aconitase, an enzyme that catalyzes the interconversion of citrate and isocitrate. This results in increased production of apoferritin and reduced production of transferrin receptors. Conversely, when iron is in short supply, these IRPs accumulate, thereby repressing translation of apoferritin while enhancing production of transferrin receptors.
The flow of iron through the plasma amounts to a total of 30-40 mg per day in the adult (∼0.46 mg/kg of body weight) (Finch and Huebers, 1982). The major internal circulation of iron involves the erythron and reticuloendothelial cells (Figure 37–3). About 80% of the iron in plasma goes to the erythroid marrow to be packaged into new erythrocytes; these normally circulate for ∼120 days before being catabolized by the reticuloendothelial system. At that time, a portion of the iron is immediately returned to the plasma bound to transferrin while another portion is incorporated into the ferritin stores of reticuloendothelial cells and returned to the circulation more gradually. Isotopic studies indicate some degree of iron wastage in this process, in which defective cells or unused portions of their iron are transferred to the reticuloendothelial cell during maturation, bypassing the circulating blood. With abnormalities in erythrocyte maturation, the predominant portion of iron assimilated by the erythroid marrow may be rapidly localized in the reticuloendothelial cells as defective red-cell precursors are broken down; this is termed ineffective erythropoiesis. The rate of iron turnover in plasma may be reduced by half or more with red-cell aplasia, with all the iron directed to the hepatocytes for storage.
Pathways of iron metabolism in humans (excretion omitted).
The most remarkable feature of iron metabolism is the degree to which body stores are conserved. Only 10% of the total is lost per year by normal men (i.e., ∼1 mg/day). Two-thirds of this iron is excreted from the gastrointestinal (GI) tract as extravasated red cells, iron in bile, and iron in exfoliated mucosal cells. The other third is accounted for by small amounts of iron in desquamated skin and in the urine. Physiological losses of iron in men vary over a narrow range, from 0.5 mg in the iron-deficient individual to 1.5-2 mg per day when excessive iron is consumed. Additional losses of iron occur in women due to menstruation. Although the average loss in menstruating women is ∼0.5 mg per day, 10% of menstruating women lose >2 mg per day. Pregnancy and lactation impose an even greater requirement for iron (Table 37–3). Other causes of iron loss include blood donation, the use of anti-inflammatory drugs that cause bleeding from the gastric mucosa, and GI disease with associated bleeding. Two much rarer causes are the hemosiderinuria that follows intravascular hemolysis, and pulmonary siderosis, where iron deposited in the lungs becomes unavailable to the rest of the body.
Table 37-3Iron Requirements for Pregnancy ||Download (.pdf) Table 37-3 Iron Requirements for Pregnancy
| ||AVERAGE (mg) ||RANGE (mg) |
|External iron loss ||170 ||150–200 |
|Expansion of red cell mass ||450 ||200–600 |
|Fetal iron ||270 ||200–370 |
|Iron in placenta and cord ||90 ||30–170 |
|Blood loss at delivery ||150 ||90–310 |
| Total requirementa ||980 ||580–1340 |
| Cost of pregnancyb ||680 ||440–1050 |
The limited physiological losses of iron point to the primary importance of absorption in determining the body's iron content (Garrick and Garrick, 2009). After acidification and partial digestion of food in the stomach, iron is presented to the intestinal mucosa as either inorganic iron or heme iron. A ferrireductase, duodenal cytochrome B (Dcytb), located on luminal surface of absorptive cells of the duodenum and upper small intestine, reduces the iron to the ferrous state, which is the substrate for the divalent metal (ion) transporter 1 (DMT1). DMT1 transports the iron to basolateral membrane, where it is taken up by another transporter, ferroportin (Fpn; SLC40A1), and subsequently reoxidized to Fe3+, primarily by hephaestin (Hp; HEPH), a transmembrane copper-dependent ferroxidase. Apo-transferrin (Tf) binds the resultant oxidized iron.
Mucosal cell iron transport and the delivery of iron to transferrin from reticuloendothelial stores are both determined by the human hemochromatosis protein, which is a major histocompatibility complex class 1 molecule encoded by the HFE gene (for High Fe) located on the short arm of chromosome 6 at 6p21.3. Regulation is finely tuned to prevent iron overload in times of iron excess while allowing for increased absorption and mobilization of iron stores with iron deficiency. A predominant negative regulator of iron absorption in the small intestine is hepcidin, a 25–amino acid peptide made by hepatocytes (Ganz, 2003). The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. A deficient hepcidin response to iron loading can contribute to iron overload and one type of hemochromatosis. In anemia of chronic disease, hepcidin production can be increased up to 100-fold, potentially accounting for characteristic features of this condition, namely poor GI uptake and enhanced sequestration of iron in the reticuloendothelial system.
Normal iron absorption is ∼1 mg per day in adult men and 1.4 mg per day in adult women; 3-4 mg of dietary iron is the most that normally can be absorbed. Increased iron absorption is seen whenever iron stores are depleted or when erythropoiesis is increased or ineffective. Patients with hereditary hemochromatosis due to HFE mutations demonstrate increased iron absorption and loss of the normal regulation of iron delivery to transferrin by reticuloendothelial cells (Ajioka and Kushner, 2003). The resulting increased saturation of transferrin permits abnormal iron deposition in nonhematopoietic tissues.
Iron Requirements and the Availability of Dietary Iron. Iron requirements are determined by obligatory physiological losses and the needs imposed by growth. Thus adult men require only 13 μg/kg per day (∼1 mg), whereas menstruating women require ∼21 μg/kg per day (∼1.4 mg). In the last two trimesters of pregnancy, requirements increase to ∼80 μg/kg per day (5-6 mg), and infants have similar requirements due to their rapid growth. These requirements (Table 37–4) must be considered in the context of the amount of dietary iron available for absorption.
Table 37-4Daily Iron Intake and Absorption ||Download (.pdf) Table 37-4 Daily Iron Intake and Absorption
|SUBJECT ||IRON REQUIREMENT (mg/kg) ||AVAILABLE IRON (mg/kg) POOR DIET–GOOD DIET ||SAFETY FACTOR AVAILABLE/REQUIREMENT |
|Infant ||67 ||33–66 ||0.5–1 |
|Child ||22 ||48–96 ||2–4 |
|Adolescent (male) ||21 ||30–60 ||1.5–3 |
|Adolescent (female) ||20 ||30–60 ||1.5–3 |
|Adult (male) ||13 ||26–52 ||2–4 |
|Adult (female) ||21 ||18–36 ||1–2 |
|Mid-to-late pregnancy ||80 ||18–36 ||0.22–0.45 |
In developed countries, the normal adult diet contains ∼6 mg of iron per 1000 calories, providing an average daily intake for adult men of between 12 and 20 mg and for adult women of between 8 and 15 mg. Foods high in iron (>5 mg/100 g) include organ meats such as liver and heart, brewer's yeast, wheat germ, egg yolks, oysters, and certain dried beans and fruits; foods low in iron (<1 mg/100 g) include milk and milk products and most nongreen vegetables. The content of iron in food is affected further by the manner of its preparation because iron may be added from cooking in iron pots.
Although the iron content of the diet obviously is important, of greater nutritional significance is the bioavailability of iron in food. Heme iron, which constitutes only 6% of dietary iron, is far more available and is absorbed independent of the diet composition; it therefore represents 30% of iron absorbed (Conrad and Umbreit, 2002).
The nonheme fraction nonetheless represents far the largest amount of dietary iron ingested by the economically underprivileged. In a vegetarian diet, nonheme iron is absorbed very poorly because of the inhibitory action of a variety of dietary components, particularly phosphates. Ascorbic acid and meat facilitate the absorption of nonheme iron. Ascorbate forms complexes with and/or reduces ferric to ferrous iron. Meat facilitates the absorption of iron by stimulating production of gastric acid; other effects also may be involved. Either of these substances can increase availability several fold. Thus assessment of available dietary iron should include both the amount of iron ingested and an estimate of its availability (Figure 37–4) (Monsen et al., 1978).
A comparison of iron requirements with available dietary iron is seen in Table 37–4. Obviously, pregnancy and infancy represent periods of negative balance. Menstruating women also are at risk, whereas iron balance in adult men and nonmenstruating women is reasonably secure. The difference between dietary supply and requirements is reflected in the size of iron stores, which are low or absent when iron balance is precarious and high when iron balance is favorable (Table 37–2). Thus in infants after the third month of life and in pregnant women after the first trimester, stores of iron are negligible. Menstruating women have approximately one-third the stored iron found in adult men, indicative of the extent to which the additional average daily loss of ∼0.5 mg of iron affects iron balance.
Effect of iron status on the absorption of nonheme iron in food. The percentages of iron absorbed from diets of low, medium, and high bioavailability in individuals with iron stores of 0, 250, 500, and 1000 mg are portrayed. (After Monsen et al., 1978; reproduced with permission by the American Journal of Clinical Nutrition. © Am J Clin Nutr. American Society for Clinical Nutrition.)
Iron Deficiency. Iron deficiency is the most common nutritional disorder (McLean et al., 2009). The prevalence of iron-deficiency anemia in the U.S. is on the order of 1-4% and depends on the economic status of the population. In developing countries, up to 20-40% of infants and pregnant women may be affected. Better iron balance has resulted from the practice of fortifying flour, the use of iron-fortified formulas for infants, and the prescription of medicinal iron supplements during pregnancy.
Iron-deficiency anemia results from dietary intake of iron that is inadequate to meet normal requirements (nutritional iron deficiency), blood loss, or interference with iron absorption (Clark, 2009). This can have a genetic basis, as in iron-refractory iron deficiency anemia in which patients have iron deficiency that is unresponsive to oral iron, but partially responsive to parenteral iron (Finberg, 2009). Poor oral absorption also can be acquired, as in conditions associated with impaired oral absorption of vitamin B12 (Fernandez-Banares et al., 2009), or following partial gastrectomy. More severe iron deficiency is usually the result of blood loss, either from the GI tract, or in women, from the uterus. Finally, treatment of patients with erythropoietin can result in a functional iron deficiency.
Iron deficiency in infants and young children can lead to behavioral disturbances and can impair development, which may not be fully reversible. Iron deficiency in children also can lead to an increased risk of lead toxicity secondary to pica and an increased absorption of heavy metals. Premature and low-birthweight infants are at greatest risk for developing iron deficiency, especially if they are not breast-fed and/or do not receive iron-fortified formula. After the age of 2-3 years, the requirement for iron declines until adolescence when rapid growth combined with irregular dietary habits again increases the risk of iron deficiency. Adolescent girls are at greatest risk; the dietary iron intake of most girls ages 11-18 is insufficient to meet their requirements.
The recognition of iron deficiency rests on an appreciation of the sequence of events that lead to depletion of iron stores. A negative balance first results in a reduction of iron stores and eventually a parallel decrease in red-cell iron and iron-related enzymes (Figure 37–5). In adults, depletion of iron stores may be recognized by a plasma ferritin <12 μg/L and the absence of reticuloendothelial hemosiderin in the marrow aspirate. Iron-deficient erythropoiesis is identified by a decreased saturation of transferrin to <16% and/or by an increase above normal in red-cell protoporphyrin. Iron-deficiency anemia is associated with a recognizable decrease in the concentration of hemoglobin in blood. However, the physiological variation in hemoglobin levels is so great that only about half the individuals with iron-deficient erythropoiesis are identified from their anemia. Moreover, so-called normal hemoglobin and iron values in infancy and childhood are lower because of the more restricted supply of iron in young children (Dallman et al., 1980).
In mild iron deficiency, identifying the underlying cause is more important than any symptoms related to the deficiency state. Because of the frequency of iron deficiency in infants and in menstruating or pregnant women, the need for exhaustive evaluation of such individuals usually is determined by the severity of the anemia. However, iron deficiency in men or postmenopausal women necessitates a search for a site of bleeding.
Although the presence of microcytic anemia is the most common indicator of iron deficiency, laboratory tests—such as measurement of transferrin saturation, red-cell protoporphyrin, and plasma ferritin—are required to distinguish iron deficiency from other causes of microcytosis. Such measurements are particularly useful when circulating red cells are not yet microcytic because of the recent nature of blood loss, but iron supply nonetheless limits erythropoiesis. More difficult is the differentiation of true iron deficiency from iron-deficient erythropoiesis due to inflammation. In the latter condition, iron stores actually are increased, but the release of iron from reticuloendothelial cells is blocked, the concentration of iron in plasma is decreased, and the supply of iron to the erythroid marrow becomes inadequate. The increased stores of iron in this condition may be demonstrated directly by examination of an aspirate of marrow or may be inferred from determination of an elevated plasma concentration of ferritin.
Sequential changes (from left to right) in the development of iron deficiency in the adult. Red rectangles indicate abnormal test results. RE marrow Fe, reticuloendothelial hemosiderin; RBC, red blood cells. (Adapted from Hillman RS and Finch CA. Red Cell Manual, 7th ed. FA Davis Co., Philadelphia, 1997. Used with permission.)
Treatment of Iron Deficiency
General Therapeutic Principles. The response of iron-deficiency anemia to iron therapy is influenced by several factors, including the severity of anemia, the ability of the patient to tolerate and absorb medicinal iron, and the presence of other complicating illnesses. Therapeutic effectiveness is best measured by the resulting increase in the rate of production of red cells. The magnitude of the marrow response to iron therapy is proportional to the severity of the anemia (level of erythropoietin stimulation) and the amount of iron delivered to marrow precursors.
The patient's ability to tolerate and absorb medicinal iron is a key factor in determining the rate of response to therapy. The small intestine regulates absorption, and with increasing doses of oral iron, limits the entry of iron into the bloodstream. This provides a natural ceiling on how much iron can be supplied by oral therapy. In the patient with a moderately severe iron-deficiency anemia, tolerable doses of oral iron will deliver, at most, 40-60 mg of iron per day to the erythroid marrow. This is an amount sufficient for production rates of two to three times normal.
Complicating illness also can interfere with the response of an iron-deficiency anemia to iron therapy. By decreasing the number of red-cell precursors, intrinsic disease of the marrow can blunt the response. Inflammatory illnesses suppress the rate of red-cell production, both by reducing iron absorption and reticuloendothelial release and by direct inhibition of erythropoietin and erythroid precursors. Continued blood loss can mask the response as measured by recovery of the hemoglobin or hematocrit.
Clinically, the effectiveness of iron therapy is best evaluated by tracking the reticulocyte response and the rise in the hemoglobin or the hematocrit. An increase in the reticulocyte count is not observed for at least 4-7 days after beginning therapy. A measurable increase in the hemoglobin level takes even longer. A decision as to the effectiveness of treatment should not be made for 3-4 weeks after the start of treatment. An increase of ≥20 g/L in the concentration of hemoglobin by that time should be considered a positive response, assuming that no other change in the patient's clinical status can account for the improvement and that the patient has not been transfused.
If the response to oral iron is inadequate, the diagnosis must be reconsidered. A full laboratory evaluation should be conducted, and poor compliance by the patient or the presence of a concurrent inflammatory disease must be explored. A source of continued bleeding obviously should be sought. If no other explanation can be found, an evaluation of the patient's ability to absorb oral iron should be considered. There is no justification for merely continuing oral iron therapy beyond 3-4 weeks if a favorable response has not occurred.
Once a response to oral iron is demonstrated, therapy should be continued until the hemoglobin returns to normal. Treatment may be extended if it is desirable to replenish iron stores. This may require a considerable period of time because the rate of absorption of iron by the intestine will decrease markedly as iron stores are reconstituted. The prophylactic use of oral iron should be reserved for patients at high risk, including pregnant women, women with excessive menstrual blood loss, and infants. Iron supplements also may be of value for rapidly growing infants who are consuming substandard diets and for adults with a recognized cause of chronic blood loss. Except for infants, in whom the use of supplemented formulas is routine, the use of over-the-counter mixtures of vitamins and minerals to prevent iron deficiency should be discouraged.
Therapy with Oral Iron. Orally administered ferrous sulfate is the treatment of choice for iron deficiency. Ferrous salts are absorbed about three times as well as ferric salts, and the discrepancy becomes even greater at high dosages. Variations in the particular ferrous salt have relatively little effect on bioavailability; the sulfate (feosol, others), fumarate (hemocyte, feostat, others), succinate, gluconate (fergon, others), aspartate, other ferrous salts, and polysaccharide-ferrihydrite complex (niferex, others), are absorbed to approximately the same extent. The effective dose of all of these preparations is based on iron content.
Other iron compounds have utility in fortification of foods. Reduced iron (metallic iron, elemental iron) is as effective as ferrous sulfate, provided that the material employed has a small particle size. Large-particle ferrum reductum and iron phosphate salts have a much lower bioavailability, and their use for the fortification of foods is undoubtedly responsible for some of the confusion concerning effectiveness. Ferric edetate has been shown to have good bioavailability and to have advantages for maintenance of the normal appearance and taste of food.
The amount of iron, rather than the mass of the total salt in iron tablets, is important. It also is essential that the coating of the tablet dissolve rapidly in the stomach. Surprisingly, because iron usually is absorbed in the upper small intestine, certain delayed-release preparations have been reported to be effective and have been said to be even more effective than ferrous sulfate when taken with meals. However, reports of absorption from such preparations vary. Because a number of forms of delayed-release preparations are on the market and information on their bioavailability is limited, the effectiveness of most such preparations must be considered questionable.
A variety of substances designed to enhance the absorption of iron has been marketed, including surface-acting agents, carbohydrates, inorganic salts, amino acids, and vitamins. When present in an amount of ≥200 mg, ascorbic acid increases the absorption of medicinal iron by at least 30%. However, the increased uptake is associated with a significant increase in the incidence of side effects; therefore, the addition of ascorbic acid seems to have little advantage over increasing the amount of iron administered. It is inadvisable to use preparations that contain other compounds with therapeutic actions of their own, such as vitamin B12, folate, or cobalt, because the patient's response to the combination cannot easily be interpreted.
The average dose for the treatment of iron-deficiency anemia is ∼200 mg of iron per day (2-3 mg/kg), given in three equal doses of 65 mg. Children weighing 15-30 kg can take half the average adult dose; small children and infants can tolerate relatively large doses of iron, e.g., 5 mg/kg. The dose used is a compromise between the desired therapeutic action and the toxic effects. Prophylaxis and mild nutritional iron deficiency may be managed with modest doses. When the object is the prevention of iron deficiency in pregnant women, e.g., doses of 15 to 30 mg of iron per day are adequate to meet the 3- to 6-mg daily requirement of the last two trimesters. When the purpose is to treat iron-deficiency anemia, but the circumstances do not demand haste, a total dose of ∼100 mg (35 mg three times daily) may be used.
The responses expected for different dosage regimens of oral iron are given in Table 37–5. These effects are modified by the severity of the iron-deficiency anemia and by the time of ingestion of iron relative to meals. Bioavailability of iron ingested with food is probably one-half or one-third of that seen in the fasting subject (Grebe et al., 1975). Antacids also reduce iron absorption if given concurrently. It is always preferable to administer iron in the fasting state, even if the dose must be reduced because of GI side effects. For patients who require maximal therapy to encourage a rapid response or to counteract continued bleeding, as much as 120 mg of iron may be administered four times a day. Sustained high rates of red-cell production require an uninterrupted supply of iron, and oral doses should be spaced equally to maintain a continuous high concentration of iron in plasma.
The duration of treatment is governed by the rate of recovery of hemoglobin and the desire to create iron stores. The former depends on the severity of the anemia. With a daily rate of repair of 2 g of hemoglobin per liter of whole blood, the red-cell mass usually is reconstituted within 1-2 months. Thus an individual with a hemoglobin of 50 g per liter may achieve a normal complement of 150 g/L in ∼50 days, whereas an individual with a hemoglobin of 100 g/L may take only half that time. The creation of stores of iron requires many months of oral iron administration. The rate of absorption decreases rapidly after recovery from anemia, and after 3-4 months of treatment, stores may increase at a rate of not much more than 100 mg/month. Much of the strategy of continued therapy depends on the estimated future iron balance. Patients with an inadequate diet may require continued therapy with low doses of iron. If the bleeding has stopped, no further therapy is required after the hemoglobin has returned to normal. With continued bleeding, long-term, high-dose therapy clearly is indicated.
Table 37-5Average Response to Oral Iron ||Download (.pdf) Table 37-5 Average Response to Oral Iron
| ||ESTIMATED ABSORPTION || |
|TOTAL DOSE OF IRON (mg/day) ||% ||mg ||INCREASE IN Blood Hb (g/L/day) |
|35 ||40 ||14 ||0.7 |
|105 ||24 ||25 ||1.4 |
|195 ||18 ||35 ||1.9 |
|390 ||12 ||45 ||2.2 |
Untoward Effects of Oral Preparations of Iron. Intolerance to oral preparations of iron primarily is a function of the amount of soluble iron in the upper GI tract and of psychological factors. Side effects include heartburn, nausea, upper gastric discomfort, and diarrhea or constipation. A good policy is to initiate therapy at a small dosage, to demonstrate freedom from symptoms at that level, and then gradually to increase the dosage to that desired. With a dose of 200 mg of iron per day divided into three equal portions, symptoms occur in ∼25% of treated individuals versus 13% among those receiving placebo; this increases to ∼40% when the dosage of iron is doubled. Nausea and upper abdominal pain are increasingly common at high dosage. Constipation and diarrhea, perhaps related to iron-induced changes in the intestinal bacterial flora, are not more prevalent at higher dosage, nor is heartburn. If a liquid is given, one can place the iron solution on the back of the tongue with a dropper to prevent transient staining of teeth.
The normal individual apparently is able to control absorption of iron despite high intake, and it is only individuals with underlying disorders that augment the absorption of iron who run the hazard of developing iron overload (hemochromatosis). However, hemochromatosis is a relatively common genetic disorder, present in 0.5% of the population.
Iron Poisoning. Large amounts of ferrous salts are toxic, but fatalities are rare in adults. Most deaths occur in children, particularly between the ages of 12 and 24 months. As little as 1-2 g of iron may cause death, but 2-10 g usually is ingested in fatal cases. The frequency of iron poisoning relates to its availability in the household, particularly the supply that remains after a pregnancy. The colored sugar coating of many of the commercially available tablets gives them the appearance of candy. All iron preparations should be kept in childproof bottles.
Signs and symptoms of severe poisoning may occur within 30 minutes after ingestion or may be delayed for several hours. They include abdominal pain, diarrhea, or vomiting of brown or bloody stomach contents containing pills. Of particular concern are pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and cardiovascular collapse. If death does not occur within 6 hours, there may be a transient period of apparent recovery, followed by death in 12-24 hours. The corrosive injury to the stomach may result in pyloric stenosis or gastric scarring. Hemorrhagic gastroenteritis and hepatic damage are prominent findings at autopsy. In the evaluation of a child thought to have ingested iron, a color test for iron in the gastric contents and an emergency determination of the concentration of iron in plasma can be performed. If the latter is <63 μmol (3.5 mg/L), the child is not in immediate danger. However, vomiting should be induced when there is iron in the stomach, and an x-ray should be taken to evaluate the number of pills remaining in the small bowel (iron tablets are radiopaque). Iron in the upper GI tract can be precipitated by lavage with sodium bicarbonate or phosphate solution, although the clinical benefit is questionable. When the plasma concentration of iron is greater than the total iron-binding capacity (63 μmol; 3.5 mg/L), deferoxamine should be administered (Chapter 67). Shock, dehydration, and acid-base abnormalities should be treated in the conventional manner. Most important is the speed of diagnosis and therapy. With early effective treatment, the mortality from iron poisoning can be reduced from as high as 45% to ∼1%.
Therapy with Parenteral Iron. When oral iron therapy fails, parenteral iron administration may be an effective alternative (Silverstein and Rodgers, 2004). The rate of response to parenteral therapy is similar to that which follows usual oral doses. Common indications are iron malabsorption (e.g., sprue, short bowel syndrome), severe oral iron intolerance, as a routine supplement to total parenteral nutrition, and in patients who are receiving erythropoietin (Eschbach et al., 1987). In particular, when hemodialysis patients are started on erythropoietin, oral iron therapy alone generally is insufficient to provide an optimal hemoglobin response. It therefore is recommended that sufficient parenteral iron be given to maintain a plasma ferritin level between 100 and 800 μg/L and a transferrin saturation of 20-50% (Goodnough et al., 2000).
Parenteral iron also has been given to iron-deficient patients and pregnant women to create iron stores, something that would take months to achieve by the oral route. The belief that the response to parenteral iron, especially iron dextran, is faster than oral iron is open to debate. In otherwise healthy individuals, the rate of hemoglobin response is determined by the balance between the severity of the anemia (the level of erythropoietin stimulus) and the delivery of iron to the marrow from iron absorption and iron stores. When a large intravenous dose of iron dextran is given to a severely anemic patient, the hematologic response can exceed that seen with oral iron for 1-3 weeks. Subsequently, however, the response is no better than that seen with oral iron.
Parenteral iron therapy should be used only when clearly indicated because acute hypersensitivity, including anaphylactic and anaphylactoid reactions, can occur in 0.2-3% of patients (Faich and Strobos, 1999). Other reactions to intravenous iron include headache, malaise, fever, generalized lymphadenopathy, arthralgias, urticaria, and in some patients with rheumatoid arthritis, exacerbation of the disease.
Four iron formulations are available in the U.S. These are iron dextran (dexferrum or infed), sodium ferric gluconate (ferrlecit), ferumoxytol (feraheme), and iron sucrose (venofer). Ferumoxytol is a semisynthetic carbohydrate-coated superparamagnetic iron oxide nanoparticle that is approved for treatment of iron-deficiency anemia in patients with chronic kidney disease (Balakrishnan et al., 2009). The indications for the iron dextran preparations include treatment of any patient with documented iron deficiency and intolerance or irresponsiveness to oral iron. In contrast, the indications for the ferric gluconate and iron sucrose are limited to patients with chronic kidney disease who have a documented iron deficiency, although broader applications are being advocated (Wish, 2008). Iron dextran is the only preparation that can be given as a total-dose infusion, which is the entire dose of elemental iron required to replace iron stores. However, ferric gluconate and iron sucrose are administered as a fixed dose every week for several weeks until total iron stores are replenished.
Iron Dextran. Iron dextran injection (infed or dexferrum) is a colloidal solution of ferric oxyhydroxide complexed with polymerized dextran (molecular weight, ∼180,000 Da) that contains 50 mg/mL of elemental iron. The use of low-molecular-weight iron dextran has reduced the incidence of toxicity relative to that observed with high molecular weight preparations (imferon) (Auerbach and Al Talib, 2008). Iron dextran can be administered by either intravenous (preferred) or intramuscular injection. When given by deep intramuscular injection, it is gradually mobilized via the lymphatics and transported to reticuloendothelial cells; the iron then is released from the dextran complex. Intravenous administration gives a more reliable response. Given intravenously in a dose <500 mg, the iron dextran complex is cleared exponentially with a plasma t1/2 of 6 hours. When ≥1 g is administered intravenously as total dose therapy, reticuloendothelial cell clearance is constant at 10-20 mg/hour. This slow rate of clearance results in a brownish discoloration of the plasma for several days and an elevation of the serum iron for 1-2 weeks.
Once the iron is released from the dextran within the reticuloendothelial cells, it is either incorporated into stores or transported via transferrin to the erythroid marrow. Although a portion of the processed iron is rapidly made available to the marrow, a significant fraction is only gradually converted to usable iron stores. All of the iron eventually is released, although many months are required before the process is complete. During this time, the iron dextran stores in reticuloendothelial cells can confuse the clinician who attempts to evaluate the iron status of the patient.
Intramuscular injection of iron dextran should only be initiated after a test dose of 0.5 mL (25 mg of iron). If no adverse reactions are observed, the injections can proceed. The daily dose ordinarily should not exceed 0.5 mL (25 mg of iron) for infants weighing <4.5 kg (10 lb), 1 mL (50 mg of iron) for children weighing <9 kg (20 lb), and 2 mL (100 mg of iron) for other patients. Iron dextran should be injected only into the muscle mass of the upper outer quadrant of the buttock using a z-track technique (displacement of the skin laterally before injection). However, local reactions and the concern about malignant change at the site of injection (Weinbren et al., 1978) make intramuscular administration inappropriate except when the intravenous route is inaccessible.
A test injection of 0.5 mL of undiluted iron dextran or an equivalent amount (25 mg of iron) diluted in saline also should precede intravenous administration of a therapeutic dose of iron dextran. The patient should be observed for signs of immediate anaphylaxis and for an hour after injection for any signs of vascular instability or hypersensitivity, including respiratory distress, hypotension, tachycardia, or back or chest pain. When widely spaced total-dose infusion therapy is given, a test dose injection should be given before each infusion because hypersensitivity can appear at any time. Furthermore, the patient should be monitored closely throughout the infusion for signs of cardiovascular instability. Delayed hypersensitivity reactions also are observed, especially in patients with rheumatoid arthritis or a history of allergies. Fever, malaise, lymphadenopathy, arthralgias, and urticaria can develop days or weeks following injection and last for prolonged periods of time. Therefore, iron dextran should be used with extreme caution in patients with rheumatoid arthritis or other connective tissue diseases, and during the acute phase of an inflammatory illness. Once hypersensitivity is documented, iron dextran therapy must be abandoned.
Before initiating iron dextran therapy, the total dose of iron required to repair the patient's iron-deficient state should be calculated. Relevant factors are the hemoglobin deficit, the need to reconstitute iron stores, and continued excess losses of iron, as seen with hemodialysis and chronic GI bleeding. Iron dextran solution (50 mg/mL of elemental iron) can be administered undiluted in daily doses of 2 mL until the total dose is reached or given off label as a single total-dose infusion. In the latter case, the iron dextran should be diluted in 250-1000 mL of 0.9% saline and infused over an hour or more.
With repeated doses of iron dextran—especially multiple total-dose infusions such as those sometimes used in the treatment of chronic GI blood loss—accumulations of slowly metabolized iron dextran stores in reticuloendothelial cells can be impressive. The plasma ferritin level also can rise to levels associated with iron overload. Although disease-related hemochromatosis has been associated with an increased risk of infections and cardiovascular disease, this has not been shown to be true in hemodialysis patients treated with iron dextran (Owen, 1999). It seems prudent, however, to withhold the drug whenever the plasma ferritin rises above 800 μg/L.
Sodium Ferric Gluconate. Sodium ferric gluconate is an intravenous iron preparation with a molecular size of ∼295,000 Da and an osmolality of 990 mOsm/kg−1 (Balakrishnan et al., 2009). Administration of ferric gluconate at doses ranging from 62.5-125 mg during hemodialysis is associated with transferrin saturation exceeding 100% (Zanen et al., 1996). Hemodialysis patients who had ferritin levels between 500 and 1200 ng/mL and transferrin saturations of ≤25% while undergoing treatment with erythropoietin had improved hemoglobin values following treatment with ferric gluconate, resulting in reduced requirements for erythropoietin (Kapoian et al., 2008).
Unlike iron dextran, which requires processing by macrophages that may require several weeks, ∼80% of sodium ferric gluconate is delivered to transferrin with in 24 hours. Sodium ferric gluconate also has a lower risk of inducing serious anaphylactic reactions than iron dextran (Sengolge et al., 2005). No deaths were reported with 25 million infusions of sodium ferric gluconate, whereas there were 31 infusion-related deaths reported from approximately half the number of patients treated with iron dextran (Faich and Strobos, 1999). Thus, sodium ferric gluconate has become the preferred agent for parenteral iron therapy. Currently iron dextran is reserved for noncompliant patients or for those who are seriously inconvenienced by the multiple infusions that may be required for treatment with sodium ferric gluconate or iron sucrose.
Iron Sucrose. Iron sucrose is complex of polynuclear iron (III)-hydroxide in sucrose with a molecular weight of 252,000 Da and an osmolality of 1316 mOsm/kg−1 (Balakrishnan et al., 2009). Following intravenous injection, the complex is taken up by the reticuloendothelial system, where it dissociates into iron and sucrose. Iron sucrose is generally administered in daily amounts of 100-200 mg within a 14-day period to a total cumulative dose of 1000 mg. It can be administered repeatedly to hemodialysis patients as maintenance therapy without inducing hypersensitivity (Aronoff et al., 2004).
Like sodium ferric gluconate, iron sucrose appears to be better tolerated and to cause fewer adverse events than iron dextran (Hayat, 2008). This agent is FDA-approved for the treatment of iron deficiency in patients with chronic kidney disease. However, iron sucrose has been used effectively to treat iron deficiency observed in other clinical settings (al-Momen et al., 1996; Bodemar et al., 2004). However, one study reported that iron sucrose may be most likely of available parenteral iron preparations to induce renal tubular injury because of its high renal uptake (Zager et al., 2004), potentially resulting in tubulointerstitial damage with chronic repeated use (Agarwal, 2006).
Copper deficiency is extremely rare because the amount present in food is more than adequate to provide the needed body complement of slightly more than 100 mg. There is speculation that marginal deficiency of copper can contribute to development or progression of a number of chronic disorders, such as diabetes or cardiovascular disease (Uriu-Adams and Keen, 2005). However, there is no evidence that copper ever needs to be added to a normal diet, either prophylactically or therapeutically. Even in clinical states associated with hypocupremia (sprue, celiac disease, and nephrotic syndrome), effects of copper deficiency usually are not demonstrable. Anemia due to copper deficiency has been described in individuals who have undergone intestinal bypass surgery (Zidar et al., 1977), in those who are receiving parenteral nutrition (Dunlap et al., 1974), in malnourished infants (Graham and Cordano, 1976), and in patients ingesting excessive amounts of zinc (Hoffman et al., 1988).
Copper has redox properties similar to that of iron, which simultaneously is essential and potentially toxic to the cell (Kim et al., 2008). Cells have virtually no free copper. Instead copper is stored by metallothioneins and distributed by specialized chaperones to sites that make use of its redox properties (Lalioti et al., 2009). Transfer of copper to nascent cuproenzymes is performed by individual or collective activities of P-type ATPases, ATP7A and ATP7B, which are expressed in all tissues (Linz and Lutsenko, 2007). In mammals, the liver is the organ most responsible for the storage, distribution, and excretion of copper. Mutations in ATP7A or ATP7B that interfere with this function have been found responsible for Wilson's disease or Menkes syndrome (steely hair syndrome) (de Bie et al., 2007), respectively, which can result in life-threatening hepatic failure.
Copper deficiency in experimental animals interferes with the absorption of iron and its release from reticuloendothelial cells (Gambling et al., 2008). The associated microcytic anemia is related to a decrease in the availability of iron to the normoblasts, and perhaps even more importantly, to decreased mitochondrial production of heme. It may be that the specific defect in the latter case is a decrease in the activity of cytochrome oxidase. Other pathological effects involving the skeletal, cardiovascular, and nervous systems have been observed in copper-deficient experimental animals. In humans, the prominent findings have been leukopenia, particularly granulocytopenia, and anemia. Concentrations of iron in plasma are variable, and the anemia is not always microcytic. When a low plasma copper concentration is determined in the presence of leukopenia and anemia, a therapeutic trial with copper is appropriate. Daily doses up to 0.1 mg/kg of cupric sulfate have been given by mouth, or 1-2 mg per day may be added to the solution of nutrients for parenteral administration. The daily U.S. Recommended Daily Allowance (RDA) of copper ranges from 1,300 μg for nursing women to 200 μg for infants 0-6 months of age.
Harris and associates first described pyridoxine-responsive anemia in 1956. Subsequent reports suggested that the vitamin might improve hematopoiesis in up to 50% of patients with either hereditary or acquired sideroblastic anemia. These patients characteristically have impaired hemoglobin synthesis and accumulate iron in the perinuclear mitochondria of erythroid precursor cells, so-called ringed sideroblasts. Hereditary sideroblastic anemia is an X-linked recessive trait with variable penetrance and expression that results from mutations in the erythrocyte form of δ-aminolevulinate synthase. Affected men typically show a dual population of normal red cells and microcytic, hypochromic cells in the circulation. In contrast, idiopathic acquired sideroblastic anemia and the sideroblastic anemias associated with a number of drugs, inflammatory states, neoplastic disorders, and preleukemic syndromes show a variable morphological picture. Moreover, erythrokinetic studies demonstrate a spectrum of abnormalities, from a hypoproliferative defect with little tendency to accumulate iron to marked ineffective erythropoiesis with iron overload of the tissues (Solomon and Hillman, 1979).
Oral therapy with pyridoxine is of proven benefit in correcting the sideroblastic anemias associated with the antituberculosis drugs isoniazid and pyrazinamide, which act as vitamin B6 antagonists. A daily dose of 50 mg of pyridoxine completely corrects the defect without interfering with treatment, and routine supplementation of pyridoxine often is recommended (see Chapter 56). In contrast, if pyridoxine is given to counteract the sideroblastic abnormality associated with administration of levodopa, the effectiveness of levodopa in controlling Parkinson's disease is decreased. Pyridoxine therapy does not correct the sideroblastic abnormalities produced by chloramphenicol or lead.
Patients with idiopathic acquired sideroblastic anemia generally fail to respond to oral pyridoxine, and those individuals who appear to have a pyridoxine-responsive anemia require prolonged therapy with large doses of the vitamin, 50-500 mg per day. Unfortunately, the early enthusiasm for treatment with pyridoxine was not reinforced by results of later studies. Moreover, even when a patient with sideroblastic anemia responds, the improvement is only partial because both the ringed sideroblasts and the red-cell defect persist, and the hematocrit rarely returns to normal. Nonetheless, in view of the low toxicity of oral pyridoxine, a therapeutic trial with pyridoxine is appropriate.
As shown in studies of normal subjects, oral pyridoxine in a dosage of 100 mg three times daily produces a maximal increase in red-cell pyridoxine kinase and the major pyridoxal phosphate–dependent enzyme glutamic-aspartic aminotransferase (Solomon and Hillman, 1978). For an adequate therapeutic trial, the drug is administered for at least 3 months while the response is monitored by measuring the reticulocyte index and the hemoglobin concentration. The occasional patient who is refractory to oral pyridoxine may respond to parenteral administration of pyridoxal phosphate. However, oral pyridoxine in doses of 200-300 mg per day produces intracellular concentrations of pyridoxal phosphate equal to or greater than those generated by therapy with the phosphorylated vitamin.
Pure red-cell aplasia that responded to the administration of riboflavin was reported in patients with protein depletion and complicating infections. Lane and associates induced riboflavin deficiency in humans and demonstrated that a hypoproliferative anemia resulted within a month. The spontaneous appearance in humans of red-cell aplasia due to riboflavin deficiency undoubtedly is rare, if it occurs at all. It has been described in combination with infection and protein deficiency, both of which are capable of producing a hypoproliferative anemia. However, it seems reasonable to include riboflavin in the nutritional management of patients with gross, generalized malnutrition.