Hypoproliferative anemias are the most common anemias, and in the clinic, iron deficiency anemia is the most common of these followed by the anemia of inflammation. The anemia of inflammation, similar to iron deficiency, is related in part to abnormal iron metabolism. The anemias associated with renal disease, inflammation, cancer, and hypometabolic states are characterized by a suboptimal erythropoietin response to the anemia.
Iron is a critical element in the function of all cells, although the amount of iron required by individual tissues varies during development. At the same time, the body must protect itself from free iron, which is highly toxic in that it participates in chemical reactions that generate free radicals such as singlet O2 or OH–. Consequently, elaborate mechanisms have evolved that allow iron to be made available for physiologic functions while at the same time conserving this element and handling it in such a way that toxicity is avoided.
The major role of iron in mammals is to carry O2 as part of hemoglobin. O2 is also bound by myoglobin in muscle. Iron is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria. Iron distribution in the body is shown in Table 93-1. Without iron, cells lose their capacity for electron transport and energy metabolism. In erythroid cells, hemoglobin synthesis is impaired, resulting in anemia and reduced O2 delivery to tissue.
Figure 93-1 outlines the major pathways of internal iron exchange in humans. Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein. Transferrin is a bilobed glycoprotein with two iron-binding sites. Transferrin that carries iron exists in two forms—monoferric (one iron atom) or diferric (two iron atoms). The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min. Because almost all of the iron transported by transferrin is delivered to the erythroid marrow, the clearance time of transferrin-bound iron from the circulation is affected most by the plasma iron level and the erythroid marrow activity. When erythropoiesis is markedly stimulated, the pool of erythroid cells requiring iron increases, and the clearance time of iron from the circulation decreases. The half-clearance time of iron in the presence of iron deficiency is as short as 10–15 min. With suppression of erythropoiesis, the plasma iron level typically increases, and the half-clearance time may be prolonged to several hours. Normally, the iron bound to transferrin turns over 6–8 times per day. Assuming a normal plasma iron level of 80–100 μg/dL, the amount of iron passing through the transferrin pool is 20–24 mg/d.
FIGURE 93-1
Internal iron exchange. Normally 80% of iron passing through the plasma transferrin pool is recycled from senescent red cells. Absorption of ∼1 mg/d is required from the diet in men, and 1.4 mg/d in women to maintain homeostasis. As long as transferrin saturation is maintained between 20 and 60% and erythropoiesis is not increased, use of iron stores is not required. However, in the event of blood loss, dietary iron deficiency, or inadequate iron absorption, up to 40 mg/d of iron can be mobilized from stores. RE, reticuloendothelial.
The iron-transferrin complex circulates in the plasma until it interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apotransferrin (not carrying iron) has very little affinity. Although transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the greatest number of receptors (300,000–400,000/cell) is the developing erythroblast.
Once the iron-bearing transferrin interacts with its receptor, the complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at the low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into circulation and the transferrin receptor re-anchors into the cell membrane. At this point a certain amount of the transferrin receptor protein may be released into circulation and can be measured as soluble transferrin receptor protein. Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin. This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron incorporated into hemoglobin subsequently enters the circulation as new red cells are released from the bone marrow. The iron is then part of the red cell mass and will not become available for reutilization until the red cell dies.
In a normal individual, the average red cell life span is 120 days. Thus, 0.8–1% of red cells is replaced each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system, and the red cell undergoes phagocytosis. Once within the RE cell, the ingested hemoglobin is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin. It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady-state (and even mildly accelerated) erythropoiesis.
Because each milliliter of red cells contains 1 mg of elemental iron, the amount of iron needed to replace those red cells lost through senescence amounts to 20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d. However, to achieve a maximum proliferative erythroid marrow response to anemia, additional iron must be available. With markedly stimulated erythropoiesis, demands for iron are increased by as much as six- to eightfold. With extravascular hemolytic anemia, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with intravascular hemolysis or blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores. Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s proliferative response is blunted, and hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia.
Whereas blood loss or hemolysis places a demand on the iron supply, inflammatory conditions interfere with iron release from stores and can result in a rapid decrease in the serum iron (see below).
The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally. Iron may also enter the body through red cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow; this accounts for the great prevalence of iron deficiency worldwide—currently estimated at more than one billion people.
The amount of iron required from the diet to replace losses averages ∼10% of body iron content a year in men and 15% in women of childbearing age. Dietary iron content is closely related to total caloric intake (∼6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed. In the United States, the average iron intake in an adult male is 15 mg/d with 6% absorption; for the average female, the intake is 11 mg/d with 12% absorption. An individual with iron deficiency can increase iron absorption to ∼20% of the iron present in a meat-containing diet but only 5–10% of the iron in a vegetarian diet. As a result, one-third of the female population in the United States has virtually no iron stores. Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by ∼50%. When ionizable iron salts are given together with food, the amount of iron absorbed is reduced. When the percentage of iron absorbed from individual food items is compared with the percentage for an equivalent amount of ferrous salt, iron in vegetables is only about one-twentieth as available, egg iron one-eighth, liver iron one-half, and heme iron one-half to two-thirds.
Infants, children, and adolescents may be unable to maintain normal iron balance because of the demands of body growth and lower dietary intake of iron. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg, and iron supplements are strongly recommended for pregnant women in developed countries.
Iron absorption takes place largely in the duodenum and proximal small intestine and is a carefully regulated process. For absorption, iron must be taken up by the luminal cell. That process is facilitated by the acidic contents of the stomach, which maintains the iron in solution. At the brush border of the absorptive cell, the ferric iron is converted to the ferrous form by a ferrireductase. Transport across the membrane is accomplished by divalent metal transporter type 1 (DMT-1, also known as natural resistance macrophage-associated protein type 2 [Nramp 2] or DCT-1). DMT-1 is a general cation transporter. Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.
Iron absorption is influenced by a number of physiologic states. Erythroid hyperplasia stimulates iron absorption even in the face of normal or increased iron stores, and hepcidin levels are inappropriately low. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. The molecular mechanism underlying this is the production of erythroferrone (ERFE) by developing erythroblasts. ERFE suppresses hepcidin production and, over time, this may lead to iron overload and tissue damage. In iron deficiency, hepcidin levels are also low and iron is much more efficiently absorbed; the contrary is true in states of secondary iron overload. The normal individual can reduce iron absorption in situations of excessive intake or medicinal iron intake; however, while the percentage of iron absorbed goes down, the absolute amount goes up. This accounts for the acute iron toxicity occasionally seen when children ingest large numbers of iron tablets. Under these circumstances, the amount of iron absorbed exceeds the transferrin binding capacity of the plasma, resulting in free iron that affects critical organs such as cardiac muscle cells.
Iron deficiency is one of the most prevalent forms of malnutrition. Globally, 50% of anemia is attributable to iron deficiency and accounts for approximately nearly a million 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.
The progression to iron deficiency can be divided into three stages (Fig. 93-2). 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.
FIGURE 93-2
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 15="" a="" as="" becomes="" despite="" dwindling="" falls="" g="" hemoglobin="" impaired.="" iron="" is="" long="" normal="" of="" once="" period="" range="" remains="" saturation="" serum="" span="" stores.="" synthesis="" the="" this="" to="" transferrin="" unaffected="" within="">
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.
Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency (Table 93-2).
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 or post-menopausal female 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.
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 <20 a="" diurnal="" in="" iron.="" is="" saturation="" serum="" the="" there="" transferrin="" variation="">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. 93-3). 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 absent="" are="" body="" diagnostic="" g="" iron="" levels="" of="" p="" stores.="" such="">
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 93-3). 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 ring sideroblasts.
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 cells.="" deficiency="" dl="" g="" in="" iron="" of="" red="" values="">100 μg/dL are seen. The most common causes of increased red cell protoporphyrin levels are absolute or relative iron deficiency and lead poisoning.
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 93-4). 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.
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.
TREATMENTIron-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 and an intact gastrointestinal tract, 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 93-5). 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 at least 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 2–3 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 or menstrual 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 has been a concern largely driven by the high adverse reaction rate to high-molecular-weight iron dextran. The newer iron complexes that are available, such as ferumoxytol (Feraheme), sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), low-molecular-weight (LMW) iron dextran (InFed), and ferric carboxymaltose (Injectafer), have much lower rates of adverse effects. Ferumoxytol delivers 510 mg of iron per injection; ferric gluconate 125 mg per injection; LMW iron dextran up to 1500 mg; 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 any intravenous iron preparation, 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 an iron preparation. 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 one iron preparation have been safely treated with other parenteral iron preparations. If a large dose of LMW 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 LMW 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.
In addition to mild to moderate iron-deficiency anemia, the hypoproliferative anemias can be divided into four categories: (1) chronic inflammation, (2) renal disease, (3) endocrine and nutritional deficiencies (hypometabolic states), and (4) marrow damage (Chap. 98). With chronic inflammation, renal disease, or hypometabolism, endogenous EPO production is inadequate for the degree of anemia observed. For the anemia of chronic inflammation, the erythroid marrow also responds inadequately to stimulation, due in part to defective iron reutilization. As a result of the lack of adequate EPO stimulation, an examination of the peripheral blood smear will disclose only an occasional polychromatophilic (“shift”) reticulocyte. In cases of iron deficiency or marrow damage, appropriate elevations in endogenous EPO levels are typically found, and shift reticulocytes will be present on the blood smear.
AI—which encompasses inflammation, infection, tissue injury, and conditions (such as cancer) associated with the release of proinflammatory cytokines—is one of the most common forms of anemia seen clinically. It is the most important anemia in the differential diagnosis of iron deficiency because many of the features of the anemia are brought about by inadequate iron delivery to the marrow, despite the presence of normal or increased iron stores. This is reflected by a low serum iron, increased red cell protoporphyrin, a hypoproliferative marrow, transferrin saturation in the range of 15–20%, and a normal or increased serum ferritin. The serum ferritin values are often the most distinguishing features between true iron-deficiency anemia and the iron-restricted erythropoiesis associated with inflammation. Typically, serum ferritin values increase threefold over basal levels in the face of inflammation. These changes are due to the effects of inflammatory cytokines and hepcidin, the key iron regulatory hormone, acting at several levels of erythropoiesis (Fig. 93-4).
FIGURE 93-4
Suppression of erythropoiesis by inflammatory cytokines. Through the release of tumor necrosis factor (TNF) and interferon β (IFN-β), neoplasms and bacterial infections suppress erythropoietin (EPO) production and the proliferation of erythroid progenitors (erythroid burst-forming units and erythroid colony-forming units [BFU/CFU-E]). The mediators in patients with vasculitis and rheumatoid arthritis include interleukin 1 (IL-1) and IFN-γ. The red arrows indicate sites of inflammatory cytokine inhibitory effects. RBC, red blood cell.
Interleukin 1 (IL-1) directly decreases EPO production in response to anemia. IL-1, acting through accessory cell release of interferon γ (IFN-γ), suppresses the response of the erythroid marrow to EPO—an effect that can be overcome by EPO administration in vitro and in vivo. In addition, tumor necrosis factor (TNF), acting through the release of IFN-β by marrow stromal cells, also suppresses the response to EPO. Hepcidin, made by the liver, is increased in inflammation via an IL-6 mediated pathway, and acts to suppress iron absorption and iron release from storage sites. The overall result is a chronic hypoproliferative anemia with classic changes in iron metabolism. The anemia is further compounded by a mild to moderate shortening in red cell survival.
With chronic inflammation, the primary disease will determine the severity and characteristics of the anemia. For example, many patients with cancer also have anemia that is typically normocytic and normochromic. In contrast, patients with long-standing active rheumatoid arthritis or chronic infections such as tuberculosis will have a microcytic, hypochromic anemia. In both cases, the bone marrow is hypoproliferative, but the differences in red cell indices reflect differences in the availability of iron for hemoglobin synthesis. Occasionally, conditions associated with chronic inflammation are also associated with chronic blood loss. Under these circumstances, the measurement of soluble transferrin protein may be necessary to rule out absolute iron deficiency. However, the administration of iron in this case will correct the iron deficiency component of the anemia and leave the inflammatory component unaffected.
The anemia associated with acute infection or inflammation is typically mild but becomes more pronounced over time. Acute infection can produce a decrease in hemoglobin levels of 2–3 g/dL within 1 or 2 days; this is largely related to the hemolysis of red cells near the end of their natural life span. The fever and cytokines released exert a selective pressure against cells with more limited capacity to maintain the red cell membrane. In most individuals, the mild anemia is reasonably well tolerated, and symptoms, if present, are associated with the underlying disease. Occasionally, in patients with preexisting cardiac disease, moderate anemia (hemoglobin 10–11 g/dL) may be associated with angina, exercise intolerance, and shortness of breath. The erythropoietic profile that distinguishes the anemia of inflammation from the other causes of hypoproliferative anemias is shown in Table 93-6.
Progressive CKD is usually associated with a moderate to severe hypoproliferative anemia; the level of the anemia correlates with the stage of CKD. Red cells are typically normocytic and normochromic, and reticulocytes are decreased. The anemia is primarily due to a failure of EPO production by the diseased kidney and a reduction in red cell survival. In certain forms of acute renal failure, the correlation between the anemia and renal function is weaker. Patients with the hemolytic-uremic syndrome increase erythropoiesis in response to the hemolysis, despite renal failure. Polycystic kidney disease also shows a smaller degree of EPO deficiency for a given level of renal failure. By contrast, patients with diabetes or myeloma have more severe EPO deficiency for a given level of renal failure.
Assessment of iron status provides information to distinguish the anemia of CKD from the other forms of hypoproliferative anemia (Table 93-6) and to guide management. Patients with the anemia of CKD usually present with normal serum iron, TIBC, and ferritin levels. However, those maintained on chronic hemodialysis may develop iron deficiency from blood loss through the dialysis procedure. Iron must be replenished in these patients to ensure an adequate response to EPO therapy (see below).
Patients who are starving, particularly for protein, and those with a variety of endocrine disorders that produce lower metabolic rates, may develop a mild to moderate hypoproliferative anemia. The release of EPO from the kidney is sensitive to the need for O2, not just O2 levels. Thus, EPO production is triggered at lower levels of blood O2 content in disease states (such as hypothyroidism and starvation) where metabolic activity, and thus O2 demand, is decreased.
The difference in the levels of hemoglobin between men and women is related to the effects of androgen and estrogen on erythropoiesis. Testosterone and anabolic steroids augment erythropoiesis; castration and estrogen administration to males decrease erythropoiesis. Patients who are hypothyroid or have deficits in pituitary hormones also may develop a mild anemia. Pathogenesis may be complicated by other nutritional deficiencies because iron and folic acid absorption can be affected by these disorders. Usually, correction of the hormone deficiency reverses the anemia.
Anemia may be more severe in Addison’s disease, depending on the level of thyroid and androgen hormone dysfunction; however, anemia may be masked by decreases in plasma volume. Once such patients are given cortisol and volume replacement, the hemoglobin level may fall rapidly. Mild anemia complicating hyperparathyroidism may be due to decreased EPO production as a consequence of the renal effects of hypercalcemia or to impaired proliferation of erythroid progenitors.
Decreased dietary intake of protein may lead to mild to moderate hypoproliferative anemia; this form of anemia may be prevalent in the elderly. The anemia can be more severe in patients with a greater degree of starvation. In marasmus, where patients are both protein- and calorie-deficient, the release of EPO is impaired in proportion to the reduction in metabolic rate; however, the degree of anemia may be masked by volume depletion and becomes apparent after refeeding. Deficiencies in other nutrients (iron, folate) may also complicate the clinical picture but may not be apparent at diagnosis. Changes in the erythrocyte indices on refeeding should prompt evaluation of iron, folate, and B12 status.
A mild hypoproliferative anemia may develop in patients with chronic liver disease from nearly any cause. The peripheral blood smear may show spur cells and stomatocytes from the accumulation of excess cholesterol in the membrane from a deficiency of lecithin-cholesterol acyltransferase. Red cell survival is shortened, and the production of EPO is inadequate to compensate. In alcoholic liver disease, nutritional deficiencies are common and complicate the management. Folate deficiency from inadequate intake, as well as iron deficiency from blood loss and inadequate intake, can alter the red cell indices.
Anemia is common in people over age 65 years. It has been estimated to affect about 11% of community living older adults and up to 40% of nursing home residents. In at least one-third of these anemic people, a cause for the anemia is not found. Patients with the unexplained anemia of aging do not have nutrient deficiency or renal dysfunction and while older people can have an increase in systemic inflammatory cytokines (the inflammation of aging), the levels are not high enough to mimic the anemia of chronic inflammation. If hepcidin levels are elevated at all, they are minimally so.
Investigations into the cause(s) of this form of anemia have noted that erythropoietin levels are generally in the normal range, that is, they are inappropriately low for the hemoglobin level. In general, in older people who maintain a normal hemoglobin level, erythropoietin levels increase with age. This compensatory increase to maintain normal oxygen delivery seems to be due to a relative resistance to erythropoietin stimulation; studies of red cell life span in older people have not noted a decrease in red cell survival. More data on mechanism are needed.
The importance of this unexplained anemia of aging is that low hemoglobin levels are associated with increases in falls, hospitalizations, development of frailty, and mortality. It is not clear whether reversing the anemia would influence these increased risks.
TREATMENTHypoproliferative Anemias
Many patients with hypoproliferative anemias experience recovery of normal hemoglobin levels when the underlying disease is appropriately treated. For those in whom such reversals are not possible—such as patients with end-stage kidney disease, cancer, and chronic inflammatory diseases—symptomatic anemia requires treatment. The two major forms of treatment are transfusions and EPO.
TRANSFUSIONS
Thresholds for transfusion should be determined based on the patient’s symptoms. In general, patients without serious underlying cardiovascular or pulmonary disease can tolerate hemoglobin levels above 7–8 g/dL and do not require intervention until the hemoglobin falls below that level. Patients with more physiologic compromise may need to have their hemoglobin levels kept above 11 g/dL. Usually, a unit of packed red cells increases the hemoglobin level by 1 g/dL. Transfusions are associated with certain infectious risks (Chap. 109), and chronic transfusions can produce iron overload. Importantly, the liberal use of blood has been associated with increased morbidity and mortality, particularly in the intensive care setting. Therefore, in the absence of documented tissue hypoxia, a conservative approach to the use of red cell transfusions is preferable.
ERYTHROPOIETIN
EPO is particularly useful in anemias in which endogenous EPO levels are inappropriately low, such as CKD or AI. Iron status must be evaluated and iron replaced to obtain optimal effects from EPO. In patients with CKD, the usual dose of EPO is 50–150 U/kg three times a week intravenously. Hemoglobin levels of 10–12 g/dL are usually reached within 4–6 weeks if iron levels are adequate; 90% of these patients respond. Once a target hemoglobin level is achieved, the EPO dose can be decreased. A decrease in hemoglobin level occurring in the face of EPO therapy usually signifies the development of an infection or iron depletion. Aluminum toxicity and hyperparathyroidism can also compromise the response to EPO. When an infection intervenes, it is best to interrupt the EPO therapy and rely on transfusions to correct the anemia until the infection is adequately treated. The dose of EPO needed to correct chemotherapy-induced anemia in patients with cancer is higher, up to 300 U/kg three times a week, and only ∼60% of patients respond. Because of evidence that there is an increased risk of thromboembolic complications and tumor progression with EPO administration, the risks and benefits of using EPO in such patients must be weighed carefully, and the target hemoglobin should be that necessary to avoid transfusions.
Longer-acting preparations of EPO can reduce the frequency of injections. Darbepoetin alfa, a molecularly modified EPO with additional carbohydrate, has a half-life in the circulation that is three to four times longer than recombinant human EPO, permitting weekly or every other week dosing.
Orally bioavailable EPO mimetics that act to increase the biological half-life of active hypoxia-induced factor (HIF) are demonstrating activity to increase hemoglobin levels in patients with chronic renal disease and other settings.
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