Elsevier

Nutrition

Volume 23, Issues 7–8, July–August 2007, Pages 603-614
Nutrition

Review article
Nutritional iron deficiency: an evolutionary perspective

https://doi.org/10.1016/j.nut.2007.05.002Get rights and content

Abstract

Iron deficiency, with or without iron-deficiency anemia, is so ubiquitous that it affects all populations of the world irrespective of race, culture, or ethnic background. Despite all the latest advances in modern medicine, improved nutrition, and the ready availability of cheap oral iron, there is still no good explanation for the widespread persistence of iron deficiency. It is possible that the iron deficiency phenotype is very prevalent because of many factors other than the commonly cited causes such as a decreased availability or an increased utilization of iron. Several thousand years ago, human culture changed profoundly with the agrarian revolution, when humans turned to agriculture. Their diet became iron deficient and new epidemic infections emerged due to crowding and lifestyle changes. There is convincing evidence that iron deficiency protects against many infectious diseases such as malaria, plague, and tuberculosis as shown by diverse medical, historical, and anthropologic studies. Thus, this change of diet increased the frequency of iron deficiency, and epidemic infections exerted a selection pressure under which the iron deficiency phenotype survived better. Multiple evolutionary factors have contributed in making iron deficiency a successful phenotype. We analyze some of the recent findings of iron metabolism, the theories explaining excessive menstruation in human primates, the unexplained relative paucity of hemochromatosis genes, the former medical practice of “blood-letting,” and other relevant historical data to fully understand the phenomenon of iron deficiency. We suggest that, due to a long evolutionary persistence of iron deficiency, efforts at its prevention will take a long time to be effective.

Introduction

Iron deficiency is so widespread in humans that it affects all ethnic groups without exception despite the fact that iron is the fourth most common element on earth. It is responsible for anemia in approximately 15% of the world’s population; its overall prevalence is quoted to be around 50% in developing and 10% in developed countries [1], [2]. Children, adolescent women, and women of childbearing age are especially prone to develop iron-deficiency anemia (IDA). Among pregnant women in some developing countries, iron deficiency is more common than iron sufficiency [3]. Latent iron deficiency (iron deficiency without anemia) is at least as common as IDA itself, making iron deficiency at least twice as frequent as IDA [4], [5], [6], [7]. However, there is still no good explanation for the extensive persistence of this phenomenon of iron deficiency. Traditionally, it is well accepted that iron deficiency develops due to multiple well-known mechanisms, alone or in combination, i.e., an inadequate intake, a reduced absorption, a physiologic increase in demand, or an excessive loss of iron. In the developed countries, fortification of food with iron for the past five decades has dramatically decreased the prevalence of IDA [8], [9], [10]. Despite all the modern advances in medicine, improved nutrition and ready availability of low cost oral iron, iron deficiency remains a worldwide problem of epidemic proportions.

Over the past decade, new findings related to iron metabolism, especially from the studies of latent iron deficiency and hemochromatosis, have further added to our understanding of the origins of iron deficiency. These findings have shown that some hemochromatosis genes, which increase the absorption of iron and could prevent iron deficiency, are less harmful than previously believed [11]. Yet, their frequencies in world populations remain low [12]. The reasons for common hemochromatosis genes not being more common and thus making iron deficiency less frequent in populations is unclear, making reasons behind the high prevalence of iron deficiency even more mysterious.

To better understand the phenomenon of iron deficiency, we scrutinized new findings of iron metabolism, the various theories, and historical data relevant to this problem. Iron deficiency seems to have become more frequent only during the past 10 000 y, after the agrarian revolution, when a change in human diet increased iron deficiency. Multiple cultural changes at that time led to the emergence of new infectious diseases which seriously threatened human survival. There are several lines of evidence to suggest that iron deficiency could protect against infection. We contend that humans may have “failed to adapt” [13], genetically and culturally, to continuous deficiency of iron because relative iron deficiency was protective against many infectious diseases.

Iron-deficiency anemia is suspected when a decreased hemoglobin level is found in association with microcytosis (a small mean cell volume [MCV] on automated blood cell counts), and its diagnosis is confirmed when a decrease in iron stores is established. Thus, absence of iron staining in the bone marrow aspirate is the “gold standard” for diagnosis of iron deficiency despite its multiple methodologic problems (e.g., improper staining of iron) [14], [15]. A rapid and inexpensive screening test is the determination of the level of zinc protoporphyrin, which is increased in iron deficiency. A more specific test is TfR, whose level is also increased in iron deficiency. The most frequently used measurement of iron stores is serum ferritin or, alternatively, a combined finding of decreased level of serum iron with an increased level of total iron-binding protein. Ferritin levels are directly proportional to the total body iron. However, its synthesis is increased in the presence of inflammatory or malignant diseases and this may produce a false elevation of ferritin although iron stores are low or absent [11].

Although IDA is the most common cause of low MCV, the α- and β-thalassemia traits and other less frequent anemias are also responsible for a small MCV with or without a small decrease in hemoglobin level. In some populations, a small MCV in anemic subjects can be presumed to be due to IDA. This approximation of the frequency of IDA is valid only if the frequencies of α- and β-thalassemia genes are low in the studied population. However, in many regions of the world, especially in developing countries where IDA is most common, the thalassemia trait also is common. In addition, α-thalassemia may have a direct effect on the development or persistence of iron deficiency in α-thalassemia gene carriers [16]. Consequently, estimating the prevalence of IDA from the frequency of small MCV alone in population studies is difficult and bound to produce falsely high rates of IDA.

After IDA was pathophysiologically and clinically defined in the 1930s [17], it became evident that it was a highly prevalent hematologic condition especially among children and young women in Europe and North America [18]. In the 1970s, screening for IDA with prophylactic administration of iron to infants and fortification of food with iron were started in the developed countries. Therefore, the prevalence of IDA in the industrialized world started decreasing [8], [9], [10]. Despite supplementation of the human diet with iron, a fraction of younger children (9%), adolescent girls (9%), and women of childbearing age (11%) continue to remain iron deficient [19]. This suggests that saturating iron stores, even when iron is available, may be difficult in children and young women. Thus, it is conceivable that failure to readily correct iron deficiency could be due to an unrecognized genetic and cultural predisposition, manifesting through diet and altered processing of food.

In the developing countries, prevalence of IDA is estimated to be 56% among pregnant and 41% among non-pregnant women. In South Asia, more pregnant women have IDA (62%) than a normal hemoglobin level [2], [3]; this is also true for women and children in some African countries [7]. Although many reports have not excluded other causes of microcytic anemia that could lead to overestimation of the prevalence of IDA [20], in many parts of the world the prevalence of IDA is sufficiently high to be considered a “statistical normality” [21]. This high frequency of IDA at first could suggest a possibility of human failure to adapt to iron deficiency [13]. However, a contrary explanation, that IDA is an outcome of successful adaptation and a “normal” state of iron stores, at least under certain environmental conditions, is more likely especially in view of new findings of a high prevalence of covert iron deficiency in human populations.

Latent iron deficiency is a state of decreased iron stores without anemia. In normal individuals, latent iron deficiency has been shown to progress through two well-defined biochemical phases: 1) an early phase of iron deficiency, in which a decreased ferritin level is the only biochemical manifestation, and 2) a later phase of iron deficiency, in which, in addition to a low ferritin, serum transferrin receptor (TfR) level is elevated [4]. Serum TfR is a washout of the receptors normally present on the erythroid cells of the bone marrow. The TfR on the surface of the cells internalizes the iron bound to serum transferrin, and cell then uses iron for synthesis of hemoglobin. When iron is in short supply, there is a compensatory increase in the expression of TfR on erythroid cells. As TfR is partially released into the blood, its rising serum concentration signifies the beginning of iron-deficient erythropoiesis, which is a later phase of the latent iron deficiency [11]. Over the past decade, studies have been published indicating that latent iron deficiency is as frequent as IDA in the same population. In one retrospective study of healthy normal non-anemic women from Finland, the frequency of latent iron deficiency was 49% [4]. In Indian nursing students, the prevalences of latent iron deficiency and IDA were 28% and 20%, respectively [5]. In Mexican pregnant women and schoolchildren, frequencies of latent iron deficiency were 86% and 14% and those of IDA were 46% and 10%, respectively [6], [22]. In Africa, latent iron deficiency was as frequent as IDA in children and women; in men, latent iron deficiency was more frequent than IDA [7]. Obviously, the definition of latent iron deficiency (early phase, with only a low ferritin, or late phase, with a high TfR level) influenced the frequency of latent iron deficiency found in one study [23]. Despite this caveat, the available data indicate that covert iron deficiency is at least as frequent as overt iron deficiency (IDA), if not more common. This means that the prevalence of overall iron deficiency (latent iron deficiency plus IDA) is at least twice that of IDA in the same population. Because the conservative estimate of the worldwide prevalence of IDA is around 15% [1], these data suggest that the prevalence of iron deficiency is not <30%.

In the past decade, at least a dozen variants of the five genes (HFE, HEMPS, JIV, 2TfR, and FP) involved in iron hemostasis were discovered (hemochromatosis genes). The carriers of one or two of these genes have normal or increased iron stores and a variable tendency to hyperferremia. However, their worldwide frequency, with the exception of the C282Y and H63D mutations of the HFE gene, is very low [12]. C282Y and H63D allele increase iron absorption in the small intestine [24]. The homozygotes of both genes, heterozygotes of C282Y, and female heterozygotes of H63D have a higher ferritin level than non-carriers of the genes. In addition, female heterozygotes of C282Y have a higher average hemoglobin level than female non-carriers [12], [25]. Among Europeans, the mean frequency of C282Y is 9% (range 3–28) and the frequency of H63D alleles is 5% (in Southern Europe up to 28%). In non-European populations, their corresponding frequencies are <1% and 4% [12]. Because the hemochromatosis genes increase absorption of iron and could ameliorate iron deficiency, the obvious question is: Why are their frequencies not any higher in the different populations of the world? The traditional answer is that the genes are harmful and are being constantly eliminated from populations with premature death of homozygotes. However, new findings outlined below cast doubts on this explanation.

Genetic hemochromatosis (e.g., homozygosity of C282Y) infrequently progresses to clinical hemochromatosis and rarely causes death. It seldom affects females and in males appears mostly after their prime reproductive age (>40 y) [11], [26]. Therefore, it is unlikely for homozygotes to be removed from populations before they transmit genes to the next generation. The downward pressure on the frequency of C282Y in populations (balanced polymorphism) appears to be small. This further supports the finding of the similar frequencies of the gene in younger and older generations in the same population [11], [26]. The same argument applies to H63D allele, which has a significantly milder phenotype than C282Y allele. Nonetheless, other explanations have been offered for the increased frequency of C282Y and H63D among Europeans (gene drift, positive selection due to protection against Yersinia pestis epidemics, positive selection to protect against iron deficiency, unknown effect of the genes, i.e., pleiotropic effect) and their low frequency among non-Europeans (a low gene mutability, positive selection of short duration) [25], [27], [28].

Proximity of the HFE gene to and its structural similarity with the genes involved in immune defense from infections suggest its possible role in protection against infection. The HFE gene is located within major histocompatibility complex (MHC) class I genes that are involved in the control of immune protection against infection [12]. The odds that the HFE gene is located by chance within 200-gene big MHC of 20 000 human genes is 1 in 100 [29]. In addition, there is 37% structural identity of HFE with MHC class I gene HLA-A2 [12]. Thus, the location and structure of the HFE and HLA genes suggest that the non-immune protection against infection (through control of availability of iron to microbes) and the immune protection against infection may have a common origin.

Section snippets

Importance of iron for microbe virulence

Iron is an indispensable element for the metabolism of all micro-organisms. In humans, as in all micro-organisms, iron is present in very small amounts. In response to infection, humans lower the level of the available iron by increasing the synthesis of apoferritin, which binds the free iron molecule, restricting its availability to the infectious agent. Consequently, the level of serum ferritin increases, whereas the level of serum iron decreases. This mechanism of non-immunologic protection

Relative fitness of iron-deficient phenotype

Iron-deficiency anemia impairs cognitive, immune, and reproductive functions and decreases work performance [61], [62], [63], [64], [65]. However, it can be found even in well-performing athletes, suggesting a negligible negative effect on performance [61]. Most individuals with IDA have a mild or moderate decrease of hemoglobin level, are physiologically adapted, and clinically asymptomatic. In men, in whom a good physical performance is historically more important for survival than in women,

Rhetoric of risk factors of IDA

The core concepts for the risk factors of nutritional IDA that are typically cited are combinations of 1) “a low bioavailability of iron” in plants; 2) “a low intake of meat,” which has a higher content and bioavailability of iron than plants; 3) “low content and bioavailability of iron in mother’s milk”; 4) “intake of cow’s milk,” which has low bioavailability of iron and increases iron loss; 5) “consumption of tea,” which decreases absorption of iron; 6) “the rapid growth” in infancy and

Genetically controlled risk factors of iron deficiency?

The genetics of iron metabolism are poorly understood. High ferritin and transferrin saturation levels are more common among Asians and Blacks than European Whites, presumably for genetic reasons [73]. Europeans have a much higher frequency of C282Y and H63D gene carriers, which are associated with a higher transferrin saturation than carriers of only wild-type alleles who are more frequent among Asians and Blacks [12], [25], [73]. Small differences in hemoglobin levels between the races and

Agrarian revolution

The agrarian revolution is a landmark in the evolution of human culture that begun 10 000 y ago with the cultivation of plants and domestication of animals. It started independently in several geographic regions (China, Middle East, North America, and Africa) and then spread over thousands of years throughout the world. Farming caused a transition from a nomadic, hunter-gatherer lifestyle to a new sedentary, plant and animal cultivation lifestyle resulting in a major change in food production

Iron deficiency memes: culture that favors iron deficiency?

There is a growing acceptance that social norms, learned skills, and customs including dietary practices—also known as cultural genes and memes—could mutate, undergo selection, and be transmitted in a way analogous to gene transmission. This cultural evolution is comparable to the genetic evolution that shapes the genome, although the former is faster [104], [105]. Customs such as vegetarianism, which is associated with lower iron stores [106], and habitual consumption of tea and coffee are

Conclusions

Several millennia ago, the agrarian revolution was sparked by the development of agriculture. The introduction of farming and domestication of animals in early human settlements had a profound effect on human civilization. One of the transformations that occurred was the change of the human diet. For thousands of years before the agrarian revolution, hunter-gatherers were genetically and culturally adapted to a diet that was heavily meat based. In the agrarian period, meat consumption was

Acknowledgments

The authors acknowledge with gratitude the critical comments of Dr. Salah Gariballa.

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