The etiology of the anemia of chronic disease and infection

J Clin Epidemiol Vol. 47, No. 1, pp. 23-33, 1994 Copyright 0 1994ElsevierScienceLtd Printed in GreatBritain. All rights reserved 0895-4356/94$6.00+ 0.00

Pergamon

THE ETIOLOGY OF THE ANEMIA OF CHRONIC DISEASE AND INFECTION S. KENT,‘*

E. D. WEINBERG’

and P. STUART-MACADAM~

‘Anthropology Program, Old Dominion University, Norfolk, VA 23529, *Department of Biology,

Indiana University, Bloomington, IN 47405, U.S.A. and ‘Department of Anthropology, University of Toronto, Toronto, Ontario, Canada MS.31Al (Received in revised form I I August 1993)

Abstract-Anemia of infection and chronic disease has traditionally been considered a disorder associated with infections/inflammation. We instead propose that the anemia of infection and chronic disease confers protection from pathogen or neoplastic invasion. There is substantial microbiological and medical research that indicates that the anemia of infection and chronic disease may be a non-specific immunological defense. We suggest it is analogous to fever, which was also originally considered to be a disorder in need of treatment but which is now seen as a positive response of the host to microbial invasion. We suggest that these two non-specific defenses against microorganism proliferation may have evolved together as complementary strategies the body

employs to ward off disease. Chronic disease Anemia Iron fortification

Infection

Hypoferremia

defense as we suggest, are current medical practices potentially contrary to reducing morbidity? Below we review epidemiological, hematological and microbiological data that indicate the anemia of infection and chronic disease is a nonspecific defense the body employs to ward off bacterial, parasitic, and neoplastic invasion. One difficulty in assessing the cause, impact, and significance of anemia is that routine laboratory tests do not always differentiate iron deficiency anemia, a disorder in need of correction, from anemia resulting from infections, inflammation, and/or cancer. Because each type of anemia is characterized by low hemoglobin levels, the two anemias can be misdiagnosed [6]. Although hemoglobin levels usually exceed 6-7 g/d1 in the anemia of infection and chronic disease while they can be lower in iron deficiency anemia, both types of anemia also have subnormal serum iron and transferrin saturation values. Since hemoglobin is often the only test conducted to determine anemia [7-91, patients with anemia of infection and chronic disease

INTRODUCTION

The widespread practice of iron supplementation and food fortification is based on the correlation of low hematocrit/hemoglobin values with high morbidity and the assumption that dietary iron deficiency is a major cause of acquired anemia. The question we are asking is whether or not correlation necessarily equals causation. Anemia is often regarded as a disorder requiring dietary and/or medical intervention. For example, a common medical practice is the administration of iron to individuals with low iron levels, even if they are not malnourish [l--5]. Activation of the hypoferremic response occurs in a wide range of diseases ranging from microbial infections to neoplasia. Is there an explanation of the etiology of the anemia of infection and chronic disease that might account for its common association with a wide spectrum of disorders? And, if related to a host’s *Author for correspondence. CE47:1-E’

Iron

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S. KENT et al.

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have been misidentified as suffering from dietax-y-induced iron deficiency [lo, 111. For one example, “Out of 29 patients ‘diagnosed’ as having iron deficiency anaemia, only 11 patients in fact had true iron deficiency when reviewed by the authors. Most patients had the anaemia of chronic disease that was misdiagnosed as iron deficiency. There is a strong clinical impression amongst hematologists that this problem of misdiagnosis is not unique to hospital based specialists but also applies more widely” [lo]. Apart from bone marrow aspiration, serum ferritin is the most sensitive diagnostic test to distinguish iron deficiency anemia from anemia of infection and chronic disease because it is an indirect measure of the body’s iron stores-individuals with iron deficiency have subnormal levels and individuals with the anemia of infection and chronic disease have normal to raised serum ferritin levels [ 12, 131. MICROORGANISMS, IRON REQUIREMENTS, AND THE ANEMIA OF INFECTION AND CHRONIC DISEASE

The role of iron in enhancing infections has been detailed in a number of publications [14-191. Basically, “iron appears to enhance virulence by interfering with two non-specific defence mechanisms. One is the denial to the infecting bacterium of iron essential for its

in-uiuo growth by reason of its being tightly bound to proteins like transferrin and lactoferrin. . . . The other is the bactericidal action of lysosomal cationic proteins of neutrophils, which is neutralized by excess iron . . .” [20]. Most microbial as well as animal and plant cells need iron to serve as a catalyst for DNA synthesis and for a variety of electron transport and redox reactions [21]. Microorganisms rely on their hosts for sufficient iron levels since it is difficult for them to store iron in a non-toxic form. Therefore iron is as important to microorganisms and neoplastic cells as it is for normal healthy individuals. Pathogens have evolved an array of mechanisms to extract iron from their hosts, some of which are listed in Table 1 [22]. In turn, potential hosts have developed an array of methods to withhold iron from these pathogens, while at the same time retaining access to sufficient iron for their own metabolism. Microbial genera stimulated by excess iron are listed in Table 2. Note that the genera represented are those which currently commonly attack humans in a variety of environments and which are thought to have plagued past populations as well [23,24]. In any particular genus the strains can be categorized into one of four groups according to their ability to extract iron from hosts [25]. Strains of group I are so strongly virulent

Table 1. Strategies of microbial pathogens for acquisition of host iron 1181 Strategy

Selected examples

I. Synthesize a transferrin receptor protein and insert it into erythrocyte membrane to force uptake of Fe-transferrin by infected erythrocyte

Plasmodium falciparum

II. Synthesize protein receptor that binds Fe-lactoferrin derived from genital secretions

Trichomonas vaginalis

III. Synthesize protein receptor that binds Fe-transferrin derived from host fluids

Borderella, Hemophilus, Neisseria

IV. Enzymatically reduce ferric iron at cytoplasmic membrane in order to assimilate the solubilized ferrous ions

Listeria, Streptococcus

V. Occupy host intracellular niches (oxidation state of iron supply not known) VI. Acquire ferric ions from transferrin by use of siderophores plus protein receptors that bind and transport the ferric chelates VII. Synthesize hemolysins that rupture erythrocyte membranes to release hemoglobin; latter is then digested to

*

.

Legionella, Salmonella, Yersinia

Many bacterial and fungal pathogens

Many bacterial pathogens

Etiology of Anemia of Chronic Disease and Infection

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Table 2. Microbial genera that contain strains whose growth in body fluids, cells, tissues, and/or intact vertebrate hosts is stimulated by excess iron [ 151 Gram negative bacteria Acineiobacter Aeromonas Alcaligenes Bacteroides Enterobacter Escherichia Klebsiella Legionella Moraxella

Neisseria Pasteurella Proteus Pseudomonas Salmonella Shigella Vibrio Yersinia

that they can extract iron even from iron-deficient host tissues. In group II, virulence correlates directly with the quantity of iron available from the host, giving a hypoferremic host an advantage over the pathogens. Group III strains are so weakly virulent that they can grow only in hosts with a severe iron overload whereas group IV remain avirulent even in hosts with excessive iron. A distinction between the ability or lack of ability to overcome host iron withholding defense mechanisms can often be made on established taxonomic bases. For example, 100% of 29 strains of Neisseria gonorrhoeae and of 21 strains of N. meningitidis can obtain iron from transferrin with a normal amount of iron whereas only 22% of 45 non-pathogenic neisseria strains can obtain iron under the same conditions [26,27].

IRON WITHHOLDING

DEFENSES

In order to withhold growth essential iron from pathogens, humans and other vertebrates station powerful iron-binding proteins, such as transferrin or lactoferrin, at potential invasion sites [15]. Two atoms of iron can be bound to one transferrin molecule, which is found primarily in plasma and lymph [28]. Lactoferrin is a major component of the specific granules of circulating neutrophils that is released on degranulation of these cells in a septic area. After combining with iron at the invaded site, the iron-saturated protein is ingested by macrophages. Breast milk has long been recognized for its ability to provide protection to infants from specific infectious microorganisms [29,30]. We suggest one of the mechanisms of protection is the binding of iron to lactoferrin, thereby reducing the amount of available iron for micro-

Gram positive and Fungi and Acid-fast bacteria protozoa Bacillus Clostridium Corynebacterium Erysipelothrix Listeria Mycobacterium Staphylococcus Streptococcus

Candida Cryptococcus Entamoeba Histoplasma Naegleria Plasmodium Torulopsis Trichomonas Trichophyton Trichosporon Trypanosoma

organisms. An important factor is the maternal transfer of lactoferrin together with slgA antibody (secretory immunoglobulin A) to the infant. Without lactoferrin the antibody is inactive [3 11.Breast milk gives infants immunity to a wide range of microorganisms [32-381. Non-breast fed infants living under conditions of poor sanitation have mortality rates five times higher than breast fed infants living under the same conditions [30]. Also, infants who live under conditions of good sanitation but are not breast fed have a higher mortality rate than breast fed infants living under the same conditions [30]. The immunity afforded by lactoferrin and slgA can be inhibited, and microorganism virulence be enhanced, by saturation with iron [39]. As a result, the host “responds to systemic bacterial infection by . . . moving iron into the parenchymal storage sites and decreasing iron absorption by the small intestine.” [39]. Another host defense is the lowering of plasma iron. In a classic study, the mean value of plasma iron in healthy persons was 17.8 PM, whereas individuals with active infections had a mean level of 5.5 PM [40]. Iron saturation of transferrin dropped from the normal mean of 30% to a mean of 15%. The shift in iron becomes enhanced as the clinical condition worsens, and returns to normal as the patient improves. Although plasma iron increases in infected persons when excess iron is consumed, the rate is much lower than with healthy individuals [41]. Another mechanism which denies iron to microbes is the diversion of iron to the liver and spleen by a block in normal iron release to plasma transferrin from macrophages that have acquired iron from decaying erythrocytes [18,42]. Some studies indicate iron increases microbicidal action; other research suggests that iron inhibits such action. Several explanations

S. KENT et al.

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for the apparent contradiction exist, including the intracellular location of iron in the macrophage [43]. A comprehensive review of studies linking iron deficiency with impaired immunological response concludes that iron deficient individuals do not suffer severe infective complications seen in other congenital or acquired immunological syndromes [44]. Therefore, it “seems likely . . . that despite the fundamental importance of iron in maintaining the integrity of immune function, humans can tolerate the extremes of deficiency . . . and survive in a relatively healthy state” [44]. Until the danger of microbial invasion has ceased, additional iron will be taken out of circulation and stored in intracellular ferritin, thus resulting in the anemia of infection and chronic disease. This explains why individuals with the anemia of infection and chronic disease have subnormal serum iron, hemoglobin, and transferrin saturation values but normal to elevated serum ferritin values. The shift in iron metabolism is induced by the hormone, interleukin-1. The presence of microbial cell wall products stimulates the mononuclear-cell phagocytes to synthesize and release interleukin-1 [22]. Interleukin- 1 “activates lactoferrin release from neutrophils, with a consequent reduction of the iron available for bacteria . . , At the same time interleukin-1 promotes fever, and the situation for bacteria may become critical, as iron requirements increase at elevated temperatures” [22]. Additional cytokines that induce hypoferremia are interleukin-6 and tumor necrosis factor [45]. Moreover, macrophages activated by interferon-gamma can be induced to form a flavoprotein that converts L-arginine to nitric oxide + L-citrulline [45]. Nitric oxide causes efflux of non-heme iron from neoplastic and infected host cells. Furthermore, in the absence of L-arginine, interferon-gamma-induced infected macrophages can lower their net uptake of iron. Cellular depletion of the metal via either mechanism suppresses DNA synthesis and the functioning of aerobic respiratory mechanisms of the protozoan, fungal, or bacterial intracellular pathogens as well as of adjacent neoplastic cells [45]. HYPOFERREMIA:

A DEFENSE

The proposition that the anemia of infection and chronic disease represents a normal physiological defense against invading pathogens has

been evaluated by examining conditions of infection and excess iron availability. In a well known study, the incidence of Escherichia coli sepsis significantly increased when infants were given intramuscular iron dextran [46,47]. Other research substantiates an association between an increased incidence of E. co/i sepsis, as well as malaria and other infections, and the administration of iron to a variety of age groups [48-561. In addition, infants with respiratory infections given iron-dextran had a longer hospital stay and a higher morbidity than those not given iron [49]. Iron overload is also associated with the pathogenesis of Vibrio vulniJicus and N. meningitides infections in both in vivo and in vitro mediums [57,58]. Other studies demonstrate that the “serum of babies whose mothers received Imferon infusions showed reduced ability to contain bacterial multiplication and also had impaired opsonizing function, whereas the bactericidal capacity of blood phagocytes and nitroblue tetrazolium tests were normal” [59]. The incidence of tuberculosis, pyelonephritis, shigellosis, salmonellosis, systemic candidiasis, septicemia, and puerperal fever is higher in patients with hemolytic anemias associated with a high iron availability or with iron overload from various conditions in contrast to individuals with normal or low iron levels [20]. Children with various etiologies of iron overload were found to have septicemia caused by Yersinia enterocolitica [60-641. Infection with Vibrio vulnificus is markedly enhanced in persons with excessive iron [65]. Studies show that within 24 hours after exposure to microbes, serum iron levels fall and a resistance to otherwise lethal doses of a variety of pathogens is produced [66]. In diseases such as leukemia, patients have been observed with sera that was 96-100% saturated (normal is 16-50%), making iron much more accessible to pathogens, and, as a consequence, leukemia patients are known to be unusually susceptible to infection [67,68]. The cause of death for 78% of 161 leukemia patients in one study was attributed to infection and not directly to the leukemia itself [67]. Increased iron availability, and therefore a high rate of infection, is also associated with sickle cell anemia, thalassemia major, bartonellosis, and hepatitis where plasma iron is more available due to hemolysis. Persons suffering from asplenia and alcohol abuse develop iron overload in specific tissues and fluids, which increases the frequency and pathogenesis of bacterial strains

Etiology of Anemia of Chronic Disease and Infection

that are not highly virulent in normal hosts [69]. Hyperferremia has been shown to enhance the virulence of E. coli, Bacillus subtilis and Salmonella typhimurium [70-721. Animals experimentally injected with iron also were more susceptible to a variety of microorganisms [73]. In guinea pigs given iron and E. coli, the number of organisms in the small intestine increased 10,000 times compared with the controls, which did not receive iron [74]. The mortality rate of mice injected with Candida albicans was directly related to the concentration of iron injected, which negated and reversed the endotoxin-induced non-specific resistance of the hosts [75]. As early as 1973 Kochan concluded that: “The availability of iron in hyperferremia favors the growth of many parasites and is therefore associated with suceptibility to bacterial infections and with a rapid progression of disease. The state of hypoferremia is beneficial to the host; parasites fail to obtain sufficient quantities of growth-essential iron and therefore fail to multiply, or multiply with considerable difficulty . . .” [73]. In order to combat host defenses, siderophores can deliver iron to microorganisms in several ways [39], thereby enhancing the pathogens’ ability to extract iron from their host. However, fever from infections reduces the ability of some gram negative bacteria to acquire the host’s iron because high temperatures prevent the formation of siderophores. Thus, fever may serve as a countermeasure to microorganisms by suppressing siderophore synthesis [76]. It has been noted that “a single episode of fever and/or inflammation in man appears to restrict the release of iron from effete red blood cells by the reticuloendothelial system, leading to a decrease in serum iron concentration and to stimulation of the production of ferritin [to store iron] for a prolonged period” [77]. A number of in vitro and in viuo studies suggest that fever, coupled with hypoferremia, enhance resistance to bacterial infection [67,78]. Today fever is recognized to be a defense against disease rather than a disorder [79-811. We suggest that one of the beneficial aspects of fever involves the need for and ability of pathogens to acquire iron and that fever evolved along with hypoferremia as part of the host response to invasion.

CLINICAL OBSERVATIONS

OF HYPOFERREMIA

If hyperferremia stimulates microbial growth, does its opposite, hypoferremia, retard such

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growth and thereby afford an individual protection? Several lines of evidence suggest that lower levels of iron protect the body from a variety of potential insults by making iron less accessible to microorganisms and neoplastic cells. As noted above, this can be seen in serum ferritin levels which are subnormal in dietary iron deficiency caused by a lack of iron and are normal to elevated in anemia of infection and chronic disease caused by the body shifting iron to storage (Table 1) [ 12, 15, 16,82-861. Normal to elevated serum ferritin values indicate the body is storing iron, taking it out of circulation; the body is not deficient from dietary sources. [87,88]. The role of hypoferremia as protection can be seen in mildly anemic African Turkana. They have a lower incidence of infectious diseases, such as malaria, brucellosis, amebic dysentery, and various viral infections, than Turkana who are not anemic [55]. Although possibly related to factors other than iron levels, including decreased levels of phosphorus and potassium, deaths among starvation victims during refeeding programs were attributed to the increase in iron availability and the resulting increase in infectious diseases [53]. That is, iron was ingested as part of the refeeding program, which activated parasitic and bacterial infections. Furthermore, in a study of 110 patients in Africa, those with anemia had fewer malarial attacks than those with higher iron levels. Anemic but malaria asymptomatic patients developed malaria after iron therapy was initiated. A similar observation was made among the Maasai wherein anemic individuals had a significantly lower incidence of amoebae. Examination of the bovine milk consumed by Maasai “showed that it not only had a concentration of iron below the minimum necessary for the growth of E. histolytica but also contained partly saturated lactoferrin and transferrin, which may actively compete with the parasite in the colon for ambient iron.“. The operation of the hypoferremic response can even be observed with mild viral infections, perhaps because the body is not able to distinguish between proliferating viruses and proliferating bacteria. Healthy, well-nourished infants immunized with live measles vaccine developed significantly lowered serum iron, transferrin saturation, and hemoglobin levels and significantly increased serum ferritin levels that persisted for 14 to 30 days [89]. According to the investigators, it would be impossible to distinguish iron deficiency anemia from anemia

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of infection and chronic disease without the iron, serum iron and transferrin saturation serum ferritin values. Even those values failed to means were significantly lower than either the be irrefutable because they were still well within 1969 or the 1987 study means but serum ferritin the normal range for serum ferritin, though values were normal or elevated in 92% of the significantly higher than prior to inoculation hypoferremic adults [96]. (most serum ferritin values were under If hypoferremia operates in response to heavy 50 ng/ml) [89]. The same rise in serum ferritin and chronic pathogen loads, then it should be levels was noted in anemic children from Niger visible in the hematology of a population. Other who suffered from malaria, although as in the researchers have noted that mortality levels are previous study, levels were still within what are lower among sedentary !Kung Basarwa but usually considered to be normal limits [90]. morbidity levels are higher [97]. Physical examThese examples illustrate the hypoferremic de- inations, ethnographic observations, and inforfense in action against various pathogens and mant interviews revealed a high level of the difficulty in distinguishing it from dietarymorbidity among the Kutse Basarwa, but not a induced anemia without measuring serum deficient diet [96]. Both the 1987 !Kung and ferritin levels before and after infection. 1988 Kutse Basarwa hematological studies indiThe susceptibility of patients with viral infec- cate that hypoferremia is common in tions to secondary bacterial infections has been situations of high morbidity. Iron extraction by widely documented [91-931. Several expla- microbes is impeded as a direct consequence of the hypoferremia. nations have been posited for this vulnerability. Noting the relationship between accessibility and pathogens, it has been proposed that IRON AS A LIMITING FACTOR IN DISEASE “fulminating viral illness can induce hemorPROLIFERATION rhage . . ., one of the components of enhanced susceptibility to bacterial growth may simply be How can the preceding observations be reca surfeit of iron derived from extravasated onciled with those studies that report an associhemoglobin [9 1,921. ation between hypoferremia and infectious Research among recently sedentary and still diseases, morbidity, and mortality? According nomadic Basarwa (“Bushmen” or San) at Dobe to Keusch and Farthing, none of the studies in the Kalahari of Botswana illustrates hypofersurveyed “permit reliable conclusions about remia operating in a modern population. While whether iron deficiency alone predisposes [one] nomadic and dispersed, !Kung Basarwa in 1969 to infection and if iron supplementation and were judged to be mostly healthy; only a very correction of iron deficiency as the sole intervenfew individuals had anemia of any kind [94]. tion can reduce prevalence and morbidity from The same group which still had an adequate infection” [98]. Many studies reporting a predisiron intake, but a newly sedentary way of life, position of hypoferremic individuals to infecwas retested in 1987 [95]. The number of indi- tion and poor performance have a number of viduals with below normal serum iron and problems in research design due to a variety of transferrin saturation levels rose significantly factors: iron deficiency anemia is not distinbetween 1969 and 1987 (serum iron p = 0.001 guished from the anemia of infection and males; p = 0.013 females; and transferrin satu- chronic disease; many of the subjects in the ration p = 0.004 males, p = 0.000females) [95]. studies have multiple health problems; patients Diet cannot explain the rise in hypoferremia. usually are not matched for overall nutritional Sedentism without adequate sanitation prostatus; and the introduction of iron-fortified motes infectious agents [95]. Hypoferremia as a foods is not necessarily the only change which occurred during the study period (e.g. an andefense against disease in a sedentary context where infectious diseases are endemic explains thelminthic drug is administered in addition to the drop in mean values for 1987 serum iron and iron). In a number of these studies, other factransferrin saturation, even though iron intake tors, such as housing and sanitation practices, did not substantially change. This is corrooften combine with anemia making it very difficult to delineate causal from spurious asborated by the large number of hypoferremic individuals with normal to elevated serum fer- sociations [99]. No one denies that someone who is severely ritin values (77% of hypoferremic adults) [95]. At Kutse, another Kalahari community tested deficient from blood loss will perform at a lower in 1988 where diet was known to be adequate in level than a normal control. However, because

Etiology of Anemia of Chronic Disease and Infection

iron can stimulate appetites [loo], when anemia is corrected other factors unintentionally introduced in many performance studies are also corrected, such as improved calories, protein, vitamins, and in the case of anemia of infection and chronic disease, a reduction of disease and/or parasite load. Is it the increase in iron that is causing the improvement in skills or is it the improvement in overall health, calorie intake, etc.? We believe that in these cases, cause has been confused with effect. In other words, correlation does not equal causation. Low iron may be a consequence of the body’s defense against an infection and therefore highly correlated while not necessarily being a cause. An individual may succumb to the virulence of microorganisms because the reduction in available iron was not sufficient to subdue the pathogens, not because of the anemia itself (as is the case with fever, which otherwise provides protection against disease). By understanding the physiology of anemia and the role of iron in disease, it is possible to understand a range of well known phenomena, from the benefits of breast feeding to hypoferremia in patients with neoplasia, to the anemia associated with pregnancy. Pregnancy is often accompanied by a mild hypoferremia that has been linked to the nutritional needs associated with the rapid growth of a fetus (the classic “anemia” of pregnancy is also often an artifact of measurement wherein the volume of plasma increases and dilutes the red cells, although the absolute red cell mass is not low). We suggest research is needed to determine whether or not slight hypoferremia helps defend mother and fetus from invading pathogens [lOl, 1021. Such a defense may be particularly valuable during the latter phases of gestation when cell mediated immunity becomes lessened to avoid immunological rejection of the fetus [loll. Recent studies do not recommend the indiscriminate use of iron supplementation for pregnant women [103, 1041. For example, a study of 35,423 pregnant women found no reliable association between anemia and problem pregnancies leading to the following conclusions: “When the hematocrits of women in term labor were compared with those of women in preterm labor, a spurious dose-response effect for anemia was created. We conclude that anemia is not a strong factor in the pathogenesis of preterm birth and that comparison of hematocrits from women who are in preterm and term labor produces biased results” [104]. It was noted that there is

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“not . . . sufficient evidence to justify a randomized clinical trial of treatment of borderline anemia during preganancy ” [ 1041. Anemia of infection and chronic disease appears to play a part in the defense against neoplasia and chronic inflammatory diseases, such as rheumatoid arthritis. Studies indicate that elevated iron levels stimulate joint inflammation. Treatment of arthritis with intravenous iron results in increased inflammation and increased toxicity of superoxide [ 1051. Moreover, excessive iron in inflamed lesions catalyzes production of oxygen radicals that proceed to destroy host lipid membranes [105]. Men and postmenopausal women are particularly vulnerable to excess dietary iron produced by food fortification [ 1061. The indiscriminate fortification of food is putting these populations at risk for contracting a variety of diseases, including cancer [106]. Studies indicate that hyperferremia in men increases the risk of cancer and that hypoferremia in women decreases the risk of lung cancer [107-1091.

DISCUSSION

Our suggestion that hypoferremia is an adaptive response to microbial and neoplastic cell invasion accounts for its high prevalence and wide geographic distribution through time [llO, 1111. It also accounts for a wide spectrum of phenomena, from the reported slight reduction of hemoglobin often associated with a smallpox revaccination [ 1121, a seemingly innocuous procedure, to the anemia of pregnancy, neoplasia, chronic diseases such as rheumatoid arthritis, and bacterial, parasitic, and viral infections. Our view of hypoferremia as a body’s defense rather than a disorder links otherwise seemingly unrelated phenomena while also explaining the frequency and perpetuation of anemia in both Western and non-Western countries. We do not, however, include in this interpretation of the anemia of infection and chronic disease true cases of iron deficiency, as that which can occur with extremely inadequate diets with insufficient iron, calories, and other nutrients or from severe blood loss. We see the differential rates of iron absorption as part of the body’s iron sparing mechanism wherein the body regulates the amount of iron absorbed in order to prevent the accumulation of too much iron. When the body needs more iron, it extracts more from the same food items. Absorption of iron varies from 15-35%

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for meat, fish, and poultry (heme iron) and 2-20% for other foods (non-heme iron), depending on whether or not a person is deficient [113]. The more iron deficient an individual, due to blood loss or other causes, the more iron is absorbed. For instance, j-10% of iron is absorbed in healthy Western adults, whereas as much as 25% is absorbed from the same food by iron deficient adults [lo]. According to O’Neill-Cutting and Crosby, iron deficient “people absorbed more iron than the normal iron replete: the intestine can adjust its avidity to match the body’s requirement” [42]. However, individuals with the anemia of infection and chronic disease do not significantly increase the amount of iron absorbed because they are not deficient in iron, i.e. iron stores are normal or elevated as evident by serum ferritin levels or bone marrow aspirations. In contrast, individuals suffering from dietary iron deficiency and/or blood loss do absorb more from the same exact diet. We suggest that mild to moderate reductions in iron availability may be one of the many non-specific defenses against rapid cell proliferation, one that specifically inhibits pathogen proliferation. However, we are not questioning the health problems caused by an extremely unbalanced, nutritionally deficient diet, as that observed by Stonich and others [114]. We propose that most diets, particularly in Western nations where grains and cereals are fortified with iron, are not causes of anemia. Routine iron supplements may increase rather than decrease morbidity. We might want to re-evaluate iron fortification and supplementation programs that affect the availability of iron (e.g. WIC only approves iron-fortified infant formula for disadvantaged infants). Wadsworth noted that “A notion has evolved that young children and pregnant women cannot meet their requirements for iron by ingestion of their usual diets unless iron salts have been added. The human race has survived, and sometimes flouished, for hundreds of thousands of years . . . without the purposeful addition to foods of inorganic forms of iron” [115]. Demographics, extreme diets, heavy pathogen loads and virulent microorganisms can transform a mild condition into a severe one necessitating medical intervention. Several recent studies have also linked high iron levels to heart disease and low levels to protection against heart disease [116, 1171. We suggest that the role of iron in health and disease, and specifically the cause and conse-

quence of chronic acquired anemia, needs to be reassessed.

CONCLUSIONS

Hypoferremia in persons chronically exposed to microbial invaders because of poor sanitation, sedentism, and aggregation may be beneficial in thwarting potential threats to the health of an individual. Anemia of infection and chronic disease defends against the proliferation of microbial and neoplastic cells and may have evolved together with fever as comp!ementary strategies the body employs to ward off disease. Transferrin, lactoferrin, and fever all reduce iron availability when the body is confronted with danger from rapidly proliferating cells. The hypoferremic condition is produced by lowering the amount of available plasma iron and depositing it in storage where it is less accessible to invading cells, by elevating body temperature to inhibit siderophore production, and by the inhibition of intestinal iron absorption. are most grateful to Steven Kent MD, Nancy Rikalo MD, and RA Stuart PhD, for their valuable comments on a rough draft.

Acknowledgements-We

REFERENCES 1. Palti H, Adler B, Hurvitz J, Tamir D, Freier S. Use of iron supplements in infancy: A field trial. Bull WHO 1987; 65: 81-94. 2. Haschke F, Pietschnig B, Vanura H et al. Iron intake and iron nutritional status of infants fed iron-fortified beikost with meat. Am J CIin Nutr 1988; 74: 108-I 12. 3. Mejia L, Chew F. Hematological effect of supplementing anemic children with vitamin A alone and in combination with iron. Am J Clin Nutr 1988; 48: 595-600. 4. Schulz-Iell G, Buss R, Oldigs H-D, Diirner K, Schaub J. Iron balances in infant nutrition. Acta Paediatr Stand 1987; 76: 585-591. 5. Charoenlaro. P. Dhanamitta S. Kaewvichit R et al. A WHO collaborative study on iion supplementation in Burma and in Thailand. Am J Clin Nutr 1988; 47: 280-297. 6. Wadsworth, G. The concentration of hemoglobin in circulating blood and the influence of iron in the diet. In: Stuart-Macadam P, Kent, S, Eds. Diet, Demography, and Disease: Changing Views of Anemia. New York: Aldine de Gruyter; 1992; 63-104. I. Bhatt R, Joshi S, Shah M. Total dose intravenous infusion of iron-dextran (Imferon) in severe anemia. Am J Obstet Gynecol 1966; 94: 1098-1102. 8. Jackson R, Jackson L. Biological and behavioral contributors to anemia during pregnancy in Liberia, West Afica. Hum Biol 1987; 59: 38?-597.. 9. Thiele M. Gedes ME. Nobman E. Petersen K. High prevalenck of iron deficiency anemia among Alaskan Native children. JAMA 1988; 259: 2532. 10. Arthur CK, Isbister JP. Iron deficiency: misunderstood, misdiagnosed and mistreated. Drugs 1987; 33: 171-182.

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Etiology of Anemia of Chronic Disease and Infection Il. Fairbanks V, Beutler E. Iron. In: Shils M, Young V, Eds. Modern Nutrition in Health and Disease. Philadelphia: Lea and Febiger; 1988; 1933226. 12. Burns E, Goldberg N, Lawrence C, Wenz B. Clinical utility of serum tests for iron deficiency in hospitalized uatients. Am J Clin Path 1990: 93: 240-245. 13. Guyatt G, Patterson C, Ah M et al. Diagnosis of iron-deficiency anemia in the elderly. Am J Med 1990; 88: 205-209. 14. Weinberg E. Iron and susceptibility to infectious disease. Science 1974; 184: 952-956. 15 Weinberg E. Iron withholding: A defense against infection and neoplasia. Physiol Rev 1984; 64: 65-102. 16. Weinberg E. Microorganism. McGraw-Hill Yearbook of Science & Technology. 1986; 282-283. 17. Weinberg E. Cellular iron metabolism in health and disease. Drug Metab Rev 1990; 22: 531-579. 18. Weinberg E. Iron withholding: A defense against disease. In: Stuart-Macadam P, Kent S, Eds. Diet, Demography, and Disease: Changing Perspectives of Anemia. New York: Aldine de Gruyter; 1992; 105-150. 19. Brock J. Iron and the outcome of infection. Br J Med 1986; 293: 518-519. 20. Miles AA, Khimji PL, Maskell J. The variable response of bacteria to excess ferric iron in host tissues. J Med Microbial

J Ciin Invest 1946; 25: 65-80.

1979; 12: 17-28.

21. Neilands JB. Iron absorption and transport in microorganisms. In: Darby W, Broquist H, Olson R, Eds. Annual Review of Nutrition 1981; 1: 27-46. 22. Martinez JL, Delgado-Iribarren A, Baquero F. Mechanisms of iron acquisition and bacterial virulence. FEM Microbial Rev 1990; 75: 45-56. 23. Cole M, Arnold RR, Mestecky J, Prince S, Kulhavy A, McGhee JR. Studies with human lactoferrin and Streptococcus mutans. In: Stiles HM, Loesche W, O’Brien T, Eds. Microbial Aspects of Dental Caries. Washington, DC: Information Retrieval, Inc.; 1976; 3599373. 24. Tupasi T, Velmonte M, Sanvictores ME et al. Determinants of morbidity and mortality due to acute respiratory infections: implications for intervention. J Infect Dis 1988; 157: 615-623. 25. Payne S, Finkelstein R. The critical role of iron in host-bacterial interactions. J Clin Invest 1978; 61: 142881440. 26. Schade AL. Significance of serum iron for the growth, biological characteristics, and metabolism of Stuphylococcus aureus. Biochem Zeitschrift

34. Forman MR, Graubard BI, Hoffman HJ, Beren R, Harley EE, Bennett P. The Pima infant feeding study: breast-feeding and respiratory infections during the first vear of life. In J Euidemiol 1984: 13: 447-453. 35. Raiha N. Nutritional proteins in milk’and the protein requirement of normal infants. Pediatrics 1985; 75: 136-141. 36. Ryder RW, Singh N, Reeves WC, Kapikian AZ, Greenberg HB, Sack RB. Evidence of immunity induced by naturally acquired rotavirus and Norwalk virus infection on two remote Panamanian Islands. J Infect Dis 1985; 151: 99-105. 37. Gryboski J, Walker WW. Gastrointestinal Problems in the Infant, 2nd edn. Philadelphia, PA: WB Saunders; 1983. 38. Duffy L, Byers T, Riepenhoff-Talty M, La Scholea L, Zielezny M, Ogra P. The effects of infant feeding on rotavirus-induced gastroenteritis: a prospective study. Am J Public Health 1986: 76: 259-263. 39. Bezkorovainy A. Biochemistry of nonheme iron in man. Clin Physiol Biochem 1989; 7: 1-17. 40. Cartwright Gi Lee GR. The anaemia of chronic disorders. Br J Haematol 1971: 21: 147-152. 41. Cartwright G, Lauritsen GA, Humphries S, Jones PJ, Merrill IM, Wintrobe MM. The anemia of infection.

1963; 338: 140-148.

27. Michelson PA, Sparling PF. Ability of Neisseria gonorrhoea, Neisseria meningitides, and commensal Neisseria species to obtain iron from transferrin and iron compounds. Infect Immunol 1981; 33: 555-564. 28. Noyes W. Anemia as a result of the insufficiency in the production of red cells. In: Litchtman M, Ed. Hematology and Oncology. New York: Grune & Stratton; 1985: 23-28. 29. Martorell R. O’Gara C. Breastfeeding, infant health, and socioeconomic status. Med Anthropol 1985; 9: 173-195. 30. Habicht J-P, DaVanzo J, Butz W. Mother’s milk and sewage: their interactive effects on infant mortality. Pediatrics 1988; 18: 456-461. 31. Boesman-Finkelstein M, Finkelstein RA. Antimicrobial effects of human milk: inhibitory activity on enteric pathogens. FEMS Microbial Lett 1985; 27: 167-174. 32. Clemens J, Stanton B, Stall B, Shahid N, Banu H, Chowdhury AK. Breast feeding as a determinant of severity in shigellosis Am J Epidemiol 1986; 123: 710-720.

33. Arnon S, Damus K, Thompson B, Midura T, Chin J. Protective role of human milk against sudden death from infant botulism. J Pedatr 1982; 100: 568-573.

42. O’Neil-Cutting M, Crosby W. Blocking of iron absorption by a preliminary oral dose of iron. Arch Intern Med 1987; 147: 4899491. 43. Weinberg E. Roles of iron in function of activated macrophages. J Nutr Immuuol 1992; 1: 41-63. 44 Farthing MJ. Iron and immunity. Acta Paediatr Stand Suppl 1989; 44-52.

45. Weinberg, E. Cellular acquisition of iron and the iron-withholding defense against microbial and neoplastic invasion. In: Lauffer, RB Ed. Iron and Human Disease. Boca Raton Fl:CRC Press; 1992; 179-205. 46 Barry DM, Reeve AW. Increased incidence of gramnegative neonatal sepsis with intramuscular iron administration Pediatrics 1977; 60: 908-912. 47 Barry DM, Reeve AW. Iron injections and serious gram-negative infections in Polynesian newborns. N Z Med J 1973; 78: 376. 48 Becroft DM, Dix MR, Farmer K. Intramuscular irondextran and susceptibility of neonates to bacterial infections. Arch Dis Child 1977: 52: 7788781. 49. Oppenheimer SJ, Gibson FD, MacFarlane SB et al. Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans R Sot Trouical Med Hvs 1986: 80: 603-612. 50. Oppenheimer SJ, MacFarlane SB, Moody JB, Bunari 0, Hendrickse RG. Effect of iron prophylaxis on morbidity due to infectious disease: report on clinical studies in Papua New Guinea. Trans R Sot Tropical I_

Med Hyg 1986; 80: 596-602.

51. Masawe AE, Muindi JM, Swai GB. Infections in iron deficiency and other types of anaemia in the tropics. Lancet 1974; 2: 314-317.

52. Murray MJ, Murray A, Murray CJ. The salutary effect of milk on amoebiasis and its reversal by iron. Br Med J 1980a; 280: 1351-1352. 53. Murray MJ, Murray A. Starvation suppression and refeeding activation of infection: an ecological necessity? Lancet 1977; 1: 123-125. 54. Murray MJ, Murray A, Murray N, Murray M. Somali food shelters in the Ogaden famine and their impact on health. Lancet 1976; 1: 1283-1285. 55. Murray MJ, Murray A, Murray CJ. An ecological interdependence of diet and disease? Am J Clin Nutr 1980b; 33: 697-701. 56. Haddock R, Cousens S, Guzman C. Infant diet and salmonellosis. Am J Public Health 1991; 81: 997-1000.

S. KENTer al.

32

51. Wright A, Simpson L, Oliver J. Role of iron in the pathogenesis of Vibrio uulnifcus infections. Infect Immanol 198 1; 34: 503-507. 58. Calver G, Kenny C, Kushner D. Inhibition of the growth of Neisseria meningitides by reduced ferritin and other iron-binding agents Infect lmtmmol 1979; 25: 880-890. 59. Webster M, Waitkins S, Stott A. Impaired bacteriological responses in babies after maternal iron dextran infusion. J Clin Path01 1981: 34: 651-654. 60. Butzler JP, Alexander M, Segers A, Cremer N, Blum D. Enteritis, abscess, and septicemia due to Yersinia enterocolitica in a child with Thalassemia. J Pediatr 1978; 93: 619-621. 61. Boelaert J, van Landuty H, Valcke Y. The role of iron overload in Yersinia enterocolitia and Yersinia pseudotuberculosis bacteremia in hemodialysis patients. J Infect Dis 1987: 156: 384-389. 62. Melby K, Slordadl S, Gutteberg TJ, Nordb SA. Septicaemia due to Yersinia enferocolirica after oral overdoses of iron. Br Med J 1982; 285: 467-468. 63. Robbins-Browne RM, Rabson AR, Koornhof HJ. Generalized infection with Yersinia enterocolitica and the role of iron. Contrib Microbial Immunol 1979; 5: 277-282. 64. Scharnetzky M, Kiinie R, Lakomek M, Tillman W, Schriiter W. Prophylaxis of systemic Yersiniosis in Thalassemia Major. Lnncet 1984; 1: 791-792. 65. Morris JG, Wright AC, Simpson LM, Wood PK, Johnson DE, Oliver JD. Virulence of Vibrio uuln@xs: association with utilization of transferrin-bound iron, and lack of correlation with levels of cytotoxin or protease production. FEMS Microbial L&t 1987; 40: 55-59. 66. Payne S. Iron and virulence in the family Enterobacteriabeae. CRC Critl Rev Microbial 198s; 16(2): 81. 61. Kluger MJ. Bullen JJ. Clinical and nhvsioloaical aspects. In: B;llen JJ, Griffiths E, Eds. Iion and Iifection. New York: John Wiley; 1987; 243-282. 68. Gordeuk V, Brittenham G, McLaren G, Spagnuolo P. Hyperferremia in immunosuppressed patients with acute nonlymphocytic leukemia and the risk of infection. J Lab Clin Med 1986; 108: 466-472. 69. Weinberg E. DF-2 sepsis: A sequela of sideremia. Med Hypotheses 1987; 24: 287-289. 70. Bullen JJ, Rogers H, Griffiths E. Bacterial iron metabolism in infection and immunity. In: Neilands JB, Ed. Microbial Iron Metabolism: A Comprehensive Treatise. New York: Academic Press; 1974. 71. Bullen JJ, Rogers H, Griffiths E. Role of iron in bacterial infection. Curr Top Microbial Immunol 1978; 80: l-35. 72. Walsh BL, Warren RA. Iron uptake in Salmonella typhimurium. Can J Microbial 1971; 17: 213-216. 73. Kochan I. The role of iron in bacterial infections, with special consideration of host-tubercle bacillus interaction. Carr top Microbial Inununol 1973; 60: l-30. 74. Bullen JJ, Rogers H, Leigh L. Iron binding proteins in milk and resistance to Escherichia coli infection in infants. Br Mad J 1972; 1: 69-75. 75. Elin R. Wolff S. The role of iron in nonsnecific resistance to infection induced by endotoxin. J. Immunol 1974; 112: 737-745. 76. Lee GR. The anemia of chronic disease. Semin Hematol 1983; 20: 61-80. 77. Elin R, Wolff S, Finch C. Effect of induced fever on serum iron and ferritin concentrations in man. Blood 1977; 49: 147-153. 78. Jansson LT, Kling S, Dallman PR. Anemia in children with acute infections seen in a primary care pediatric outpatient clinic. Ped Infect Dis 1986; 5: 424-427.

79. Jampel H, Duff G, Gershon R, Atkins E, Durum S.

80.

81. 82.

83.

84. 85. 86.

Fever and immunoregulation. J Exp Mad 1983; 157: 1229-1238. Kluger M, Rothenburg B. Fever and reduced iron: their interaction as host defense response to bacterial infection. Science 1979; 203: 374-376. Roberts N. Impact of temperature elevation on immunologic defenses. Rev Infect Dis 1991; 13: 462-472. Kent S. Anemia through the ages: Changing perspectives and their implications. In: Stuart-Macadam P, Kent S, Eds. Diet, Demography, and Disease: Changing Views of Anemia. New York: Aldine de Gruyter; 1992: l-30. Dallman P. The nutritional anemias. In: Nathan D, Oski F, Eds. Hematology of Infancy and Childhood. Philadelphia, PA: WB Saunders; 1974; 97-135. Weinberg E. Infection and iron metabolism. Am J Clin Nutr 1977; 30: 1485-1490. Weinberg E. Iron and infection. Microbial Rev 1978; 42: 45-66. Zanella A, Gridelli L, Berzuini A et al. Sensitivity and predictive value of serum ferritin and free erythrocyte protoporphyrin for iron deficiency. J Lab Clin Med

1989; 113: 73-78. 87. Henry J. Clinical Diagnosis and Management by Lab-

oratory Methods, 17th edn. Philadelphla, PA: WB Saunders; 1984. 88. Worwood M, Serum ferritin. In: Cook J, Ed. Iron. New York: Churchill Livingstone; 1980; 59-89. 89. Olivares M, Walter T, Osorio M, Chaudud P, Schlesinger L. Anemia of a mild viral infection: the measles vaccine as a model. Pediatrics 1989; 84: 851-855.

90. Adelekan D, Thurnham D. Plasma ferritin concentrations in anemic children: relative importance of malaria, riboflavin deficiency, and other infection. Am J Clin Nutr 1990; 51: 453-456. 91. Babiuk L. Viral-bacterial synergistic interactions in respiratory infections. In: Kurstak E, Ed. Applied Virology. New York: Academic Press; 1984; 431-443. 92. Babiuk L. Virus-induced gastroenteritis. In: Kurstak E, Ed. Applied Virology. New York: Academic Press; 1984; 444-454. 93. Mills E. Viral infections predisposing to bacterial infections. AM Rev Med 1984; 35: 469-479. 94. Metz J, Hart D, Harpending HC, Iron, folate, and vitamin B,, nutrition in a hunger-gatherer people: a studv of the !Kuna Bushmen. Am J Clin Nutr 1971: 24: 229-242. 95. Kent S, Lee R. A hematological study of !Kung Kalahari foragers: an eighteen year comparison. In: Stuart-Macadam P, Kent S, Eds. Diet, Demography and Disease:

96.

97.

98. 99.

Changing Perspectives

of Anemia. New

York: Aldine de Gruyter; 1992; 173-199. Kent S, Dunn D. The health status of a recently sedentary Kalahari village: Implications for the past and the future. Am J Trop Mad Hyg 1993; 48: 554-567. Harpending H, and Wandsnider L. Population structures of Ghanzi and Ngamiland !Kung, In: Crawford M, Mielke J, Eds. Current Developments in Anthropological Genetics. New York: Plenum Press; 1984: Vol. 2; 29-50. Keusch G, Farthing M. Nutrition and infection. Ann Rev Nutr 1986; 6: 131-154. Lozoff B, Jimenez E, Wolf A. Long-term developmental outcome of infants with iron deficiency, N Engl J Med 1991; 325: 687-694.

100. Kent S. Weinberg E, Stuart-Macadam P. Dietary and prophylactic iron supplements: Helpful or harmful? Human Nature 1990: 1: 53-79. 101. Weinberg E. Pregnancy-associated immune suppression: risks and mechanisms. Microbial Pathogenesis 1987; 3: 393-397.

Etiology of Anemia of Chronic Disease and Infection 102. Stuart-Macadam P. Nutrition and anaemia in past human populations. In: Kennedy BY, LeMoine GM, Eds. Diet and Subsistence: Current Archaeological Perspectives. Calargy: CHACMOOL; 1988. 103. Hibbard B. Iron and folate supplements during pregnancy: supplementation is valuable only in selected patients. & Med J 1988; 297: 1324-1326. 104. Klebanoff M. Shiono P. Heinz W. Berendes W. Rhoads G. Facts and aitifacts about anemia and preterm delivery. JAMA 1989; 262: 511-515. 105. Biemond P, Swark AJ, van Euk HG, Koster JF. Superoxide dependent iron release from ferritin in inflammatory diseases. J Free Rad Biol Med 1988; 4: 185-198. 106. Finch C. Introduction: knights of the oval table. J Intern Med 1989; 226: 345-348. 107. Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med 1988; 319: 1047-1052. 108. Stevens R. Iron and the risk of cancer. Med Oncol Tumor Pharmacother 1990; 7(2/3): 177-181. 109. Selby J, Friedman G. Epidemiologic evidence of an association between body iron stores and risk of cancer. Int J Cancer 1988; 41: 677-682.

33

110. Kent S. The influence of sedentism and aggregation on porotic hyperostosis and anaemia: a case study. Man 1986; 21: 60-636. 111. Stuart-Macadam P. Porotic hyperostosis: representative of a childhood condition Am J Physical Anthropol 1985; 66: 391-398. 112. Reizenstein P. Hematologic Stress Syndrome: The Biological Response to Disease. New York: Praeger; 1983. 113. Monsen E. Iron nutrition and absorption: dietary factors which impact iron bioavailability. J Am Diet Assoc 1988; 88: 786-790. 114. Stonich S. The political economy of environmental destruction: food security in Hondours. In: Whiteford S, Ferguson A, Eds. Harvest of Want: Food Security in Mexico and Central America. Boulder: Westview; 1991; 35-55. 115. Wadsworth G. Nutritional factors in anaemia. World Rev Nutr Diet 1975; 21: 75-150. 116. Salonen JT. Nvvssiinen K. Kornela H. Tuomilehto J. Seppinen k, .%lonen R. High’stored’iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 86(3); 1992; 803-S 11. 117. Sullivan J. The iron paradigm of ischemic heart disease. Am Heart J 117; 1989; 1177-1188.