Iron deficiency is the most common cause of chronic anemia. Like other forms of chronic anemia, iron deficiency anemia leads to pallor, fatigue, dizziness, exertional dyspnea, and other gener-alized symptoms of tissue hypoxia. The cardiovascular adaptations to chronic anemia—tachycardia, increased cardiac output, vaso-dilation—can worsen the condition of patients with underlying cardiovascular disease.Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia. Iron-containing heme is also an essential component of myo-globin, cytochromes, and other proteins with diverse biologic functions.
Free inorganic iron is extremely toxic, but iron is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron absorption, trans-port, and storage (Figure 33–1). The system uses specialized trans-port, storage, ferrireductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglo-bin synthesis and adequate iron stores (Table 33–1). A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system. Nearly all of the iron used to sup-port hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes. Normally, only a small amount of iron is lost from the body each day, so dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods.
However, in special populations with either increased iron requirements (eg, growing children, pregnant women) or increased losses of iron (eg, menstruating women), iron requirements can exceed normal dietary supplies and iron deficiency can develop.
The average American diet contains 10–15 mg of elemental iron daily. A normal individual absorbs 5–10% of this iron, or about 0.5–1 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 1–2 mg/d in menstruating women and may be as high as 3–4 mg/d in pregnant women.Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 33–1). Iron in other foods, especially veg-etables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferrireductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells.
Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron by the divalent metal transporter DMT1, and absorption of iron com-plexed with heme (Figure 33–1). Together with iron split from absorbed heme, the newly absorbed iron can be actively trans-ported into the blood across the basolateral membrane by a trans-porter known as ferroportin and oxidized to ferric iron (Fe3+) by the ferroxidase hephaestin. The liver-derived hepcidin inhibits intestinal cell iron release by binding to ferroportin and triggering its internalization and destruction. Excess iron is stored in intesti-nal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin.
Iron is transported in the plasma bound to transferrin, a β-globulin that can bind two molecules of ferric iron (Figure 33–1). The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. In endo-somes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin. The transferrin-transferrin receptor complex is recycled to the cell membrane, where the transferrin dissociates and returns to the plasma. This process provides an efficient mechanism for supplying the iron required by developing red blood cells.
Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells and a reduction in hepatic hepcidin release. Iron store depletion and iron deficiency anemia are associated with an increased concentra-tion of serum transferrin.
In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (Figure 33–1). The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity. Low hepcidin concentrations result in iron release from these storage sites; high hepcidin concentrations inhibit iron release. Ferritin is detectable in serum. Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores.
There is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg of iron per day. Because the body’s ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body’s needs. As noted below, impaired regula-tion of iron absorption leads to serious pathology.
The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia. This manifests as a hypochromic, microcytic anemia in which the erythrocyte mean cell volume (MCV) and the mean cell hemoglobin concen-tration are low (Table 33–2). Iron deficiency is commonly seen in populations with increased iron requirements. These include infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis and also form them at a high rate as a result of treatment with the erythrocyte growth factor erythropoietin . Inadequate iron absorption can also cause iron defi-ciency. This is seen after gastrectomy and in patients with severe small bowel disease that results in generalized malabsorption.
The most common cause of iron deficiency in adults is blood loss. Menstruating women lose about 30 mg of iron with each menstrual period; women with heavy menstrual bleeding may lose much more.
Thus, many premenopausal women have low iron stores or even iron deficiency. In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract. Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding.
Iron deficiency anemia is treated with oral or parenteral iron preparations. Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal. An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin; for these patients, parenteral iron administration is preferred.
1. Oral iron therapy—A wide variety of oral iron prepara-tions is available. Because ferrous iron is most efficiently absorbed, ferrous salts should be used. Ferrous sulfate, ferrous gluconate, and ferrous fumarate are all effective and inexpensive and are recommended for the treatment of most patients.
Different iron salts provide different amounts of elemental iron, as shown in Table 33–3. In an iron-deficient individual, about 50–100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral iron given as ferrous salt can be absorbed. Therefore, 200–400 mg of elemental iron should be given daily to correct iron deficiency most rapidly. Patients unable to tolerate such large doses of iron can be given lower daily doses of iron, which results in slower but still complete correction of iron deficiency. Treatment with oral iron should be continued for 3–6 months after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores.
Common adverse effects of oral iron therapy include nausea, epigastric discomfort, abdominal cramps, constipation, and diar-rhea. These effects are usually dose-related and can often be over-come by lowering the daily dose of iron or by taking the tablets immediately after or with meals. Some patients have less severe gastrointestinal adverse effects with one iron salt than another and benefit from changing preparations. Patients taking oral iron develop black stools; this has no clinical significance in itself but may obscure the diagnosis of continued gastrointestinal blood loss.
2. Parenteral iron therapy—Parenteral therapy should bereserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone. This includes patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoie-tin, various postgastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, and malabsorption syndromes.
The challenge with parenteral iron therapy is that parenteral administration of inorganic free ferric iron produces serious dose-dependent toxicity, which severely limits the dose that can be administered. However, when the ferric iron is formulated as a colloid containing particles with a core of iron oxyhydroxide sur-rounded by a core of carbohydrate, bioactive iron is released slowly from the stable colloid particles. In the United States, the three available forms of parenteral iron are iron dextran, sodium ferricgluconate complex, and iron sucrose.
Iron dextran is a stable complex of ferric oxyhydroxide anddextran polymers containing 50 mg of elemental iron per millili-ter of solution. It can be given by deep intramuscular injection or by intravenous infusion, although the intravenous route is used most commonly. Intravenous administration eliminates the local pain and tissue staining that often occur with the intramuscular route and allows delivery of the entire dose of iron necessary to correct the iron deficiency at one time. Adverse effects of intrave-nous iron dextran therapy include headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urti-caria, bronchospasm, and, rarely, anaphylaxis and death. Owing to the risk of a hypersensitivity reaction, a small test dose of iron dextran should always be given before full intramuscular or intra-venous doses are given. Patients with a strong history of allergy and patients who have previously received parenteral iron dextran are more likely to have hypersensitivity reactions after treatment with parenteral iron dextran. The iron dextran formulations used clinically are distinguishable as high-molecular-weight and low-molecular-weight forms. In the United States, the InFeD preparation is a low-molecular-weight form while DexFerrum is a high-molecular-weight form. Clinical data—primarily from observational studies—indicate that the risk of anaphylaxis is largely associated with high-molecular-weight formulations.
are alternative parenteral iron preparations. These agents can be given only by the intravenous route. They appear to be less likely than high-molecular-weight iron dextran to cause hypersensitivity reactions.
For patients treated chronically with parenteral iron, it is important to monitor iron storage levels to avoid the serious toxic-ity associated with iron overload. Unlike oral iron therapy, which is subject to the regulatory mechanism provided by the intestinal uptake system, parenteral administration—which bypasses this regulatory system—can deliver more iron than can be safely stored. Iron stores can be estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron-binding capacity (TIBC).
Acute iron toxicity is seen almost exclusively in young children who accidentally ingest iron tablets. As few as 10 tablets of any of the commonly available oral iron preparations can be lethal in young children. Adult patients taking oral iron preparations should be instructed to store tablets in child-proof containers out of the reach of children. Children who are poisoned with oral iron experience necrotizing gastroenteritis, with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dysp-nea. Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death. Urgent treatment is necessary. Whole bowel irrigation should be performed to flush out unabsorbed pills. Deferoxamine, a potent iron-chelating compound, can be given intravenously to bind iron that has already been absorbed and to promote its excre-tion in urine and feces. Activated charcoal, a highly effective adsorbent for most toxins, does not bind iron and thus is ineffec-tive. Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided.
Chronic iron toxicity (iron overload), also known as hemochro-matosis, results when excess iron is deposited in the heart, liver,pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochroma-tosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, individuals with β-thalassemia).
Chronic iron overload in the absence of anemia is most effi-ciently treated by intermittent phlebotomy. One unit of blood can be removed every week or so until all of the excess iron is removed. Iron chelation therapy using parenteral deferoxamine or the oral iron chelator deferasirox is less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phle-botomy, as is the case for many individuals with inherited and acquired causes of refractory anemia such as thalassemia major, sickle cell anemia, aplastic anemia, etc.