Section XI - Drugs Acting on the Blood and the Blood-Forming

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The short life span of mature blood cells requires their continuous replacement, a process termed hematopoiesis. New cell production must be responsive to both basal needs and situations of increased demand. For example, red blood cell production can vary over more than a fivefold range in response to anemia or hypoxia. White blood cell production increases dramatically in response to a systemic infection, and platelet production can increase severalfold when platelet destruction results in thrombocytopenia....

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Section XI. Drugs Acting on the Blood and the Blood-Forming Organs Overview The short life span of mature blood cells requires their continuous replacement, a process termed hematopoiesis. New cell production must be responsive to both basal needs and situations of increased demand. For example, red blood cell production can vary over more than a fivefold range in response to anemia or hypoxia. White blood cell production increases dramatically in response to a systemic infection, and platelet production can increase severalfold when platelet destruction results in thrombocytopenia. The regulation of hematopoiesis is complex and involves cell–cell interactions within the microenvironment of the bone marrow as well as both hematopoietic and lymphopoietic growth factors. A number of these hormonelike glycoproteins now have been identified and characterized, and, using recombinant DNA technology, their genes have been cloned and the proteins produced in quantities sufficient for use as therapeutic agents. Clinical applications now are being developed, ranging from treatment of primary hematological diseases to uses as adjunctive agents in the treatment of severe infections and in the management of patients who are undergoing chemotherapy or marrow transplantation. Hematopoiesis also requires adequate supplies of minerals, both iron and copper, and a number of vitamins, including folic acid, vitamin B12, pyridoxine, ascorbic acid, and riboflavin. Deficiencies of these minerals and vitamins generally result in characteristic anemias and, less frequently, a general failure of hematopoiesis. Therapeutic correction of a specific deficiency state depends on the accurate diagnosis of the anemic state and knowledge as to the correct dose, the use of these agents in various combinations, and the expected response. This chapter deals with the growth factors, vitamins, minerals, and drugs that affect the blood and blood-forming organs. Hematopoietic Growth Factors History Modern concepts of hematopoietic cell growth and differentiation developed beginning in the 1950s with the work of Jacobsen, Ford, and others (Jacobsen et al., 1949; Ford et al., 1956). These investigators demonstrated the role that cells from the spleen and marrow play in the restoration of hematopoietic tissue in irradiated animals. In 1961, Till and McCulloch were able to show that individual hematopoietic cells could form macroscopic hematopoietic nodules in the spleens of irradiated mice. Their work led to the concept of colony-forming stem cells. It also led to the subsequent proof that stem cells present in human bone marrow are pluripotent—that is, they give rise to granulocytes, monocytes, lymphocytes, megakaryocytes, and erythrocytes. The role of growth factors in hematopoiesis was elucidated by Bradley, Metcalf, and others using bone marrow culture techniques (Bradley and Metcalf, 1966). Individual growth factors were isolated (Metcalf, 1985; Moore, 1991), and the target cells of these factors characterized. The
pluripotent stem cell gives rise to committed progenitors, which can be identified as single colony- forming units, and to cells that are increasingly differentiated. The existence of a circulating growth factor that controls erythropoiesis was first suggested by experiments carried out by Paul Carnot in 1906 (Carnot and Deflandre, 1906). He observed an increase in the red cell count in rabbits injected with serum obtained from anemic animals and postulated the existence of a factor that he called hemapoietine. However, it was not until the 1950s that Reissmann (1950), Erslev (1953), and Jacobsen and coworkers (1957) defined the origin and actions of the hormone, now called erythropoietin. Subsequently, extensive studies of erythropoietin were carried out in patients with anemia and polycythemia, culminating in 1977 with the purification of erythropoietin from urine by Miyake and colleagues. The gene that encodes the protein was subsequently cloned and expressed at a high level in a mammalian cell system (Jacobs et al., 1985; Lin et al., 1985), producing a recombinant hormone that is indistinguishable from human urinary erythropoietin. Similarly, complementary DNA and genomic clones for granulocyte, macrophage, and, most recently, megakaryocyte colony-stimulating factors have been isolated and sufficient quantities of biologically active growth factors produced for clinical investigation (Kawasaki et al., 1985; Lee et al., 1985; Wong et al., 1985; Yang et al., 1986; Lok et al., 1994; de Sauvage et al., 1994). Growth Factor Physiology Steady-state hematopoiesis involves the production of more than 200 billion (2 x 1011) blood cells each day. This production is under delicate control, and, with increased demand, the rate can increase severalfold. The hematopoietic organ also is unique in that several mature cell types are derived from a much smaller number of pluripotent stem cells that are formed in early embryonic life. These stem cells are capable of both maintaining their own number and differentiating under the influence of cellular and humoral factors [stem cell factor (SCF), Flt3 ligand (FL), interleukin-3 (IL-3), and granulocyte/macrophage colony-stimulating factor (GM-CSF)] to produce a variety of hematopoietic and lymphopoietic cells. Stem cell differentiation can be described as a series of steps that produce so-called burst-forming units (BFU) and colony-forming units (CFU) for each of the major cell lines (Quesenberry and Levitt, 1979). Although these early progenitors (BFU and CFU) are not morphologically recognizable as precursors of a specific cell type, they are capable of further proliferation and differentiation, increasing their number by some 30-fold. Subsequently, colonies of morphologically distinct cells form under the control of an overlapping set of additional growth factors (G-CSF, M-CSF, erythropoietin, and thrombopoietin). Proliferation and maturation of the CFU for each cell line can further amplify the resulting mature cell product by another 30-fold or more, resulting in greater than 1000 mature cells produced for each committed stem cell (Lajtha et al., 1969). Hematopoietic and lymphopoietic growth factors are produced by a number of marrow cells and peripheral tissues. The growth factors are glycoproteins and are active at very low concentrations, usually on more than one committed cell lineage. Most show synergistic interactions with other factors, as well as "networking," wherein stimulation of a cell lineage by one growth factor induces the production of additional growth factors. Finally, growth factors generally exert actions at several points in the processes of cell proliferation and differentiation and in mature cell function (Metcalf, 1985). Some of the overlapping effects of the more important hematopoietic growth factors are illustrated in Figure 54–1 and listed in Table 54–1.
Figure 54–1. Sites of Action of Hematopoietic Growth Factors in the Differentiation and Maturation of Marrow Cell Lines. A self-sustaining pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic and lymphopoietic cells. Stem cell factor (SCF), ligand (FL), interleukin-3 (IL-3), and granulocyte/macrophage colony-stimulating factor (GM-CSF), together with cell–cell interactions in the marrow, stimulate stem cells to form a series of burst-forming units (BFU) and colony-forming units (CFU): CFU-GEMM, CFU-GM, CFU-Meg, BFU-E, and CFU-E (GEMM, granulocyte, erythrocyte, monocyte, and megakaryocyte; GM, granulocyte and macrophage; Meg, megakaryocyte; E, erythrocyte). After considerable proliferation, further differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte colony-stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M- CSF), thrombopoietin, and erythropoietin. Each of these factors also influences the proliferation, maturation, and, in some cases, the function of the derivative cell line (seeTable 54–1). Erythropoietin While erythropoietin is not the sole growth factor responsible for erythropoiesis, it is the most
important regulator of the proliferation of committed progenitors (BFU-E and CFU-E). In its absence, severe anemia is invariably present. Erythropoiesis is controlled by a highly responsive feedback system in which a sensor in the kidney can detect changes in oxygen delivery to increase the secretion of erythropoietin, which then stimulates a rapid expansion of erythroid progenitors. Erythropoietin is produced primarily by peritubular interstitial cells of the kidney under the control of a single gene on human chromosome 7. The gene product is a protein containing 193 amino acids, of which the first 27 are cleaved during secretion (Jacobs et al., 1985; Lin et al., 1985). The final hormonal peptide is heavily glycosylated and has a molecular weight of approximately 30,000 daltons. Once released, erythropoietin travels to the marrow, where it binds to a receptor on the surface of committed erythroid progenitors and is internalized. With anemia or hypoxemia, renal synthesis rapidly increases by 100-fold or more, serum erythropoietin levels rise, and marrow progenitor cell survival, proliferation, and maturation are dramatically stimulated. This finely tuned feedback loop can be disrupted at any point—by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin. With an infection or an inflammatory state, erythropoietin secretion, iron delivery, and progenitor proliferation are all suppressed by inflammatory cytokines. Recombinant human erythropoietin (epoetin alfa), produced using a mammalian cell line (Chinese hamster ovary cells), is virtually identical to endogenous hormone. Small differences in the carbohydrate portion of the molecule do not appear to affect the kinetics, potency, or immunoreactivity. Currently available preparations of epoetin alfa include EPOGEN and PROCRIT, supplied in single-use vials of from 2000 to 10,000 U/ml for intravenous or subcutaneous administration. When injected intravenously, epoetin alfa is cleared from plasma with a half-life of 10 hours. However, the effect on marrow progenitors is sufficiently sustained that it need not be given more often than three times a week to achieve an adequate response. No significant allergic reactions have been associated with the intravenous or subcutaneous administration of epoetin alfa, and antibodies have not been detected, even after prolonged administration. Therapeutic Uses Recombinant erythropoietin therapy can be highly effective in a number of anemias, especially those associated with a poor erythropoietic response. As first shown by Eschbach and coworkers in 1987, there is a clear dose-response relationship between the epoetin alfa dose and the rise in hematocrit in anephric patients, with eradication of their anemia at higher doses. Epoetin alfa also has been shown to be effective in the treatment of anemias associated with surgery, AIDS, cancer chemotherapy, prematurity, and certain chronic inflammatory illnesses. Anemia of Chronic Renal Failure Patients with the anemia of chronic renal disease are ideal candidates for epoetin alfa therapy. The response in predialysis, peritoneal dialysis, and hemodialysis patients is dependent on severity of the renal failure, the erythropoietin dose and route of administration, and iron availability (Eschbach et al., 1989; Kaufman et al., 1998; Besarab et al., 1999). The subcutaneous route of administration is preferred over the intravenous, since absorption is slower and the amount of drug required is reduced by 20% to 40%. Iron supply is especially critical. Adequate iron stores, as reflected by an iron saturation of transferrin of at least 30% and a plasma ferritin greater than 400 g/l, must be maintained, usually by repeated injections of iron dextran (see"Therapy with Parenteral Iron"). The patient must be closely monitored during therapy, and the dose of epoetin alfa must be adjusted to obtain a gradual rise in the hematocrit, over a 2- to 4-month period, until a final hematocrit of
33% to 36% is reached. Treatment to hematocrit levels greater than 36% is not recommended. A study of patients treated to hematocrits above 40% showed a higher incidence of myocardial infarction and death (Besarab et al., 1998). Furthermore, the drug should never be used to replace emergency transfusion in patients who need immediate correction of a life-threatening anemia. It is currently recommended that the patient be started on a dose of 80 to 120 U/kg of epoetin alfa, given subcutaneously, three times a week. It can be given on a once-a-week schedule, but considerably more drug is required for an equivalent effect. If the response is poor, the dose should be progressively increased. The final maintenance dose of epoetin alfa can vary from as little as 10 U/kg to more than 300 U/kg, with an average close to 75 U/kg, three times a week, in most patients. Children under the age of 5 years generally require a higher dose. Resistance to therapy is commonly seen in the patient who develops an inflammatory illness or becomes iron deficient, so that close monitoring of general health and iron status is essential. Less common causes of resistance include occult blood loss, folic acid deficiency, carnitine deficiency, inadequate dialysis, aluminum toxicity, and osteitis fibrosa cystica secondary to hyperparathyroidism. The most common side effect of epoetin alfa therapy is aggravation of hypertension, seen in 20% to 30% of patients and most often associated with a too-rapid rise in hematocrit. Blood pressure control usually can be attained by either increasing antihypertensive therapy or ultrafiltration in dialysis patients or by reducing the epoetin alfa dose to slow the hematocrit response. An increased tendency to vascular access thrombosis in dialysis patients also has been reported, but this remains controversial. Anemia in AIDS Patients Epoetin alfa therapy has been approved for the treatment of HIV-infected patients, especially those on zidovudine therapy (Fischl et al., 1990). Excellent responses to doses of 100 to 300 U/kg, given subcutaneously three times a week, generally are seen in patients with zidovudine-induced anemia. In the face of advanced disease, marrow damage, and elevated serum erythropoietin levels (greater than 500 IU/L), therapy is less effective. Cancer-Related Anemias Epoetin alfa therapy, 150 U/kg three times a week or 450 to 600 U/kg once a week, can reduce the transfusion requirement in cancer patients undergoing chemotherapy. It also has been used to treat patients with multiple myeloma, with improvement in both their anemia and sense of well-being. Here again, a baseline serum erythropoietin level may help to predict the response. Surgery and Autologous Blood Donation Epoetin alfa has been used perioperatively to treat anemia and reduce the need for transfusion. Patients undergoing elective orthopedic and cardiac procedures have been treated with 150 to 300 U/kg of epoetin alfa once daily for the 10 days preceding surgery, on the day of surgery, and for 4 days after surgery. As an alternative, 600 U/kg can be given on days –21, –14, and –7 prior to surgery, with an additional dose on the day of surgery. This can correct a moderately severe preoperative anemia, hematocrit 30% to 36%, and reduce the need for transfusion. Epoetin alfa also has been used to improve autologous blood donation (Goodnough et al., 1989). However, as a routine, the potential benefit is small while the expense is considerable. Patients treated for 3 to 4 weeks with epoetin alfa (300 to 600 U/kg twice a week), are able to donate only 1 or 2 more units than untreated patients, and most of the time this goes unused. Still, the ability to stimulate
erythropoiesis for blood storage can be invaluable in the patient with multiple alloantibodies to homologous red blood cells. Other Uses Epoetin alfa has been designated an orphan drug by the United States Food and Drug Administration (FDA) for the treatment of the anemia of prematurity and patients with myelodysplasia. In the latter case, even very high doses of more than 1000 U/kg 2 to 3 times a week have had limited success. The possible use of very high dose therapy in other hematological disorders, such as sickle cell anemia, is still under study. Highly competitive athletes have used epoetin alfa to increase their hemoglobin levels ("blood doping") and improve performance. Unfortunately, this misuse of the drug has been implicated in the deaths of several athletes, and it should be discouraged. Myeloid Growth Factors The myeloid growth factors are glycoproteins that stimulate the proliferation and differentiation of one or more myeloid cell lines. They also enhance the function of mature granulocytes and monocytes. Recombinant forms of several of the growth factors have now been produced, including GM-CSF (Lee et al., 1985), G-CSF (Wong et al., 1985), IL-3 (Yang et al., 1986), M-CSF or CSF-1 (Kawasaki et al., 1985), SCF (Huang et al., 1990), and, most recently, thrombopoietin (Lok et al., 1994; de Sauvage et al., 1994; Kaushansky et al., 1994; Table 54–1). The myeloid growth factors are produced naturally by a number of different cells including fibroblasts, endothelial cells, macrophages, and T cells (Figure 54–2). They are active at extremely low concentrations. GM-CSF is capable of stimulating the proliferation, differentiation, and function of a number of the myeloid cell lineages (Figure 54–1). It acts synergistically with other growth factors, including erythropoietin, at the level of the BFU. GM-CSF stimulates the CFU- GEMM (granulocyte/erythrocyte/macrophage/megakaryocyte), CFU-GM, CFU-M, CFU-E, and CFU-Meg (megakaryocyte) to increase cell production. It also enhances the migration, phagocytosis, superoxide production, and antibody-dependent cell media toxicity of neutrophils, monocytes, and eosinophils. Figure 54–2. Cytokine–Cell Interactions. Macrophages, T cells, B cells, and marrow stem cells interact via several cytokines [IL (interleukin)-1, IL-2, IL-3, IL-4, IFN (interferon)- , GM-CSF, and G-CSF] in response to a bacterial or a foreign antigen challenge. SeeTable 54–1 for the functional activities of these various cytokines.
The activity of G-CSF is more focused. Its principal action is to stimulate the proliferation, differentiation, and function of the granulocyte lineage. It acts primarily on the CFU-G, although it can also play a synergistic role with IL-3 and GM-CSF in stimulating other cell lines. G-CSF enhances phagocytic and cytotoxic activities of neutrophils. Unlike GM-CSF, G-CSF has little effect on monocytes, macrophages, and eosinophils. At the same time, G-CSF reduces inflammation by inhibiting IL-1, tumor necrosis factor, and interferon gamma. Granulocyte/Macrophage Colony-Stimulating Factor (GM-CSF) Recombinant human GM-CSF (sargramostim) is a 127–amino acid glycoprotein produced in yeast. Except for the substitution of a leucine in position 23 and variable levels of glycosylation, it is identical to endogenous GM-CSF. While sargramostim, like natural GM-CSF, has a wide range of effects on cells in culture, its primary therapeutic effect is the stimulation of myelopoiesis. The initial clinical application of sargramostim was in patients undergoing autologous bone marrow transplantation. By shortening the duration of neutropenia, transplant morbidity was significantly reduced without a change in long-term survival or risk of inducing an early relapse of the malignant process (Brandt et al., 1988; Rabinowe et al., 1993). The role of GM-CSF therapy in allogeneic transplantation is less clear. The effect of the growth factor on neutrophil recovery is less pronounced in patients receiving prophylactic treatment for graft-versus-host disease (GVHD), and studies have failed to show a significant effect on transplant mortality, long-term survival, the appearance of GVHD, or disease relapse. However, it may improve survival in transplant patients who exhibit early graft failure (Nemunaitis et al., 1990). It also has been used to mobilize CD34- positive progenitor cells for peripheral blood stem cell collection for transplantation following myeloablative chemotherapy. Sargramostim has been used to shorten the period of neutropenia and reduce morbidity in patients receiving intensive chemotherapy (Gerhartz et al., 1993). It also will stimulate myelopoiesis in some patients with cyclic neutropenia, myelodysplasia, aplastic anemia, or AIDS-associated neutropenia (Groopman et al., 1987; Vadhan-Raj et al., 1987). Sargramostim (LEUKINE) is administered by subcutaneous injection or slow intravenous infusion at a dose of 125 to 500 g/m2 per day. Plasma levels of GM-CSF rise rapidly after subcutaneous injection and then decline, with a half-life of 2 to 3 hours. When given intravenously, infusions should be maintained over 3 to 6 hours. With the initiation of therapy, there is a transient decrease in the absolute leukocyte count secondary to margination and sequestration in the lungs. This is followed by a dose-dependent, biphasic increase in leukocyte counts over the next 7 to 10 days.
Once the drug is discontinued, the leukocyte count returns to baseline within 2 to 10 days. When GM-CSF is given in lower doses, the response is primarily neutrophilic, while at larger doses, monocytosis and eosinophilia are observed. Following bone marrow transplantation or intensive chemotherapy, sargramostim is given daily during the period of maximum neutropenia until a sustained rise in the granulocyte count is observed. Frequent blood counts are essential to avoid an excessive rise in the granulocyte count. The dose may be increased if the patient fails to respond after 7 to 14 days of therapy. However, higher doses are associated with more pronounced side effects, including bone pain, malaise, flulike symptoms, fever, diarrhea, dyspnea, and rash. Patients can be extremely sensitive to GM-CSF, demonstrating an acute reaction to the first dose, characterized by flushing, hypotension, nausea, vomiting, and dyspnea, with a fall in arterial oxygen saturation due to sequestration of granulocytes in the pulmonary circulation. With prolonged administration, a few patients may develop a capillary leak syndrome, with peripheral edema and both pleural and pericardial effusions. Granulocyte Colony-Stimulating Factor (G-CSF) Recombinant human G-CSF (filgrastim, NEUPOGEN) is a 175–amino acid glycoprotein produced in Escherichia coli. Unlike natural G-CSF, it is not glycosylated and carries an extra N-terminal methionine. The principal action of filgrastim is the stimulation of CFU-G to increase neutrophil production (Figure 54–1). It also enhances the phagocytic and cytotoxic functions of neutrophils. Filgrastim has been shown to be effective in the treatment of severe neutropenia following autologous bone marrow transplantation and high-dose chemotherapy (Lieschke and Burgess, 1992). Like GM-CSF, filgrastim shortens the period of severe neutropenia and reduces morbidity secondary to bacterial and fungal infections. When used as a part of an intensive chemotherapy regimen, it can decrease the frequency of both hospitalization for febrile neutropenia and interruptions in the chemotherapy protocol. G-CSF also has proven to be effective in the treatment of severe congenital neutropenias. In patients with cyclic neutropenia, G-CSF therapy, while not eliminating the neutropenic cycle, will increase the level of neutrophils and shorten the length of the cycle sufficiently to prevent recurrent bacterial infections (Hammond et al., 1989). Filgrastim therapy can improve neutrophil counts in some patients with myelodysplasia or marrow damage (moderately severe aplastic anemia or tumor infiltration of the marrow). The neutropenia of AIDS patients receiving zidovudine also can be partially or completely reversed. Filgrastim is now routinely used in the patient undergoing peripheral blood stem cell (PBSC) collection and a stem cell transplant. It encourages the release of CD34+ progenitor cells from the marrow, reducing the number of collections necessary for transplant. Moreover, filgrastim-mobilized PBSCs appear more capable of rapid engraftment. PBSC-transplanted patients require fewer days of platelet and red blood cell transfusions and a shorter duration of hospitalization than do patients receiving autologous bone marrow transplants. Filgrastim is administered by subcutaneous injection or intravenous infusion over at least 30 minutes at a dose of 1 to 20 g/kg per day. A usual starting dose in a patient receiving myelosuppressive chemotherapy is 5 g/kg per day. The distribution and clearance rate from plasma (half-life of 3.5 hours) are similar for both routes of administration. A continuous 24-hour intravenous infusion can be used to produce a steady-state serum concentration of the growth factor. As with GM-CSF therapy, filgrastim given daily following bone marrow transplantation or intensive chemotherapy will increase granulocyte production and shorten the period of severe neutropenia. Frequent blood counts should be obtained to determine the effectiveness of the treatment. The dosage may need to be adjusted according to the granulocyte response, and the duration of therapy will depend on the specific application. In marrow transplantation and intensive
chemotherapy patients, continuous daily administration for 14 to 21 days or longer may be necessary to correct the neutropenia. With less intensive chemotherapy, fewer than 7 days of treatment may be needed. In AIDS patients on zidovudine or patients with cyclic neutropenia, chronic G-CSF therapy often will be required. Adverse reactions to filgrastim include mild to moderate bone pain in those patients receiving high doses over a protracted period, local skin reactions following subcutaneous injection, and, rarely, a cutaneous necrotizing vasculitis. Patients with a history of hypersensitivity to proteins produced by E. coli should not receive the drug. Marked granulocytosis, with counts greater than 100,000/ l, can occur in patients receiving filgrastim over a prolonged period of time. However, this is not associated with any reported clinical morbidity or mortality and rapidly resolves once therapy is discontinued. Mild to moderate splenomegaly has been observed in patients on long-term therapy. The therapeutic roles of other growth factors still need to be defined. M-CSF may play a role in stimulating monocyte and macrophage production, though with significant side effects, including splenomegaly and thrombocytopenia. Because of their primary effect on primitive marrow precursors, IL-3 and FL may be used in combination with GM-CSF and G-CSF. Administration of IL-3 followed by GM-CSF has been shown to give a greater neutrophil response than GM-CSF alone (Ganser et al., 1992). This combination also may be more effective in promoting the release of marrow CD34+ stem cells in patients undergoing stem cell pheresis. SCF, IL-1, IL-6, IL-9, and IL-11 need to be studied alone and in combination with each other, as well as with both GM-CSF and G-CSF. The combination of IL-3 followed by GM-CSF also needs to be studied in protocols that include the reinfusion of harvested stem cells for their growth-promoting activity. Thrombopoietin The cloning and expression of a recombinant human thrombopoietin, a cytokine that selectively stimulates megakaryocytopoiesis, is another major milestone in the development of hematopoietic growth factors as therapeutic agents (Lok et al., 1994; de Sauvage et al., 1994; Kaushansky et al., 1994). If future clinical trials live up to the early promise of the demonstrated ability of this new cytokine to increase rapidly the platelet count in animals (Harker, 1999), the combined use of thrombopoietin with G-CSF or GM-CSF together with erythropoietin will have a great impact in the treatment of primary hematological diseases and the anemia, neutropenia, and thrombocytopenia associated with high-dose chemotherapy. In a study of a small number of patients with gynecological cancers receiving carboplatin (Vadhan-Raj et al., 2000), recombinant human thrombopoietin (rHuTPO) therapy reduced the duration of severe thrombocytopenia as well as the need for platelet transfusions. Larger, randomized, controlled trials are now under way to define fully the clinical merits and safety of rHuTPO. The optimal dose and schedule of administration in various clinical settings also need to be worked out. Both rHuTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHyMGDF) give delayed platelet responses. Following a single bolus injection, platelet counts show a detectable increase by day 4 and a peak response by 12 to 14 days. The platelet count then returns to normal over the next 4 weeks. The peak platelet response follows a log-linear dose response. Platelet activation and aggregation are not affected, and patients are not at increased risk of thromboembolic disease, unless the platelet count is allowed to rise to very high levels. These kinetics need to be taken into account when planning therapy in a chemotherapy patient. Drugs Effective in Iron Deficiency and Other Hypochromic Anemias Iron and Iron Salts
Iron deficiency is the most common cause of nutritional anemia in human beings. It can result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy. When severe, it results in a characteristic microcytic, hypochromic anemia. However, the impact of iron deficiency is not limited to the erythron (Dallman, 1982). Iron also is an essential component of myoglobin; heme enzymes such as the cytochromes, catalase, and peroxidase; and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme - glycerophosphate oxidase. Iron deficiency can affect metabolism in muscle independently of the effect of anemia on oxygen delivery. This may well reflect a reduction in the activity of iron- dependent mitochondrial enzymes. Iron deficiency also has been associated with behavioral and learning problems in children and with abnormalities in catecholamine metabolism and, possibly, heat production (Pollit and Leibel, 1982; Martinez-Torres et al., 1984). Awareness of the ubiquitous role of iron has stimulated considerable interest in the early and accurate detection of iron deficiency and in its prevention. History Iron has been used in the treatment of illness since the Middle Ages and the Renaissance. However, it was not until the sixteenth century that iron deficiency was recognized as the cause of "green sickness," or chlorosis, in adolescent women. Sydenham subsequently proposed iron as a preferred therapy over bleedings and purgings, and in 1832, the French physician Pierre Blaud recognized the need to use adequate doses of iron to successfully treat chlorosis. Blaud's nephew later distributed the "veritable pills of Blaud" throughout the world. The treatment of anemia with iron followed the principles enunciated by Sydenham and Blaud until the end of the nineteenth century. At that time the teachings of Bunge, Quincke, von Noorden, and others cast doubt on their treatment of chlorosis. The dose of iron employed was reduced, and the resulting lack of efficacy brought discredit on the therapy. It was not until the third and fourth decades of the twentieth century that the lessons taught by the earlier physicians were relearned. The modern understanding of iron metabolism began in 1937 with the work of McCance and Widdowson on iron absorption and excretion and Heilmeyer and Plotner's measurement of iron in plasma. Then in 1947, Laurell described a plasma iron transport protein that he called transferrin. Hahn and coworkers (1943) were the first to use radioactive isotopes to quantitate iron absorption and define the role of the intestinal mucosa to regulate this function. In the next decade, Huff and associates (1950) initiated isotopic studies of internal iron metabolism. The subsequent development of practical clinical measurements of serum iron, transferrin saturation, plasma ferritin, and red cell protoporphyrin permitted the definition and detection of the body's iron store status and iron-deficient erythropoiesis. Iron and the Environment Iron exists in the environment largely as ferric oxide or hydroxide or as polymers. In this state, its biological availability is limited unless it is solubilized by acid or chelating agents. For example, to meet their needs, bacteria and some plants produce high-affinity chelating agents that extract iron from the surrounding environment. Most mammals have little difficulty in acquiring iron; this is explained by an ample iron intake and perhaps also by a greater efficiency in absorbing iron. Human beings, however, appear to be an exception. Although total dietary intake of elemental iron in human beings usually exceeds requirements, the bioavailability of the iron in the diet is limited.
Metabolism of Iron The body store of iron is divided between essential iron-containing compounds and excess iron, which is held in storage. From a quantitative standpoint, hemoglobin dominates the essential fraction (Table 54–2). This protein, with a molecular weight of 64,500 daltons, contains four atoms of iron per molecule, amounting to 1.1 mg of iron per milliliter of red blood cells (20 mM). Other forms of essential iron include myoglobin and a variety of heme and nonheme iron-dependent enzymes. Ferritin is a protein-iron storage complex, which exists as individual molecules or in an aggregated form. Apoferritin has a molecular weight of about 450,000 daltons and is composed of 24 polypeptide subunits; these form an outer shell within which resides a storage cavity for polynuclear hydrous ferric oxide phosphate. Over 30% of the weight of ferritin may be iron (4000 atoms of iron per ferritin molecule). Aggregated ferritin, referred to as hemosiderin and visible by light microscopy, constitutes about one-third of normal stores, a fraction that increases as stores enlarge. The two predominant sites of iron storage are the reticuloendothelial system and the hepatocytes, although some storage also occurs in muscle (Bothwell et al., 1979). Internal exchange of iron is accomplished by the plasma protein transferrin (Aisen and Brown, 1977). This 1-glycoprotein has a molecular weight of about 76,000 daltons and two binding sites for ferric iron. Iron is delivered from transferrin to intracellular sites by means of specific transferrin receptors in the plasma membrane. The iron–transferrin complex binds to the receptor, and the ternary complex is taken up by receptor-mediated endocytosis. Iron subsequently dissociates in a pH-dependent fashion in an acidic, intracellular vesicular compartment (the endosomes), and the receptor returns the apotransferrin to the cell surface, where it is released into the extracellular environment (Klausner et al., 1983). Human cells regulate their expression of transferrin receptors and intracellular ferritin in response to the iron supply. When iron is plentiful, the synthesis of transferrin receptors is reduced and ferritin production is increased. Conversely, with iron deficiency, cells express a greater number of transferrin receptors and reduce ferritin concentrations to maximize uptake and prevent diversion of iron to stores. Isolation of the genes for the human transferrin receptor and ferritin has permitted a better definition of the molecular basis of this regulation. Apoferritin synthesis is regulated by a system of cytoplasmic binding proteins (IRP-1 and -2) and an iron-regulating element on mRNA (IRE). When iron is in short supply, IRP binds to mRNA IRE and inhibits the translation of apoferritin. Conversely, when iron is abundant, binding is blocked and apoferritin synthesis increases (Klausner et al., 1993). The flow of iron through the plasma amounts to a total of 30 to 40 mg per day in the adult (about 0.46 mg/kg of body weight) (Finch and Huebers, 1982). The major internal circulation of iron involves the erythron and the reticuloendothelial cell (Figure 54–3). About 80% of the iron in plasma goes to the erythroid marrow to be packaged into new erythrocytes; these normally circulate for about 120 days before being catabolized by the reticuloendothelium. At that time a portion of the iron is immediately returned to the plasma bound to transferrin, while another portion is incorporated into the ferritin stores of the reticuloendothelial cell and is returned to the circulation more gradually. Isotopic studies indicate some degree of iron wastage in this process, wherein defective cells or unused portions of their iron are transferred to the reticuloendothelial cell during maturation, bypassing the circulating blood. When there are abnormalities in maturation of red cells, the predominant portion of iron assimilated by the erythroid marrow may be rapidly localized in the reticuloendothelial cell as defective red cell precursors are broken down; this is termed ineffective erythropoiesis. With red cell aplasia, the rate of turnover of iron in plasma may be reduced by one-half or more, with all the iron now going to the hepatocyte for storage.
Figure 54–3. Pathways of Iron Metabolism in Human Beings (Excretion Omitted). The most remarkable feature of iron metabolism is the degree to which the body store is conserved. Only 10% of the total is lost per year by normal men, i.e., about 1 mg per day. Two-thirds of this iron is excreted from the gastrointestinal tract as extravasated red cells, iron in bile, and iron in exfoliated mucosal cells. The other third is accounted for by small amounts of iron in desquamated skin and in the urine. Physiological losses of iron in men vary over a narrow range, from 0.5 mg in the iron-deficient individual to 1.5 to 2 mg per day when excessive iron is consumed. Additional losses of iron occur in women due to menstruation. While the average loss in menstruating women is about 0.5 mg per day, 10% of normal menstruating women lose over 2 mg per day. Pregnancy imposes a requirement for iron of even greater magnitude (Table 54–3). Other causes of iron loss include the donation of blood, the use of antiinflammatory drugs that cause bleeding from the gastric mucosa, and gastrointestinal disease with associated bleeding. Much rarer are the hemosiderinuria that follows intravascular hemolysis and pulmonary siderosis, wherein iron is deposited in the lungs and becomes unavailable to the rest of the body. The limited physiological losses of iron point to the primary importance of absorption as the determinant of the body's iron content. Unfortunately, the biochemical nature of the absorptive process is understood only in general terms. After acidification and partial digestion of food in the stomach, its content of iron is presented to the intestinal mucosa as either inorganic iron or heme iron. These fractions are taken up by the absorptive cells of the duodenum and upper small intestine, and the iron is transported either directly into the plasma or stored as mucosal ferritin. Absorption appears to be regulated by two separate transporters: DCT1, which controls uptake from the intestinal lumen, and a second transporter, which governs movement of mucosal cell iron across the basolateral membrane to bind to plasma protein. Mucosal cell iron transport and the delivery of iron to transferrin from reticuloendothelial stores are both determined by the HFE gene, a novel MHC
class 1 molecule localized to chromosome 6 (Peters et al., 1993). Regulation is finely tuned to prevent iron overload in times of iron excess, while allowing for increased absorption and mobilization of iron stores with iron deficiency. Normal absorption is only about 1 mg per day in the adult man and 1.4 mg per day in the adult woman, and 3 to 4 mg of dietary iron is the most that can be absorbed under normal conditions. Increased iron absorption is seen whenever iron stores are depleted or when erythropoiesis is increased and ineffective. Patients with hereditary hemochromatosis, secondary to a defective HFE gene, also demonstrate increased iron absorption, as well as loss of the normal regulation of iron delivery to transferrin by reticuloendothelial cells. The resulting increased saturation of transferrin opens the door to abnormal iron deposition in nonhematopoietic tissues. Iron Requirements and the Availability of Dietary Iron Iron requirements are determined by obligatory physiological losses and the needs imposed by growth. Thus, the adult man has a requirement of only 13 g/kg per day (about 1 mg), whereas the menstruating woman requires about 21 g/kg per day (about 1.4 mg). In the last two trimesters of pregnancy, requirements increase to about 80 g/kg per day (5 to 6 mg), and the infant has similar requirements due to its rapid growth. These requirements (Table 54–4) must be considered in the context of the amount of dietary iron available for absorption. In developed countries, the normal adult diet contains about 6 mg of iron per 1000 calories, providing an average daily intake for the adult male of between 12 and 20 mg and for the adult female of between 8 and 15 mg. Foods high in iron (greater than 5 mg/100 g) include organ meats such as liver and heart, brewer's yeast, wheat germ, egg yolks, oysters, and certain dried beans and fruits; foods low in iron (less than 1 mg/100 g) include milk and milk products and most nongreen vegetables. The content of iron in food is affected further by the manner of its preparation, since iron may be added from cooking in iron pots. Although the iron content of the diet is obviously important, of greater nutritional significance is the bioavailability of iron in food (Hallberg, 1981). Heme iron is far more available, and its absorption is independent of the composition of the diet. Heme iron, which constitutes only 6% of dietary iron, represents 30% of iron absorbed. Nevertheless, it is the availability of the nonheme fraction that deserves the greatest attention, since it represents by far the largest amount of dietary iron that is ingested by the economically underprivileged. In a vegetarian diet, nonheme iron is absorbed very poorly because of the inhibitory action of a variety of dietary components, particularly phosphates (Layrisse and Martinez-Torres, 1971). Two substances are known to facilitate the absorption of nonheme iron—ascorbic acid and meat. Ascorbate forms complexes with and/or reduces ferric to ferrous iron. While meat facilitates the absorption of iron by stimulating production of gastric acid, it is possible that some other effect, not yet identified, also is involved. Either of these substances can increase availability severalfold. Thus, assessments of available dietary iron should include not only the amount of iron ingested but also an estimate of its availability based on the intake of substances that enhance or inhibit its absorption and iron stores (Figure 54–4; Monsen et al., 1978). Figure 54–4. Effect of Iron Status on the Absorption of Nonheme Iron in Food. The percentages of iron absorbed from diets of low, medium, and high bioavailability in individuals with iron stores of 0, 250, 500, and 1000 mg are portrayed. (After Monsen et al., 1978. ©American Journal of Clinical Nutrition. Courtesy of American Society for Clinical Nutrition. With permission.)
A comparison of iron requirements with available dietary iron is made in Table 54–4. Obviously, pregnancy and infancy represent periods of negative balance. The menstruating woman also is at risk, whereas iron balance in the adult man and nonmenstruating woman is reasonably secure. The difference between dietary supply and requirements is reflected in the size of iron stores. These will be low or absent when iron balance is precarious and high when iron balance is favorable (seeTable 53–2). Thus, in the infant after the third month of life and in the pregnant woman after the first trimester, stores of iron are negligible. Menstruating women have approximately one-third the stored iron found in the adult man, indicative of the extent to which the additional average daily loss of about 0.5 mg of iron affects iron balance. Iron Deficiency The prevalence of iron-deficiency anemia depends on the economic status of the population and on the methods used for evaluation. In developing countries, as many as 20% to 40% of infants and pregnant women may be affected (WHO Joint Meeting, 1975), while studies in the United States suggest that the prevalence of iron-deficiency anemia in adult men and women is as low as 0.2% to 3% (Cook et al., 1986). Better iron balance has been achieved by the practice of fortifying flour, the use of iron-fortified formulas for infants, and the prescription of medicinal iron supplements during pregnancy. Iron-deficiency anemia results from a dietary intake of iron that is inadequate to meet normal requirements (nutritional iron deficiency), blood loss, or some interference with iron absorption. Most nutritional iron deficiency in the United States is mild. Moderate-to-severe iron deficiency is usually the result of blood loss, either from the gastrointestinal tract or, in the woman, from the uterus. Impaired absorption of iron from food results most often from partial gastrectomy or malabsorption in the small intestine. Iron deficiency in infants and young children can lead to behavioral disturbances and developmental delays. Chronic developmental defects may not be fully reversible. Iron deficiency in children also can lead to an increased risk of lead toxicity secondary to pica and an increased absorption of heavy metals. Premature and low-birth-weight infants are at greatest risk for developing iron deficiency, especially if they are not breast-fed and/or do not receive iron-fortified formula. After age 2 to 3, the requirement for iron declines until adolescence, when rapid growth combined with irregular dietary habits again increases the risk of iron deficiency. Adolescent girls are at greatest risk; the dietary iron intake of most girls ages 11 to 18 is insufficient to meet their
requirements. The recognition of iron deficiency rests on an appreciation of the sequence of events that lead to depletion of iron stores (Hillman and Finch, 1997). A negative balance first results in a reduction of iron stores and, eventually, a parallel decrease in red-cell iron and iron-related enzymes (Figure 54– 5). In adults, depletion of iron stores may be recognized by a plasma ferritin of less than 12 g per liter and the absence of reticuloendothelial hemosiderin in the marrow aspirate. Iron-deficient erythropoiesis, defined as a suboptimal supply of iron to the erythron, is identified by a decreased saturation of transferrin to less than 16% and/or by an increase above normal in red-cell protoporphyrin. Iron-deficiency anemia is associated with a recognizable decrease in the concentration of hemoglobin in blood. However, the physiological variation in hemoglobin levels is so great that only about half the individuals with iron-deficient erythropoiesis are identified from their anemia (Cook et al., 1976). Moreover, "normal" hemoglobin and iron values in infancy and childhood are different because of the more restricted supply of iron in young children (Dallman et al., 1980). Figure 54–5. Sequential Changes (from Left to Right) in the Development of Iron Deficiency in the Adult. Rectangles enclose abnormal test results. RE marrow Fe, reticuloendothelial hemosiderin; RBC, red blood cells. (After Hillman and Finch, 1997, as modified from Bothwell and Finch, 1962. Courtesy of F.A. Davis Co. With permission.) The importance of mild iron deficiency lies more in identifying the underlying cause of the deficiency than in any symptoms related to the deficient state. Because of the frequency of iron deficiency in infancy and in the menstruating or pregnant woman, the need for exhaustive evaluation of such individuals usually is determined by the severity of the anemia. However, iron deficiency in the man or postmenopausal woman necessitates a search for a site of bleeding. Although the presence of microcytic anemia is the most commonly recognized indicator of iron
deficiency, laboratory tests—such as quantitation of transferrin saturation, red cell protoporphyrin, and plasma ferritin—are required to distinguish iron deficiency from other causes of microcytosis. Such measurements are particularly useful when circulating red cells are not yet microcytic because of the recent nature of blood loss, but iron supply is nonetheless limiting erythropoiesis. More difficult is the differentiation of true iron deficiency from iron-deficient erythropoiesis due to inflammation. In the latter condition, the stores of iron are actually increased, but the release of iron from reticuloendothelial cells is blocked; the concentration of iron in plasma is decreased, and the supply of iron to the erythroid marrow becomes inadequate. The increased stores of iron in this condition may be demonstrated directly by examination of an aspirate of marrow or may be inferred from determination of an elevated concentration of ferritin in plasma (Lipschitz et al., 1974). Treatment of Iron Deficiency General Therapeutic Principles The response of iron-deficiency anemia to iron therapy is influenced by several factors, including the severity of anemia, the ability of the patient to tolerate and absorb medicinal iron, and the presence of other complicating illnesses. Therapeutic effectiveness can be best measured from the resulting increase in the rate of production of red cells. The magnitude of the marrow response to iron therapy is proportional to the severity of the anemia (level of erythropoietin stimulation) and the amount of iron delivered to marrow precursors. Studies by Hillman and Henderson (1969) demonstrated the importance of iron supply in governing erythropoiesis. Using phlebotomy to induce a moderately severe anemia (hemoglobin 7 to 10 g/dl), erythropoiesis was reduced to less than one-third of normal when the serum iron fell below 70 g/dl. In contrast, red cell production levels increased to more than three times the basal rate when the serum iron was maintained between 75 and 150 g/dl. Even higher levels of production were observed in patients with hemolytic anemias or ineffective erythropoiesis. As regards oral iron therapy, the ability of the patient to tolerate and absorb medicinal iron is a very important factor in determining the rate of response. There are clear limits to the gastrointestinal tolerance for iron. The small intestine regulates absorption and, in the face of increasing doses of oral iron, limits the entry of iron into the bloodstream. Therefore, there is a natural ceiling on how much iron can be supplied by oral therapy. In the patient with a moderately severe iron-deficiency anemia, tolerable doses of oral iron will deliver, at most, 40 to 60 mg of iron per day to the erythroid marrow. This is an amount sufficient for production rates of two to three times normal. Complicating illness also can interfere with the response of an iron-deficiency anemia to iron therapy. Intrinsic disease of the marrow can, by decreasing the number of red cell precursors, blunt the response. Inflammatory illnesses suppress the rate of red cell production, both by reducing iron absorption and reticuloendothelial release and by direct inhibition of erythropoietin and erythroid precursors. Continued blood loss can mask the response as measured by recovery of the hemoglobin or hematocrit. Clinically, the effectiveness of iron therapy is best evaluated by tracking the reticulocyte response and the rise in the hemoglobin or the hematocrit. Since it takes time for the marrow to proliferate, an increase in the reticulocyte count is not observed for 4 to 7 days or more after beginning therapy. A measurable increase in the hemoglobin level takes even longer. A decision as to the effectiveness of treatment should not be made for 3 to 4 weeks after the start of treatment. An increase of 20 g per liter or more in the concentration of hemoglobin by that time should be considered a positive response, assuming that no other change in the patient's clinical status can account for the
improvement. It also assumes that the patient has not been transfused during this time. If the response to oral iron is inadequate, the diagnosis must be reconsidered. A full laboratory evaluation should be carried out, and such factors as the presence of a concurrent inflammatory disease or poor compliance by the patient must be assessed. A source of continued bleeding obviously should be sought. If no other explanation can be found, an evaluation of the patient's ability to absorb oral iron should be considered. There is no justification for merely continuing oral iron therapy beyond 3 to 4 weeks if a favorable response has not occurred. Once a response to oral iron is demonstrated, therapy should be continued until the hemoglobin returns to normal. Treatment may be extended if it is desirable to establish iron stores. This may require a considerable period of time, since the rate of absorption of iron by the intestine will decrease markedly as iron stores are reconstituted. The prophylactic use of oral iron should be reserved for patients at high risk, including pregnant women, women with excessive menstrual blood loss, and infants. Iron supplements also may be of value for rapidly growing infants who are consuming substandard diets and for adults with a recognized cause of chronic blood loss. Except for infants, in whom the use of supplemented formulas is routine, the use of "over-the-counter" mixtures of vitamins and minerals to prevent iron deficiency should be discouraged. Therapy with Oral Iron Orally administered ferrous sulfate, the least expensive of iron preparations, is the treatment of choice for iron deficiency (Callender, 1974; Bothwell et al., 1979). Ferrous salts are absorbed about three times as well as ferric salts, and the discrepancy becomes even greater at high dosage ( Brise and Hallberg, 1962). Variations in the particular ferrous salt have relatively little effect on bioavailability, and the sulfate, fumarate, succinate, gluconate, and other ferrous salts are absorbed to approximately the same extent. Ferrous sulfate (iron sulfate;FEOSOL, others) is the hydrated salt, FeSO4·7H2O, which contains 20% iron. Dried ferrous sulfate (32% elemental iron) also is available. Ferrous fumarate (FEOSTAT, others) contains 33% iron and is moderately soluble in water, stable, and almost tasteless. Ferrous gluconate (FERGON, others) also has been successfully used in the therapy of iron-deficiency anemia. The gluconate contains 12% iron. Polysaccharide–iron complex (NIFEREX, others), a compound of ferrihydrite and carbohydrate, is another preparation with comparable absorption. The effective dose of all of these preparations is based on iron content. Other iron compounds have utility in fortification of foods. Reduced iron (metallic iron, elemental iron) is as effective as ferrous sulfate, provided that the material employed has a small particle size. Large-particle ferrum reductum and iron phosphate salts have a much lower bioavailability (Cook et al., 1973), and their use for the fortification of foods is undoubtedly responsible for some of the confusion concerning effectiveness. Ferric edetate has been shown to have good bioavailability and to have advantages for maintenance of the normal appearance and taste of food (Viteri et al., 1978). The amount of iron, rather than the mass of the total salt in iron tablets, is important. It is also essential that the coating of the tablet dissolve rapidly in the stomach. Surprisingly, since iron usually is absorbed in the upper small intestine, certain delayed-release preparations have been reported to be effective and have been said to be even more effective than ferrous sulfate when taken with meals. However, reports of absorption from such preparations vary. Because a number of different forms of delayed-release preparations are on the market and information on their bioavailability is limited, the effectiveness of most such preparations must be considered
questionable. A variety of substances designed to enhance the absorption of iron has been marketed, including surface-acting agents, carbohydrates, inorganic salts, amino acids, and vitamins. One of the more popular of these is ascorbic acid. When present in an amount of 200 mg or more, ascorbic acid increases the absorption of medicinal iron by at least 30%. However, the increased uptake is associated with a significant increase in the incidence of side effects (Hallberg et al., 1966); therefore, the addition of ascorbic acid seems to have little advantage over increasing the amount of iron administered. It is inadvisable to use preparations that contain other compounds with therapeutic actions of their own, such as vitamin B12, folate, or cobalt, since the patient's response to the combination cannot be easily interpreted. The average dose for the treatment of iron-deficiency anemia is about 200 mg of iron per day (2 to 3 mg/kg), given in three equal doses of 65 mg. Children weighing 15 to 30 kg can take half the average adult dose, while small children and infants can tolerate relatively large doses of iron—for example, 5 mg/kg. The dose used is a practical compromise between the therapeutic action desired and the toxic effects. Prophylaxis and mild nutritional iron deficiency may be managed with modest doses. When the object is the prevention of iron deficiency in pregnant women, for example, doses of 15 to 30 mg of iron per day are adequate to meet the 3- to 6-mg daily requirement of the last two trimesters. When the purpose is to treat iron-deficiency anemia, but the circumstances do not demand haste, a total dose of about 100 mg (35 mg three times daily) may be used. The responses expected for different dosage regimens of oral iron are given in Table 54–5. However, these effects are modified by the severity of the iron-deficiency anemia and by the time of ingestion of iron relative to meals. Bioavailability of iron ingested with food is probably one-half or one-third of that seen in the fasting subject (Grebe et al., 1975). Antacids also reduce the absorption of iron if given concurrently. It is always preferable to administer iron in the fasting state, even if the dose must be reduced because of gastrointestinal side effects. For patients who require maximal therapy to encourage a rapid response or to counteract continued bleeding, as much as 120 mg of iron may be administered four times a day. The timing of the dose is important. Sustained high rates of red cell production require an uninterrupted supply of iron. Oral doses should be spaced equally to maintain a continuous high concentration of iron in plasma. The duration of treatment is governed by the rate of recovery of hemoglobin and the desire to create iron stores. The former depends on the severity of the anemia. With a daily rate of repair of 2 g of hemoglobin per liter of whole blood, the red cell mass is usually reconstituted within 1 to 2 months. Thus, an individual with a hemoglobin of 50 g per liter may achieve a normal complement of 150 g per liter in about 50 days, whereas an individual with a hemoglobin of 100 g per liter may take only half that time. The creation of stores of iron is a different matter, requiring many months of oral iron administration. The rate of absorption decreases rapidly after recovery from anemia and, after 3 to 4 months of treatment, stores may increase at a rate of not much more than 100 mg per month. Much of the strategy of continued therapy depends on the estimated future iron balance of the individual. The person with an inadequate diet may require continued therapy with low doses of iron. The individual whose bleeding has stopped will require no further therapy after the hemoglobin has returned to normal. For the individual with continued bleeding, long-term, high-dose therapy is clearly indicated. Untoward Effects of Oral Preparations of Iron Intolerance to oral preparations of iron is primarily a function of the amount of soluble iron in the
upper gastrointestinal tract and of psychological factors. Side effects include heartburn, nausea, upper gastric discomfort, constipation, and diarrhea. A good policy, particularly if there has been previous intolerance to iron, is to initiate therapy at a small dosage, to demonstrate freedom from symptoms at that level, and then gradually to increase the dosage to that desired. With a dose of 200 mg of iron per day divided into three equal portions, symptoms occur in approximately 25% of individuals, compared with an incidence of 13% among those receiving placebos; this increases to approximately 40% when the dosage of iron is doubled. Nausea and upper abdominal pain are increasingly common manifestations at high dosage. Constipation and diarrhea, perhaps related to iron-induced changes in the intestinal bacterial flora, are not more prevalent at higher dosage, nor is heartburn. If a liquid is given, one can place the iron solution on the back of the tongue with a dropper to prevent transient staining of teeth. Toxicity caused by the long-continued administration of iron, with the resultant production of iron overload (hemochromatosis), has been the subject of a number of case reports (for example, seeBothwell et al., 1979). Available evidence suggests that the normal individual is able to control absorption of iron despite high intake, and it is only individuals with underlying disorders that augment the absorption of iron who run the hazard of developing hemochromatosis. However, recent data indicate that hemochromatosis may be a relatively common genetic disorder, present in 0.5% of the population. Iron Poisoning Large amounts of ferrous salts of iron are toxic but, in adults, fatalities are rare. Most deaths occur in childhood, particularly between the ages of 12 and 24 months (Bothwell et al., 1979). As little as 1 to 2 g of iron may cause death, but 2 to 10 g is usually ingested in fatal cases. The frequency of iron poisoning relates to its availability in the household, particularly the supply that remains after a pregnancy. The colored sugar coating of many of the commercially available tablets gives them the appearance of candy. All iron preparations should, therefore, be kept in childproof bottles. Signs and symptoms of severe poisoning may occur within 30 minutes or may be delayed for several hours after ingestion. They consist largely of abdominal pain, diarrhea, or vomiting of brown or bloody stomach contents containing pills. Of particular concern are pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and cardiovascular collapse. If death does not occur within 6 hours, there may be a transient period of apparent recovery, followed by death in 12 to 24 hours. The corrosive injury to the stomach may result in pyloric stenosis or gastric scarring. Hemorrhagic gastroenteritis and hepatic damage are prominent findings at autopsy. In the evaluation of the child who is thought to have ingested iron, a color test for iron in the gastric contents and an emergency determination of the concentration of iron in plasma can be performed. If the latter is less than 63 M (3.5 mg per liter), the child is not in immediate danger. However, vomiting should be induced when there is iron in the stomach, and an X-ray should be taken to evaluate the number of pills remaining in the small bowel (iron tablets are radioopaque). Iron in the upper gastrointestinal tract can be precipitated by lavage with sodium bicarbonate or phosphate solution, although the clinical benefit is questionable. When the plasma concentration of iron is greater than the total iron-binding capacity (63 M; 3.5 mg per liter), deferoxamine should be administered; dosage and routes of administration are detailed in Chapter 67: Heavy Metals and Heavy-Metal Antagonists. Shock, dehydration, and acid-base abnormalities should be treated in the conventional manner. Most important is the speed of diagnosis and therapy. With early effective treatment, the mortality from iron poisoning can be reduced from as high as 45% to about 1%.
Therapy with Parenteral Iron When oral iron therapy fails, parenteral iron administration may be an effective alternative (Bothwell et al., 1979). The rate of response to parenteral therapy is similar to that which follows usual oral doses (Pritchard, 1966). Predictable indications are iron malabsorption (sprue, short bowel, etc.), severe oral iron intolerance, as a routine supplement to total parenteral nutrition, and in patients with renal disease who are receiving erythropoietin (Eschbach et al., 1987). Parenteral iron also has been given to iron-deficient patients and pregnant women to create iron stores, something that would take months to achieve by the oral route. Parenteral iron therapy should be used only when clearly indicated, since acute hypersensitivity, including anaphylactic and anaphylactoid reactions, can occur in from 0.2% to 3% of patients. The belief that the response to parenteral iron, especially iron dextran, is faster than oral iron is open to debate (Pritchard, 1966). In otherwise healthy individuals, the rate of hemoglobin response is determined by the balance between the severity of the anemia (the level of erythropoietin stimulus) and the delivery of iron to the marrow from iron absorption and iron stores. When a large intravenous dose of iron dextran is given to a severely anemic patient, the hematologic response can exceed that seen with oral iron for 1 to 3 weeks (Henderson and Hillman, 1969). Subsequently, however, the response is no better than that seen with oral iron. This reflects the relative availability of the iron dextran stored in the reticuloendothelial system. Furthermore, inflammatory cytokines suppress both sources of iron supply equally, canceling any advantage. Iron dextran injection (INFED, DEXFERRUM) is the parenteral preparation currently in general use in the United States. It is a colloidal solution of ferric oxyhydroxide complexed with polymerized dextran (molecular weight approximately 180,000), resulting in a dark brown, viscous liquid, containing 50 mg/ml of elemental iron. It can be administered by either intramuscular or intravenous injection. When given by deep intramuscular injection, it is gradually mobilized via the lymphatics and transported to reticuloendothelial cells; the iron is then released from the dextran complex. A variable portion (10% to 50%) may become locally fixed in the muscle for several weeks or months, especially if there is a local inflammatory reaction. Intravenous administration gives a more reliable response and is preferred. Given intravenously in a dose of less than 500 mg, the iron dextran complex is cleared exponentially with a plasma half-life of 6 hours. When 1 g or more is administered intravenously as total dose therapy, reticuloendothelial cell clearance is constant at 10 to 20 mg/hour. This slow rate of clearance results in a brownish discoloration of the plasma for several days and an elevation of the serum iron level for 1 to 2 weeks. Once the iron is released from the dextran within the reticuloendothelial cell, it is either incorporated into stores or transported via transferrin to the erythroid marrow. The rate of release is variable. While a portion of the processed iron is rapidly made available to the marrow, a significant fraction is only gradually converted to usuable iron stores (Henderson and Hillman, 1969). All of the iron is eventually released (Kernoff et al., 1975), although many months are required before the process is complete. During this time, the appearance of visible iron dextran stores in reticuloendothelial cells can confuse the clinician who attempts to evaluate the iron status of the patient. Intramuscular injection of iron dextran should only be initiated following a test dose of 0.5 ml (25 mg of iron). If no adverse reactions are observed, the injection can be given according to the following schedule until the calculated total amount required has been reached. Each day's dose should ordinarily not exceed 0.5 ml (25 mg of iron) for infants under 4.5 kg (10 lb), 1.0 ml (50 mg of iron) for children under 9.0 kg (20 lb), and 2.0 ml (100 mg of iron) for other patients. Iron dextran should be injected only into the muscle mass of the upper outer quadrant of the buttock