CHAPTER 41 ANEMIA OF CHRONIC DISEASE
CHAPTER 41 ANEMIA OF CHRONIC DISEASE
ALLAN J. ERSLEV
History and Definition
Etiology and Pathogenesis
Red Cell Destruction
Red Cell Production
Clinical and Laboratory Features
Therapy, Course, and Prognosis
Most patients suffering from chronic infections, chronic inflammations, or various malignancies develop a mild to moderate anemia. This anemia, designated anemia of chronic disease, is characterized by a low serum iron level, a low to normal transferrin level, and a high to normal ferritin level. However, the anemia appears to be caused, not by these changes in iron metabolism, but, rather, by the effect of a number of suppressor cytokines. Tissues injured by infections or inflammation and neoplastic cells release cytokines, such as interleukin-1, tumor necrosis factor, and interferon gamma, known to reduce the production of erythropoietin in the kidney and impair its action in the marrow. As such, the anemia is probably caused primarily by a reduction in erythropoietin-generated red cell production. Therapeutic trials have revealed that the anemia is indeed responsive to erythropoietin, and in most cases, it can be ameliorated by the parental administration of sufficient amounts of human recombinant erythropoietin.
Acronyms and abbreviations that appear in this chapter include: AIDS, acquired immune deficiency syndrome; CFU-E, colony forming unit—erythrocyte; IL-1, interleukin-1; MRI, magnetic resonance imaging; TNF, tumor necrosis factor.
HISTORY AND DEFINITION
Weakness, weight loss, and pallor have been recognized as hallmarks of chronic illness as far back as we have medical and literary records. Yet, despite the preoccupation with blood and bloodlettings, it apparently was not recognized until the early nineteenth century that the common pallor of tuberculosis (“consumption”) was associated with a lack of blood. In their classic review, “The Anemia of Infection,”1 Cartwright and Wintrobe mention that French investigators in 1842 demonstrated that blood from patients with typhoid fever and smallpox contained a smaller mass of red cells than normal blood. The development of methods for the counting of red cells and for measuring hemoglobin concentration led to the realization that the common infections that ravaged the world, such as pneumonia, syphilis, tuberculosis, and typhoid fever, were associated with an anemia appropriately designated the anemia of infection. It is also now recognized that noninfectious disorders, such as rheumatoid arthritis, Hodgkin’s disease, and metastatic carcinoma, are associated with a similar anemia, and the names simple chronic anemia and anemia of chronic disorders or chronic disease have been introduced.2,3,4 and 5
The reason for assuming that the anemias observed in a variety of chronic clinical disorders are related is that they have certain common features. They are usually of moderate severity with hemoglobin concentrations ranging from 7 to 11 g/dl. They are associated with a low serum iron, a low iron-binding capacity, increased tissue iron stores, and a reduced rate of red cell production. Indeed, these features are so characteristic that the name sideropenic anemia with reticuloendothelial siderosis has been suggested,2 a reasonable but not a very happy addition to our collection of hematologic tongue twisters. Consequently, it appears justified to retain the name anemia of chronic disease until further clarification of the pathogenesis leads to a more appropriate designation.
ETIOLOGY AND PATHOGENESIS
The spectacular change wrought by antibiotics on the ecology of disease has led to a decrease in the incidence of chronic, incapacitating infections and true anemia of infection. However, numerous past reports on tuberculosis, lung abscess, subacute bacterial endocarditis, chronic osteomyelitis, and chronic mycotic infections, as well as more recent reports of patients with AIDS, attest to the fact that almost all chronic suppurative infections are associated with anemia.6,7,8,9,10,11 and 12 The severity of these anemias is roughly proportional to the severity of symptoms such as fever, weight loss, and general debility. It requires about 1 to 2 months of sustained infection for anemia to develop, after which time a new balance is established between red cell production and red cell destruction, and the hemoglobin level becomes stabilized.2
The anemia complicating chronic inflammatory diseases behaves functionally like the anemia complicating infections but has assumed greater importance because of the less effective therapies available. The collagen diseases, with rheumatoid arthritis13,14 and 15 as the most prominent member, are regularly associated with anemia. Regional enteritis, ulcerative colitis, and a variety of poorly understood inflammatory syndromes may also be complicated by the anemia of chronic disease.16 Of particular contemporary importance is the anemia found in patients with malignancies. This anemia, often termed anemia of cancer, is found not only in patients with metastatic and necrotizing carcinomas, but also frequently in patients with local and asymptomatic cancers, sarcomas, or lymphomas.17,18 and 19
The anemia of chronic disorders is characterized by a slightly shortened red cell life span, disturbed iron metabolism, and impaired erythropoietin-generated red cell production. Because of the moderate degree of the anemia and the modifying influence of different underlying disorders, it has been difficult to relate these observations and establish a firm pathogenetic mechanism. However, it has been suggested that the anemia is part of a “hematological stress syndrome” induced by the release of a number of cytokines in response to cellular injury, whether caused by infection, inflammation, or malignancy.20 Such cytokines could cause excessive macrophage sequestration of iron and iron-binding protein, increased splenic destruction of red cells, and suppressed erythropoietin production in the kidneys and action in the marrow.21 Furthermore, caloric malnutrition causing a decrease in transformation of tetraiodothyronine (T4) to triiodothyronine (T3) could lead to a functional hypothyroidism22 in which the decreased demands for oxygen-carrying hemoglobin are met by a reduction in the synthesis of erythropoietin.23
RED CELL DESTRUCTION
A number of studies have established that the red cell life span is moderately reduced by about 20 to 30 percent in patients with chronic illnesses.24,25 The responsible defect appears to be extracorpuscular, since red cells from patients survive normally in normal recipients.1 It has been suggested that the activation of macrophages induced by a variety of cytokines renders these cells more phagocytic both individually and as part of the splenic filter and makes them less tolerant of minor red cell changes.26 Such compulsive screening and removal of slightly damaged red cells have been observed in experimental infections if the red cells are coated with a few antibodies27 or slightly damaged by heat.28
RED CELL PRODUCTION
The presence of a low serum iron level despite adequate iron stores indicates a profound disturbance of iron metabolism. See Table 41-1. This has led to the concept that the anemia is caused by a decreased availability of iron for hemoglobin synthesis.27 However, more recent studies suggest that the presence of altered iron parameters may be of more importance for the diagnosis than for the pathogenesis of the anemia. The rate of gastrointestinal absorption of iron has been measured in a number of patients with chronic disorders, but the results have been difficult to interpret. In general, however, it appears that the intestinal absorption is moderately impaired,2,29 as also shown in dogs with turpentine-induced abscesses.1 Since the uptake of iron into intestinal cells and its subsequent incorporation by intracellular apoferritin are normal,30 the defect apparently lies in the subsequent release of iron, possibly similar to the defective iron release from macrophages and hepatic cells in patients with chronic diseases.
TABLE 41-1 IRON METABOLISM
Nevertheless, enough iron must have been released from intestinal cells to stock the iron stores, and it seems most likely that the low serum iron level is caused by impaired release of iron from macrophages to circulating transferrin or, in other words, by impaired reutilization of iron. Direct evidence for such a macrophage block was provided by experiments that showed that dogs with sterile turpentine-induced abscesses failed to reutilize iron from senescent red blood cells labeled with radioactive iron.31 Similar studies employing both labeled red cells and labeled hemoglobin solutions revealed poor reutilization of hemoglobin iron in patients with infection, cancer, Hodgkin’s disease, and rheumatoid arthritis (Fig. 41-1).32,33 and 34 Since intact red cells are degraded in macrophages and free hemoglobin is degraded in hepatic parenchymal cells,35 these studies suggest the presence of a common but still unexplained disturbance in the cellular mobilization of iron from ferritin or hemosiderin to circulating transferrin. This disturbance occurs rapidly after almost all kinds of infectious or inflammatory injuries,36 and significant hypoferremia can be observed within 24 h after both major and minor surgery37,38 (Fig. 41-2) and after pyrogen-induced fever.39 Attempts to identify and rectify the cause for the low cellular iron release have not been rewarding. Since apoferritin is an acute-phase reactant and its synthesis is stimulated by the release of a number of cytokines, it has been proposed that iron is immobilized by increased intracellular concentrations of apoferritin.40,41 Nevertheless, the relationship between the concentrations of ferritin and serum iron is not fully understood, and the search is still on for the mechanism of the iron block.
FIGURE 41-1 Utilization and reutilization of 59Fe-labeled hemoglobin solution in patients with anemia of chronic disease and in normal subjects. (Adapted from Haurani et al., with permission.34)
FIGURE 41-2 Mean serum iron concentration and iron-binding capacity plus or minus the standard deviation of nine patients undergoing cholecystectomy.
A reduced concentration of transferrin is characteristic of the anemia of chronic disorders. Turnover studies indicate a decreased rate of production,42 but the effect of infection and inflammation on its rate of destruction is controversial and confusing.43,44 Because of the low iron-binding capacity, the amount of saturated transferrin is higher in the anemia of chronic disorders than in iron-deficiency anemia, with its elevated iron-binding capacity. Since saturated transferrin has a higher affinity for the receptors on the erythroid precursor cells than does unsaturated transferrin,45 the transfer of iron to erythroid cells should be more efficient in chronic disorders than in iron deficiency. This may explain the fact that despite the low serum iron, the anemia of chronic disease is not an iron-deficiency anemia. The degree of anemia and the extent of hypochromia and microcytosis are rarely as pronounced as in true iron-deficiency anemia, and the serum concentration of transferrin receptors, a sensitive indicator of iron deficiency, is near normal.46 Finally, treatment with oral iron is ineffective,47 while treatment with recombinant erythropoietin usually is effective,48 in sharp contrast to the observations in patients with iron-deficiency anemia.
Although a normal marrow can compensate for a moderately shortened red cell life span, it needs the stimulus of erythropoietin generated by a sustained anemic hypoxia in order to do so. Consequently, an anemia may be partly but never fully compensated. In patients with chronic disease, the compensation is even less than anticipated, suggesting a decreased release of or a decreased response to erythropoietin.
Studies of the release of erythropoietin in patients with chronic disorders have produced conflicting results. In some studies erythropoietin levels have not been significantly different from those of anemic patients without chronic disorders.49,50 However, the range is wide, and several recent studies have shown convincingly that erythropoietin production in response to moderately severe anemia, although appreciable, is blunted.51,52,53,54 and 55 It seems likely that cytokines, such as inter-leukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), released by injured cells may be responsible for this blunted response. In vitro studies of erythropoietin-producing hepatoma cells have shown that these cytokines reduce the synthesis of erythropoietin.56,57 More importantly, IL-1, when added to the perfusate of an isolated rat kidney, suppresses erythropoietin production in response to hypoxia.57
Studies of the response to erythropoietin have revealed the presence of a relative erythroid resistance.58 Such studies have ranged from observations in animals with turpentine-induced abscesses59,60 to measurements of erythroid colony formation in cultured marrow exposed to sera and cells from patients with chronic disease61,62 and 63 or to purified cytokines and growth factors.21 In almost all studies soluble factors released from inflammatory cells have decreased the normal erythroid response to endogenous erythropoietin or to exogenous recombinant erythropoietin.
Three factors, TNF-a, IL-1, and gamma interferons, have attracted special attention. They are all present in plasma from patients with inflammatory or neoplastic diseases, and in some, there is a direct relationship between the plasma levels and the severity of the anemia.64,65 and 66 TNF-a is released from activated macrophages and when injected into mice it will induce a mild anemia with features characteristic of the anemia of chronic disease (low serum iron, normal ferritin, and normal white cell and platelet count).64,67,68 In human marrow cultures it will suppress BFU-E (burst forming units—erythrocytes) and CFU-E (colony forming units—erythrocytes) colony formation.69 Recent studies have suggested that this action may be indirect and mediated by a TNF-induced production of interferon beta from stromal cells.70
IL-1, released from a variety of activated cells and responsible for numerous inflammatory manifestations,65 is also present in the sera from patients with chronic disease.65 Similar to TNF, it has been shown to induce an anemia in rodents71 and to suppress erythroid colony formation in human marrow cultures.72 The latter action may also be indirect or involve the release of interferon gamma from activated T cells.72 That interferon may be the common denominator for the suppressive effect of TNF-a and IL-1 is suggested by studies showing a direct inhibition of human CFU-E by interferon gamma.73,74 However, interferon can also suppress nonerythroid progenitor cells,75 and its role in the pathogenesis of the anemia of chronic disorders is not clear.
Other factors undoubtedly play a role, but because chronic disease activates a network of interacting inflammatory cells, growth factors, precursor cells, and cytokines, the exact pathogenetic mechanisms of the anemia are far from resolved.21
CLINICAL AND LABORATORY FEATURES
The clinical manifestations of the mild to moderate anemia complicating chronic disorders are usually overshadowed by the symptoms of the underlying disease. Under physiologic conditions, a reduction in hemoglobin concentration to 7 to 11 g/dl, the level usually observed in the anemia of chronic disorders, need not be symptomatic. However, in patients with severe pulmonary impairment, fever, or physical debility, a moderate reduction in the oxygen-carrying capacity of the blood may aggravate preexisting symptoms. On physical examination there are no findings characteristic of this anemia, and the diagnosis hinges on the laboratory findings.
The anemia is traditionally described as normocytic and normo-chromic.1 However, many patients have hypochromic red cells with a mean corpuscular hemoglobin concentration (MCHC) below 31 g/dl, and some have microcytic cells with a mean corpuscular volume (MCV) of less than 80 fl.2
The absolute reticulocyte count is within the normal range or slightly elevated. Changes in the white blood cell count or platelet count are not consistent and depend exclusively on the underlying disorders.
A reduction in serum iron concentration (hypoferremia) is a sine qua non for the diagnosis of anemia of chronic disorders (Table 41-1). It occurs promptly after the onset of an infection or injury and precedes the development of anemia. The concentration of the iron-binding protein, transferrin, is moderately decreased,1,2 resulting in a higher iron saturation than in patients with iron-deficiency anemia (see Table 41-1). This relative “protection” of iron saturation may be of benefit by enhancing the transfer of iron from a reduced pool of circulating iron to immature erythroid cells.45 The decrease in transferrin levels after injury occurs more slowly than the decrease in serum iron levels (see Fig. 41-2), presumably because of the longer half-life of transferrin (8–12 days)76 compared to that of iron (90 min) and because of different metabolic functions.
Measurements of serum ferritin levels have been found useful in assessing marrow iron stores in patients with low serum iron concentrations.77 In most instances there is no overlap between levels in patients with chronic disease and increased body stores of iron and patients with iron deficiency. However, depleted iron stores in patients with chronic disease may not be as readily detected by ferritin measurements, since ferritin is an acute-phase protein and fever and infections increase its synthesis and produce inappropriately high serum levels.78 Consequently it has been suggested that only a serum ferritin level in excess of 60 µg/liter should be considered as reflecting normal or increased iron stores.79
Marrow aspirates may be difficult to interpret because the underlying disorders can be responsible for alterations in cellular patterns and structure. However, in general, the marrow is normal. The myeloid/erythroid ratio is about 3:1 or 4:1, and there is little evidence of compensatory erythroid hyperplasia. The most important information derived from a marrow examination pertains to its iron content. Iron in a marrow preparation can be found as storage iron in the cytoplasm of macrophages or as functional iron in nucleated red cells. In normal individuals a few Prussian blue–staining particles can be found inside or adjacent to many macrophages, and about one-third of nucleated red cells contain blue inclusion bodies and are called sideroblasts (Chap. 22).80 In iron deficiency there is an absence of both sideroblasts and macrophage iron. However, in the anemia of chronic disorders only sideroblasts are decreased in number; macrophage iron is increased.81 This increase in storage iron in the face of a decreased level of circulating iron and a decreased number of sideroblasts is characteristic of the anemia of chronic disorders and is found in no other diseases.
The results of red cell survival studies have varied, as would be expected when one considers the great diversity of the underlying disorders, but in general normal cells have displayed a moderately shortened survival when injected into patients with chronic disorders,24,25 and red cells from such patients have had a normal survival in normal recipients.2 These findings indicate an extracorpuscular destruction of red cells, presumably caused by infectious or inflammatory foci.
In accordance with the morphologic appearance of the marrow, measurements of plasma and red cell iron-turnover rates have disclosed a normal or only slightly increased rate of effective red cell production.33,81 The half-life of intravenously injected radioactive iron is very short, but, when adjusted for the low level of circulating iron, the calculated plasma iron turnover is only slightly higher than normal. Since 70 percent or more of the injected radioactive iron can be accounted for in circulating red cells, erythropoiesis is mostly effective with the production and release of viable cells.24,25 When these normal values are correlated with the fact that the marrow maintains a red cell mass of less than normal size, they support the direct measurements of a shortened red cell life span.
Most patients with chronic infections, inflammations, or neoplastic disorders are anemic, but such anemias should be designated anemias of chronic disease only if the anemia is moderate, the cellular pattern in the marrow is nearly normal, the serum iron and iron-binding capacity are low, the iron content of the marrow macrophages is normal or increased, and the serum ferritin is elevated (see Table 41-1). Since the underlying diseases can predispose the patients to many other hematologic disturbances, a final diagnosis of anemia of chronic disease should first be made after having ruled out other etiologic mechanisms. The following causes of anemia may, in particular, aggravate or obscure the anemia of chronic disease:
Dilution anemia. A dilution anemia has long been known to occur in patients with chronic illnesses, especially in patients with far-advanced neoplastic diseases.82 However, it is difficult to relate plasma volume to body weight in emaciated individuals, and a true relative anemia is found rarely except in patients with myeloma or macroglobulinemia.83
Drug-induced marrow suppression or drug-induced hemolysis should always be considered. As a general rule, the serum iron level will tend to be high in marrow suppression as a reflection of reduced erythroid consumption. Reticulocyte counts, haptoglobin measurement, bilirubin determination, Coombs’ test, and determination of lactic dehydrogenase activity should be done to rule out a hemolytic component.
Chronic blood loss will eliminate the characteristic macrophage siderosis, and one may have to rely on the levels of transferrin to distinguish between iron-deficiency anemia and the anemia of chronic disorders. Since the synthesis of transferrin receptors is stimulated by iron deficiency, the concentration of soluble transferrin receptors is higher in iron deficiency than in chronic disease. The simplest diagnostic approach to a patient with anemia and low or absent iron in the marrow is a therapeutic trial of iron followed by reevaluation.
Thalassemia minor is a common cause of anemia in many parts of the world, and it may be confused at times with the anemia of chronic disease. Microcytosis is usually more severe in this group of disorders than in the anemia of chronic disease and has been present throughout the lifetime of the patient, although this has often not been documented.
Renal impairment causes both a shortened red cell life span and a relative marrow failure. Although the serum iron level is either normal or high in the anemia of uremia, the diagnosis rests on the finding of an increased blood urea nitrogen or creatinine level. A diagnosis of a complicating anemia of chronic disease is difficult to make in the face of overt uremia.
Metastatic replacement of the marrow by carcinomas or lymphomas will aggravate or mimic anemia of chronic disease. The serum iron concentration is usually normal or increased, and there may be telltale signs of marrow involvement in the peripheral blood, such as poikilocytes, teardrop-shaped red cells, normoblasts, or immature myeloid cells. Serum alkaline phosphatase determinations and X-ray or MRI studies of bone may help, but direct marrow examination usually is necessary to establish a diagnosis of myelophthisic anemia.
THERAPY, COURSE, AND PROGNOSIS
Any anemia occurring in a patient with chronic debilitating disease should be thoroughly investigated in order to rule out specific deficiencies or complications. If, after such studies, the anemia can be designated an anemia of chronic disease, it rarely demands therapy. A hemoglobin level between 7 and 11 g/dl should be of concern, but it has not been definitely shown that it is detrimental to health or impedes reparative processes. Neither has a low serum iron concentration, especially when associated with a near-normal percent saturation of transferrin. To the contrary, it has even been proposed that a low iron level may be an adaptive defense mechanism against iron-dependent bacteria.84 Nevertheless, it still seems reasonable to believe that, if both serum iron and hemoglobin concentrations could be restored to normal, it would be of some benefit to a chronically ill patient.
Attempts to provide iron by mouth or parenterally have had little or no effect on the iron or hemoglobin concentration.47,85 Iron dextran will release small amounts (about 1–3%) of iron directly to transferrin,86 but the bulk of iron will be captured and retained by the monocyte-macrophage system.87 Its release, however, is blocked in anemia of chronic disease,88 and it has been suspected that the few patients who were helped by oral or parenteral iron had, in addition to the anemia of chronic disorders, an iron deficiency that contributed to the anemia.2
Cobalt chloride and androgenic steroids have been used with some effect,89,90 but side effects render them unacceptable for a fairly benign condition. If the anemia does become symptomatic, as in patients with limited cardiovascular reserves, judicious transfusions with packed cells have been employed.
Fortunately, it seems likely in the future that the anemia can be alleviated, if not completely corrected, by treatment with erythropoietin. Recombinant erythropoietin, as expected, has been found to be dramatically effective in the correction of anemia of chronic renal disease.91 It has now been introduced with a vengeance into the treatment of the anemia complicating chronic disease.92 As discussed above, these anemias are caused primarily by a cytokine-induced depression of the erythroid marrow, a depression aggravated by the fact that in most patients the production of erythropoietin is blunted, with subnormal amounts of erythropoietin produced in response to anemic hypoxia.
The administration of sufficient amounts of recombinant erythropoietin should overcome this depression. The first trials in patients with rheumatoid arthritis were encouraging94 and have been followed by numerous successful trials in anemic patients with rheumatoid arthritis,95 AIDS,96,97 and inflammatory bowel disease.98 The potential use of recombinant erythropoietin for the treatment of the anemia of cancer has received special attention.99,100,101 and 102 The marrow in these patients is often additionally suppressed by chemotherapy or radiation, but even here the use of sufficient amounts of recombinant erythropoietin has been gratifying in many patients.103,104 and 105 The same is true when a chemotherapeutic agent such as cisplatin causes renal damage with a further reduction in the production of erythropoietin.106
The treatment should begin with the administration of adequate doses, such as 10,000 units recombinant erythropoietin three times a week intravenously or subcutaneously. An increase in the concentration of hemoglobin and/or a decrease in serum ferritin during the next 2 to 3 weeks would suggest an erythroid response and demand a continuation and final modification of the doses used. In the absence of an erythroid response during the first weeks, the dose should be increased to 20,000 units three times a week. If there is still no response, the treatment should be discontinued. However, a functional iron deficiency may abbrogate an erythroid response, and oral iron (i.e., FeSO4, 300 mg tid) should be added if the ferritin concentration is less than 100 µg/liter. Significant complications have not been experienced, especially not adverse effects on blood pressure or blood coagulation. The results have varied a great deal, and attempts have been made to predict the usefulness of this expensive medication.92 It appears that the more severe the anemia and the lower the baseline endogenous erythropoietin production, the better the results. In AIDS patients no benefit was achieved if the baseline endogenous erythropoietin level was higher than 500 mU/ml.96 This is not surprising, since the injection of usual doses of recombinant erythropoietin will increase the level only minimally if the baseline is high. However, there are individual exceptions,107 and in a symptomatic patient it may be worth trying a course of recombinant erythropoietin before turning to transfusions.
The goal is obviously to maintain a hemoglobin concentration at which a patient has no overt anemic symptoms and at which a sense of well-being may assist in the defense against an underlying disease.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn