Medication Summary
The most economical and effective medical treatment for iron deficiency anemia is the oral administration of ferrous iron salts. Among the various iron salts, ferrous sulfate most commonly is used. Claims are made that other iron salts are absorbed better and have less morbidity. Generally, the toxicity is proportional to the amount of iron available for absorption. If the quantity of iron in the test dose is decreased, the percentage of the test dose absorbed is increased, but the quantity of iron absorbed is diminished.
There are advocates for the use of carbonyl iron because of the greater safety with children who ingest their mothers’ medication. Decreased gastric toxicity is claimed but not clearly demonstrated in human trials. Bioavailability is approximately 70% of a similar dose of ferrous sulfate.
Reserve parenteral iron for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron. It is expensive and has greater morbidity than oral preparations of iron.
Iron Products
Class Summary
These agents are used to provide adequate iron for hemoglobin synthesis and to replenish body stores of iron. Iron is administered prophylactically during pregnancy because of anticipated requirements of the fetus and losses that occur during delivery.
Ferrous sulfate (Feratab, Fer-Iron, Slow-FE)
Ferrous sulfate is the mainstay treatment for treating patients with iron deficiency anemia. They should be continued for about 2 months after correction of the anemia and its etiologic cause in order to replenish body stores of iron. Ferrous sulfate is the most common and cheapest form of iron utilized. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.
Carbonyl iron (Feosol, Icar)
Carbonyl iron is used as a substitute for ferrous sulfate. It has a slower release of iron and is more expensive than ferrous sulfate. The slower release affords the agent greater safety if ingested by children. On a milligram-for-milligram basis, it is 70% as efficacious as ferrous sulfate. Claims are made that there is less gastrointestinal (GI) toxicity, prompting use when ferrous salts are producing intestinal symptoms and in patients with peptic ulcers and gastritis. Tablets are available containing 45 mg and 60 mg of iron.
Ferric citrate
Ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the GI tract. After transport through the enterocytes into the blood, oxidized ferric iron circulates bound to the plasma protein transferrin, and can be incorporated into hemoglobin. Ferric citrate 1 g is equivalent to ferric iron 210 mg. It is indicated in adults with iron deficiency anemia who have CKD and are not on dialysis.
Iron dextran Complex (INFeD)
Dextran-iron replenishes depleted iron stores in the bone marrow, where it is incorporated into hemoglobin. Parenteral use of iron-carbohydrate complexes has caused anaphylactic reactions, and its use should be restricted to patients with an established diagnosis of iron deficiency anemia whose anemia is not corrected with oral therapy.
The required dose can be calculated (3.5 mg iron/g of hemoglobin) or obtained from tables in the Physician's Desk Reference. For intravenous (IV) use, this agent may be diluted in 0.9% sterile saline. Do not add to solutions containing medications or parenteral nutrition solutions.
Iron sucrose (Venofer)
Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) in adults with chronic kidney disease (either with or without hemodialysis or peritoneal dialysis). Iron deficiency in these patients is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the GI tract. There is a lower incidence of anaphylaxis with iron sucrose than with other parenteral iron products.
Ferric carboxymaltose (Injectafer)
Ferric carboxymaltose is a nondextran IV colloidal iron hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron. It is indicated for iron deficiency anemia (IDA) in patients aged 1 year and older who have intolerance or an unsatisfactory response to oral iron. It is also indicated for IDA in adults with nondialysis-dependent chronic kidney disease.
The FDA has also approved ferric carboxymaltose for iron replacement as treatment of iron deficiency with heart failure and New York Heart Association class II/III to improve exercise capacity.
Ferrous gluconate (Fergon)
Ferrous gluconate replaces iron found in hemoglobin, myoglobin, and enzymes; allows the transportation of oxygen via hemoglobin. It is indicated in the prevention and treatment of iron-deficiency anemias.
Ferrous fumarate (Feostat, Ferro-Sequels, Nephro Fer)
Ferrous fumarate is a replacement of iron stores found in hemoglobin, myoglobin, and enzymes; works to transport oxygen via hemoglobin. . It is indicated in the prevention and treatment of iron-deficiency anemias.
Ferumoxytol (Feraheme)
Ferumoxytol is iron-carbohydrate complex released within macrophage vesicles; either enters intracellular iron storage (eg, ferritin) or transferred to plasma transferrin for transport to erythroid precursor cells for hemoglobin incorporation. It is indicated for iron deficiency anemia (IDA) in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron. Also, ferumoxytol is indicated for IDA in adults who have chronic kidney disease (CKD).
Ferric maltol (Accrufer)
An oral iron replacement that delivers iron for uptake across the intestinal wall and transfer to transferrin and ferritin. It is indicated for iron deficiency in adults.
Ferric derisomaltose (Monoferric)
Complex of iron (III) hydroxide and derisomaltose, an iron carbohydrate oligosaccharide that releases iron. Iron binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin. Ferric derisomaltose is administered IV and is indicated for iron deficiency anemia in adults who are intolerant to or have had unsatisfactory response to oral iron.
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The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron. Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.
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Sequential changes in laboratory values following blood loss are depicted. A healthy human was bled 5 L in 500-mL increments over 45 days. A moderate anemia ensued, initially with normal cellular indices and serum iron. Subsequently, the mean corpuscular volume (MCV) increased as iron was mobilized from body stores and reticulocytosis occurred. The serum iron decreased, followed by an increase in the total iron-binding capacity. Gradual decreases in the red blood cell indices occurred, with maximal microcytosis and hypochromia present 120 days after bleeding. Values returned to normal approximately 250 days after blood loss. At the end of the experiment, iron was absent from body stores (marrow) because hemoglobin has a first priority for iron. Iron-59 absorption was increased after all values returned to normal in order to replenish the body store with iron. This suggests that the serum iron, total iron-binding capacity, hemoglobin concentration, and indices were not the primary regulators of iron absorption.
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The total body iron in a 70-kg man is about 4 g. This is maintained by a balance between absorption and body losses. Although the body only absorbs 1 mg daily to maintain equilibrium, the internal requirement for iron is greater (20-25 mg). An erythrocyte has a lifespan of 120 days so that 0.8% of red blood cells are destroyed and replaced each day. A man with 5 L of blood volume has 2.5 g of iron incorporated into the hemoglobin, with a daily turnover of 20 mg for hemoglobin synthesis and degradation and another 5 mg for other requirements. Most of this iron passes through the plasma for reutilization. Iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin.
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Dietary iron contains both heme and nonheme iron. Both chemical forms are absorbed noncompetitively into duodenal and jejunal mucosal cells. Many of the factors that alter the absorption of nonheme iron have little effect upon the absorption of heme iron because of the differences in their chemical structures. Iron is released from heme within the intestinal absorptive cell by heme oxygenase and then transferred into the body as nonheme iron. Factors affecting various stages of iron absorption are shown in this diagram. The simplest model of iron absorption must consider intraluminal, mucosal, and corporeal factors.
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Ultrastructural studies of the rat duodenum from iron-deficient (top), healthy (middle), and iron-loaded (bottom) animals are shown. They were stained with acid ferrocyanide for iron, which is seen as black dots in the specimens. No staining was seen with acid ferricyanide. This indicates that iron was in the ferric redox state. Respectively, the specimens showed no iron, moderate deposits, and increased deposits with ferritin (arrow).Incubation of the specimens with iron-nitrilotriacetic acid to satiate iron-binding proteins with iron provided specimens with equal iron staining, except that the iron-loaded specimens contained ferritin. The quantity of iron in the cell is derived from both the diet and body stores. It probably is important in the regulation of the quantity of iron accepted by the absorptive cell from the gut lumen. The authors postulate that the iron either satiates iron-binding proteins with iron, up-regulates iron regulatory protein, or does both to diminish iron uptake by the absorptive cell. The consequences of these findings are depicted in the flow charts.
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Mucosal cells in the proximal small intestine mediate iron absorption. Intestinal cells are born in the crypts of Lieberkuhn and migrate to the tips of the villi. The cells are sloughed into the intestinal lumen at the end of their 2- to 3-day lifespan. Absorptive cells remain attuned to the body requirement for iron by incorporating proportionate quantities of body iron into the absorptive cells. This iron and recently absorbed iron decrease uptake of iron from the gut lumen by satiation of iron-binding proteins with iron, by stimulating an iron regulatory element, or both. The incorporation of iron into these cells in quantities proportional to body stores of iron also provides a limited method of increasing iron excretion in individuals replete in iron.
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Both nonheme iron and heme iron have 6 coordinating bonds; however, 4 of the bonds in heme bind pyrroles, making them unavailable for chelation by other compounds. Therefore, ascorbic acid chelates nonheme iron to enhance absorption but has no effect upon heme iron. Many dietary components, such as phytates, phosphates, oxalates, and tannates, bind nonheme iron to decrease nonheme iron absorption. They do not affect heme. This explains why heme is so effectively absorbed with foods containing these chelators. Iron hemoglobin structure.
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Three pathways exist in enterocytes for uptake of food iron. In the United States and Europe, most absorbed iron is derived from heme. Heme is digested enzymatically free of globin and enters the enterocyte as a metalloporphyrin. Within the cell iron is released from heme by heme oxygenase to pass into the body as inorganic iron. Most dietary inorganic iron is ferric iron. This can enter the absorptive cell via the integrin-mobilferrin pathway (IMP).Some dietary iron is reduced in the gut lumen and enters the absorptive cell via the divalent metal transporter-1 (DMT-1/DCT-1/Nramp-2). The proteins of both pathways interact within the enterocyte with paraferritin, a large protein complex capable of ferrireduction. Excess iron is stored as ferritin to protect the cell from oxidative damage. Iron leaves the cell to enter plasma facilitated by ferroportin and hephaestin, which associate with an apotransferrin receptor. The enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor.
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A 70-year-old man who is 4 years post-Whipple surgery for pancreatic adenocarcinoma had been in good health with no evidence of recurrence until he had a maroon-colored stool that was heme positive. Physical examination was unrevealing. Laboratory study values showed a WBC of 9000 cells/µL, a hemoglobin of 11.5 g/dL, a mean corpuscular volume (MCV) of 95 fL, a mean corpuscular hemoglobin concentration (MCHC) of 34 g/dL, a platelet count of 250,000 cells/µL, a creatinine level of 0.9 mg/dL, a BUN level of 27 mg/dL, a total bilirubin level of 0.4 mg/dL, a serum iron level of 160 µg/dL, a total iron-binding capacity (TIBC) of 280 µg/dL, and a ferritin level of 85 ng/mL. A peripheral smear is shown.
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A 26-year-old white man was referred with a microcytic anemia that failed to respond to treatment with ferrous sulfate over 6 months. Physical examination showed only mild pallor of mucous membranes. His stool was dark but heme negative. The CBC count showed a WBC of 6000 cells/µL, a hemoglobin level of 11 g/dL, a mean corpuscular volume (MCV) of 70 fL, a mean corpuscular hemoglobin concentration (MCHC) of 33 g/dL, a platelet count of 234,000 cells/µL, a hemoglobin electrophoresis AA, a hemoglobin A2 value of 3.8%, and a fetal hemoglobin value of 2.0%.
