Iron deficiency is one of the most prevalent forms of malnutrition. Globally, 50% of anemia is attributable to iron deficiency and accounts for approximately 841,000 deaths annually worldwide. Africa and parts of Asia bear 71% of the global mortality burden; North America represents only 1.4% of the total morbidity and mortality associated with iron deficiency.
STAGES OF IRON DEFICIENCY
The progression to iron deficiency can be divided into three stages (Fig. 126-2). The first stage is negative iron balance, in which the demands for (or losses of) iron exceed the body’s ability to absorb iron from the diet. This stage results from a number of physiologic mechanisms, including blood loss, pregnancy (in which the demands for red cell production by the fetus outstrip the mother’s ability to provide iron), rapid growth spurts in the adolescent, or inadequate dietary iron intake. Blood loss in excess of 10–20 mL of red cells per day is greater than the amount of iron that the gut can absorb from a normal diet. Under these circumstances, the iron deficit must be made up by mobilization of iron from RE storage sites. During this period, iron stores—reflected by the serum ferritin level or the appearance of stainable iron on bone marrow aspirations—decrease. As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain within normal limits. At this stage, red cell morphology and indices are normal.
Laboratory studies in the evolution of iron deficiency. Measurements of marrow iron stores, serum ferritin, and total iron-binding capacity (TIBC) are sensitive to early iron-store depletion. Iron-deficient erythropoiesis is recognized from additional abnormalities in the serum iron (SI), percent transferrin saturation, the pattern of marrow sideroblasts, and the red blood cell (RBC) protoporphyrin level. Patients with iron-deficiency anemia demonstrate all the same abnormalities plus hypochromic microcytic anemia. (From RS Hillman, CA Finch: The Red Cell Manual, 7th ed. Philadelphia, F.A.Davis and Co., 1996, with permission.)
When iron stores become depleted, the serum iron begins to fall. Gradually, the TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron stores are absent when the serum ferritin level is <15 μg/L. As long as the serum iron remains within the normal range, hemoglobin synthesis is unaffected despite the dwindling iron stores. Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes impaired. This is a period of iron-deficient erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is available, one finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin and hematocrit begin to fall, reflecting iron-deficiency anemia. The transferrin saturation at this point is 10–15%.
When moderate anemia is present (hemoglobin 10–13 g/dL), the bone marrow remains hypoproliferative. With more severe anemia (hemoglobin 7–8 g/dL), hypochromia and microcytosis become more prominent, target cells and misshapen red cells (poikilocytes) appear on the blood smear as cigar- or pencil-shaped forms, and the erythroid marrow becomes increasingly ineffective. Consequently, with severe prolonged iron-deficiency anemia, erythroid hyperplasia of the marrow develops, rather than hypoproliferation.
CAUSES OF IRON DEFICIENCY
Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency (Table 126-2).
TABLE 126-2Causes of Iron Deficiency ||Download (.pdf) TABLE 126-2Causes of Iron Deficiency
Increased Demand for Iron
Rapid growth in infancy or adolescence
Increased Iron Loss
Chronic blood loss
Acute blood loss
Phlebotomy as treatment for polycythemia vera
Decreased Iron Intake or Absorption
Malabsorption from disease (sprue, Crohn’s disease)
Malabsorption from surgery (gastrectomy and some forms of bariatric surgery)
Acute or chronic inflammation
CLINICAL PRESENTATION OF IRON DEFICIENCY
Certain clinical conditions carry an increased likelihood of iron deficiency. Pregnancy, adolescence, periods of rapid growth, and an intermittent history of blood loss of any kind should alert the clinician to possible iron deficiency. A cardinal rule is that the appearance of iron deficiency in an adult male means gastrointestinal blood loss until proven otherwise. Signs related to iron deficiency depend on the severity and chronicity of the anemia in addition to the usual signs of anemia—fatigue, pallor, and reduced exercise capacity. Cheilosis (fissures at the corners of the mouth) and koilonychia (spooning of the fingernails) are signs of advanced tissue iron deficiency. The diagnosis of iron deficiency is typically based on laboratory results.
Serum Iron and Total Iron-Binding Capacity
The serum iron level represents the amount of circulating iron bound to transferrin. The TIBC is an indirect measure of the circulating transferrin. The normal range for the serum iron is 50–150 μg/dL; the normal range for TIBC is 300–360 μg/dL. Transferrin saturation, which is normally 25–50%, is obtained by the following formula: serum iron × 100 ÷ TIBC. Iron-deficiency states are associated with saturation levels below 20%. There is a diurnal variation in the serum iron. A transferrin saturation % >50% indicates that a disproportionate amount of the iron bound to transferrin is being delivered to nonerythroid tissues. If this persists for an extended time, tissue iron overload may occur.
Free iron is toxic to cells, and the body has established an elaborate set of protective mechanisms to bind iron in various tissue compartments. Within cells, iron is stored complexed to protein as ferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the RE system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells, although hemosiderin is less readily available. Under steady-state conditions, the serum ferritin level correlates with total body iron stores; thus, the serum ferritin level is the most convenient laboratory test to estimate iron stores. The normal value for ferritin varies according to the age and gender of the individual (Fig. 126-3). Adult males have serum ferritin values averaging 100 μg/L, while adult females have levels averaging 30 μg/L. As iron stores are depleted, the serum ferritin falls to <15 μg/L. Such levels are diagnostic of absent body iron stores.
Serum ferritin levels as a function of sex and age. Iron store depletion and iron deficiency are accompanied by a decrease in serum ferritin level below 20 μg/L. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2011, with permission.)
Evaluation of Bone Marrow Iron Stores
Although RE iron stores can be estimated from the iron stain of a bone marrow aspirate or biopsy, the measurement of serum ferritin has largely supplanted these procedures for determination of storage iron (Table 126-3). The serum ferritin level is a better indicator of iron overload than the marrow iron stain. However, in addition to storage iron, the marrow iron stain provides information about the effective delivery of iron to developing erythroblasts. Normally, when the marrow smear is stained for iron, 20–40% of developing erythroblasts—called sideroblasts—will have visible ferritin granules in their cytoplasm. This represents iron in excess of that needed for hemoglobin synthesis. In states in which release of iron from storage sites is blocked, RE iron will be detectable, and there will be few or no sideroblasts. In the myelodysplastic syndromes, mitochondrial dysfunction can occur, and accumulation of iron in mitochondria appears in a necklace fashion around the nucleus of the erythroblast. Such cells are referred to as ringed sideroblasts.
TABLE 126-3Iron Store Measurements ||Download (.pdf) TABLE 126-3Iron Store Measurements
|Iron Stores ||Marrow Iron Stain, 0–4+ ||Serum Ferritin, μg/L |
|0 ||0 ||<15 |
|1–300 mg ||Trace to 1+ ||15–30 |
|300–800 mg ||2+ ||30–60 |
|800–1000 mg ||3+ ||60–150 |
|1–2 g ||4+ ||>150 |
|Iron overload ||— ||>500–1000 |
Red Cell Protoporphyrin Levels
Protoporphyrin is an intermediate in the pathway to heme synthesis. Under conditions in which heme synthesis is impaired, protoporphyrin accumulates within the red cell. This reflects an inadequate iron supply to erythroid precursors to support hemoglobin synthesis. Normal values are <30 μg/dL of red cells. In iron deficiency, values in excess of 100 μg/dL are seen. The most common causes of increased red cell protoporphyrin levels are absolute or relative iron deficiency and lead poisoning.
Serum Levels of Transferrin Receptor Protein
Because erythroid cells have the highest numbers of transferrin receptors of any cell in the body, and because transferrin receptor protein (TRP) is released by cells into the circulation, serum levels of TRP reflect the total erythroid marrow mass. Another condition in which TRP levels are elevated is absolute iron deficiency. Normal values are 4–9 μg/L determined by immunoassay. This laboratory test is becoming increasingly available and, along with the serum ferritin, has been proposed to distinguish between iron deficiency and the anemia of inflammation (see below).
Other than iron deficiency, only three conditions need to be considered in the differential diagnosis of a hypochromic microcytic anemia (Table 126-4). The first is an inherited defect in globin chain synthesis: the thalassemias. These are differentiated from iron deficiency most readily by serum iron values; normal or increased serum iron levels and transferrin saturation are characteristic of the thalassemias. In addition, the red blood cell distribution width (RDW) index is generally normal in thalassemia and elevated in iron deficiency.
TABLE 126-4Diagnosis of Microcytic Anemia ||Download (.pdf) TABLE 126-4Diagnosis of Microcytic Anemia
|Tests ||Iron Deficiency ||Inflammation ||Thalassemia ||Sideroblastic Anemia |
|Smear ||Micro/hypo ||Normal micro/hypo ||Micro/hypo with targeting ||Variable |
|Serum iron (μg/dL) ||<30 ||<50 ||Normal to high ||Normal to high |
|TIBC (μg/dL) ||>360 ||<300 ||Normal ||Normal |
|Percent saturation ||<10 ||10–20 ||30–80 ||30–80 |
|Ferritin (μg/L) ||<15 ||30–200 ||50–300 ||50–300 |
|Hemoglobin pattern on electrophoresis ||Normal ||Normal ||Abnormal with β thalassemia; can be normal with α thalassemia ||Normal |
The second condition is the anemia of inflammation (AI; also referred to as the anemia of chronic disease) with inadequate iron supply to the erythroid marrow. The distinction between true iron-deficiency anemia and AI is among the most common diagnostic problems encountered by clinicians (see below). Usually, AI is normocytic and normochromic. The iron values usually make the differential diagnosis clear, as the ferritin level is normal or increased and the percent transferrin saturation and TIBC are typically below normal.
Finally, the myelodysplastic syndromes represent the third and least common condition. Occasionally, patients with myelodysplasia have impaired hemoglobin synthesis with mitochondrial dysfunction, resulting in impaired iron incorporation into heme. The iron values again reveal normal stores and more than an adequate supply to the marrow, despite the microcytosis and hypochromia.
TREATMENT Iron-Deficiency Anemia
The severity and cause of iron-deficiency anemia will determine the appropriate approach to treatment. As an example, symptomatic elderly patients with severe iron-deficiency anemia and cardiovascular instability may require red cell transfusions. Younger individuals who have compensated for their anemia can be treated more conservatively with iron replacement. The foremost issue for the latter patient is the precise identification of the cause of the iron deficiency.
For the majority of cases of iron deficiency (pregnant women, growing children and adolescents, patients with infrequent episodes of bleeding, and those with inadequate dietary intake of iron), oral iron therapy will suffice. For patients with unusual blood loss or malabsorption, specific diagnostic tests and appropriate therapy take priority. Once the diagnosis of iron-deficiency anemia and its cause is made, there are three major therapeutic approaches. RED CELL TRANSFUSION
Transfusion therapy is reserved for individuals who have symptoms of anemia, cardiovascular instability, and continued and excessive blood loss from whatever source and who require immediate intervention. The management of these patients is less related to the iron deficiency than it is to the consequences of the severe anemia. Not only do transfusions correct the anemia acutely, but the transfused red cells provide a source of iron for reutilization, assuming they are not lost through continued bleeding. Transfusion therapy will stabilize the patient while other options are reviewed. ORAL IRON THERAPY
In the asymptomatic patient with established iron-deficiency anemia, treatment with oral iron is usually adequate. Multiple preparations are available, ranging from simple iron salts to complex iron compounds designed for sustained release throughout the small intestine (Table 126-5). Although the various preparations contain different amounts of iron, they are generally all absorbed well and are effective in treatment. Some come with other compounds designed to enhance iron absorption, such as ascorbic acid. It is not clear whether the benefits of such compounds justify their costs. Typically, for iron replacement therapy, up to 200 mg of elemental iron per day is given, usually as three or four iron tablets (each containing 50–65 mg elemental iron) given over the course of the day. Ideally, oral iron preparations should be taken on an empty stomach, since food may inhibit iron absorption. Some patients with gastric disease or prior gastric surgery require special treatment with iron solutions, because the retention capacity of the stomach may be reduced. The retention capacity is necessary for dissolving the shell of the iron tablet before the release of iron. A dose of 200 mg of elemental iron per day should result in the absorption of iron up to 50 mg/d. This supports a red cell production level of two to three times normal in an individual with a normally functioning marrow and appropriate erythropoietin stimulus. However, as the hemoglobin level rises, erythropoietin stimulation decreases, and the amount of iron absorbed is reduced. The goal of therapy in individuals with iron-deficiency anemia is not only to repair the anemia, but also to provide stores of at least 0.5–1 g of iron. Sustained treatment for a period of 6–12 months after correction of the anemia will be necessary to achieve this.
Of the complications of oral iron therapy, gastrointestinal distress is the most prominent and is seen in 15–20% of patients. Abdominal pain, nausea, vomiting, or constipation may lead to noncompliance. Although small doses of iron or iron preparations with delayed release may help somewhat, the gastrointestinal side effects are a major impediment to the effective treatment of a number of patients.
The response to iron therapy varies, depending on the erythropoietin stimulus and the rate of absorption. Typically, the reticulocyte count should begin to increase within 4–7 days after initiation of therapy and peak at 1–1½ weeks. The absence of a response may be due to poor absorption, noncompliance (which is common), or a confounding diagnosis. A useful test in the clinic to determine the patient’s ability to absorb iron is the iron tolerance test. Two iron tablets are given to the patient on an empty stomach, and the serum iron is measured serially over the subsequent 2 h. Normal absorption will result in an increase in the serum iron of at least 100 μg/dL. If iron deficiency persists despite adequate treatment, it may be necessary to switch to parenteral iron therapy. PARENTERAL IRON THERAPY
Intravenous iron can be given to patients who are unable to tolerate oral iron; whose needs are relatively acute; or who need iron on an ongoing basis, usually due to persistent gastrointestinal blood loss. Parenteral iron use has been increasing rapidly in the last several years with the recognition that recombinant erythropoietin (EPO) therapy induces a large demand for iron—a demand that frequently cannot be met through the physiologic release of iron from RE sources or oral iron absorption. The safety of parenteral iron—particularly iron dextran—has been a concern. The serious adverse reaction rate to intravenous high-molecular-weight iron dextran is 0.7%. Fortunately, newer iron complexes are available in the United States, such as ferumoxytol (Feraheme), sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), and ferric carboxymaltose (Injectafer), that have much lower rates of adverse effects. Ferumoxytol delivers 510 mg of iron per injection; ferric gluconate 125 mg per injection, ferric carboxymaltose 750 mg per injection, and iron sucrose 200 mg per injection.
Parenteral iron is used in two ways: one is to administer the total dose of iron required to correct the hemoglobin deficit and provide the patient with at least 500 mg of iron stores; the second is to give repeated small doses of parenteral iron over a protracted period. The latter approach is common in dialysis centers, where it is not unusual for 100 mg of elemental iron to be given weekly for 10 weeks to augment the response to recombinant EPO therapy. The amount of iron needed by an individual patient is calculated by the following formula:
In administering intravenous iron dextran, anaphylaxis is a concern. Anaphylaxis is much rarer with the newer preparations. The factors that have correlated with an anaphylactic-like reaction include a history of multiple allergies or a prior allergic reaction to dextran (in the case of iron dextran). Generalized symptoms appearing several days after the infusion of a large dose of iron can include arthralgias, skin rash, and low-grade fever. These may be dose-related, but they do not preclude the further use of parenteral iron in the patient. To date, patients with sensitivity to iron dextran have been safely treated with other parenteral iron preparations. If a large dose of iron dextran is to be given (>100 mg), the iron preparation should be diluted in 5% dextrose in water or 0.9% NaCl solution. The iron solution can then be infused over a 60- to 90-min period (for larger doses) or at a rate convenient for the attending nurse or physician. Although a test dose (25 mg) of parenteral iron dextran is recommended, in reality a slow infusion of a larger dose of parenteral iron solution will afford the same kind of early warning as a separately injected test dose. Early in the infusion of iron, if chest pain, wheezing, a fall in blood pressure, or other systemic symptoms occur, the infusion of iron should be stopped immediately.
TABLE 126-5Oral Iron Preparations ||Download (.pdf) TABLE 126-5Oral Iron Preparations
|Generic Name ||Tablet (Iron Content), mg ||Elixir (Iron Content), mg in 5 mL |
|Ferrous sulfate ||325 (65) ||300 (60) |
| ||195 (39) ||90 (18) |
|Extended release ||525 (105) || |
|Ferrous fumarate ||325 (107) || |
| ||195 (64) ||100 (33) |
|Ferrous gluconate ||325 (39) ||300 (35) |
|Polysaccharide iron ||150 (150) ||100 (100) |
| ||50 (50) || |