Objective: To gain insight into vitamin A deficiency as a cause of anemia.
Methods: Comprehensive review of the scientific literature.
Results: Although vitamin A deficiency is recognized to cause anemia, ‘vitamin A deficiency anemia’ lacks complete characterization as a distinct clinical entity. Vitamin A appears to be involved in the pathogenesis of anemia through diverse biological mechanisms, such as the enhancement of growth and differentiation of erythrocyte progenitor cells, potentiation of immunity to infection and reduction of the anemia of infection, and mobilization of iron stores from tissues. Epidemiological surveys show that the prevalence of anemia is high in populations affected by vitamin A deficiency in developing countries. Improvement of vitamin A status has generally been shown to reduce anemia, but the actual public health impact on anemia is unclear.
Conclusions: Further work is needed to elucidate the biological mechanisms by which vitamin A causes anemia. The inclusion of anemia as an outcome measure in future micronutrient intervention studies should help provide further insight into the anemia of vitamin A deficiency.
Vitamin A deficiency is considered to be a major public health problem in 60 (World Health Organization, 1995) to 78 (Micronutrient Initiative/UNICEF/Tulane, 1998) developing countries worldwide, and an estimated 78 to 253 million preschool children are affected by vitamin A deficiency (World Health Organization, 1995; Micronutrient Initiative/UNICEF/Tulane, 1998). Pregnant women and women of childbearing age also constitute high risk groups for vitamin A deficiency in developing countries (Christian et al, 2000). The global prevalence of anemia is high, and in developing countries about 42% of preschool children, 53% of school-age children, 44% of women of childbearing age, and 56% of pregnant women may be affected by anemia (United Nations, 2000). The causes of anemia are diverse, but among the leading etiologies in developing countries are iron deficiency, malaria, some infectious diseases, and other nutritional deficiencies that influence hemoglobin metabolism, including vitamin A. Although vitamin A deficiency is acknowledged among the causes of anemia (Oski, 1995; Lee & Herbert, 1998), the epidemiology and pathogenesis of the anemia of vitamin A deficiency have not been well characterized. The hematological picture of vitamin A deficiency anemia is still vaguely defined. Vitamin A appears to influence anemia via modulation of hematopoiesis, by enhancement of immunity to infectious diseases (Thurnham, 1993,Semba, 1998) and, hence, the anemia of infection (Means, 2000), and through the modulation of iron metabolism (Bloem, 1995). The purpose of this review is to provide a historical background to the issue, to give a critical assessment of current knowledge of the epidemiology and pathogenesis of the anemia of vitamin A deficiency, and to identify areas for future research.
In the nineteenth century, it was recognized that anemia often occurred in individuals with night blindness, and this observation led some clinicians to conclude that anemia was among the underlying causes of night blindness (Nozeran, 1865; Parinaud, 1881; Saltini, 1881; Lecoeuvre, 1896). Administration of cod-liver oil, a potent source of vitamins A and D, was widely used to treat anemia in the nineteenth century (Thompson, 1855; Greene, 1877; McArdle, 1896). Animal and human studies in the early twentieth century suggested that vitamin A deficiency was related to abnormalities of hematopoiesis and iron metabolism. Vitamin A-deficient rats developed areas of gelatinous degeneration in the bone marrow (Findlay & Mackenzie, 1922) or a reduction in hematopoietic cells in bone marrow (Wolbach & Howe, 1925). Hemosiderosis of the liver and spleen were described in autopsy studies of vitamin A-deficient infants (Blackfan & Wolbach, 1933), thus linking vitamin A deficiency to abnormalities of iron metabolism.
By the 1920s, increased susceptibility to infection and high child mortality were attributed to the lack of vitamin A (Bloch, 1924), and provision of vitamin A was shown to reduce child mortality (Blegvad, 1924). In 1924 Erik Widmark, a professor at the University of Lund, concluded ‘there must be in a population in which xerophthalmia occurs a much larger number of cases in which the deficiency in vitamin A, without producing the eye disease, is the cause of a diminished resistance to infections’ (Widmark, 1924). Vitamin A became known as the ‘anti-infective’ vitamin, and from 1920 through 1940, vitamin A underwent considerable evaluation in at least 30 clinical trials for infectious diseases at a time when there was heightened awareness of the problem of infant and child mortality in Europe and the United States (Semba, 1999b). During this period, vitamin A therapy was again noted to improve hemoglobin concentrations and reduce anemia in humans (Berglund et al, 1929; Abbott et al, 1939). The League of Nations recognized that vitamin A deficiency contributed to higher mortality rates from infectious diseases, and public health programs were aimed at improving vitamin A status in order to reduce infectious diseases morbidity and mortality (League of Nations, 1936, 1937). Recommendations were also made for the supply of iron salts to pregnant women and anemic infants (League of Nations, 1937).
In 1940, Wagner noted that adults who were given an experimental vitamin A-deficient diet for 6 months developed low hemoglobin and hematocrit (Wagner, 1940). In another study involving volunteer conscientious objectors in England, 16 adults were given a vitamin A-free diet of varying duration from 11 to 24 months (Hume & Krebs, 1949). Although no data were presented, the authors report no apparent abnormalities in hemoglobin, and it is notable that subjects on the vitamin A-free diet received red meat, a rich source of heme iron, throughout the study. Experimental animal studies showed that vitamin A deficiency in the rat (Sure et al, 1929; Frank, 1934) and dog (Crimm & Short, 1937) was characterized by anemia. The provision of vitamin A to deficient rats resulted in a rapid rise in hemoglobin, leading one group of investigators to conclude: ‘blood regeneration cannot take place without the presence of vitamin A’ (Koessler et al, 1926). Further studies in animal models showed a relationship between vitamin A deficiency and anemia. Vitamin A-deficient pony fillies developed decreased hematocrit and red blood count compared to control animals (Donaghue et al, 1981), and vitamin A-deficient rhesus monkeys developed moderate to severe anemia that was correctable with vitamin A treatment (O'Toole et al, 1974). Lower hemoglobin concentrations were found in chicks fed a vitamin A-deficient diet compared with controls (Sklan et al, 1987). Experimental vitamin A deficiency was also associated with an increase in hemoglobin and hematocrit (Sure et al, 1929; McLaren et al, 1965; Nockels & Kienholz, 1967; Corey & Hayes, 1972), a contrasting effect attributed to hemoconcentration and abnormalities of water metabolism during the later stages of vitamin A deficiency (Corey & Hayes, 1972; Mejia et al, 1979).
In 1978, Hodges and colleagues reported the impact of vitamin A deficiency upon hematopoiesis in humans (Hodges et al, 1978). Eight middle-aged male volunteers were given vitamin A-deficient diets of either (1) a liquid casein formula virtually devoid of vitamin A, (2) a solid diet of soy protein, selected vegetables, bread and desserts, all low in vitamin A, and (3) a diet composed of regular foods low in vitamin A. The vitamin A depletion time ranged from 359 to 771 days, with a slow decrease in plasma retinol noted over the depletion period. All men received 18–19 mg of iron daily but mild anemia occurred which was associated with the drop in plasma retinol. Plasma retinol concentrations of >1.05, 0.70–1.05, and <0.70 µmol/l were associated with mean hemoglobin concentrations of 156±5, 129±10 and 118±7 g/l, respectively (P<0.01). Repletion of vitamin A-deficient subjects with either β-carotene or vitamin A was associated with a rise in hemoglobin concentrations. This study provided an important demonstration of the effect of vitamin A deficiency upon anemia in humans and provided much stimulus for the laboratory and epidemiological investigation of anemia and vitamin A deficiency of the last two decades.
A close association between vitamin A deficiency and anemia has been shown in many nutritional surveys from around the world, and perhaps this is not surprising, given the widespread prevalence of nutritional anemia and vitamin A deficiency in developing countries (Bloem, 1995). Most of these epidemiological surveys did not identify the underlying causes of anemia, and often the proportion of subjects with concurrent vitamin A deficiency and anemia are not stated. The surveys generally demonstrate that there is often a high prevalence of vitamin A deficiency and anemia in the same population. The food sources that protect against respective nutritional anemia and vitamin A deficiency overlap somewhat, ie some green vegetables and liver, but in general do not coincide a great deal; thus, it is reasonable to expect that populations at risk of these two nutritional problems would differ.
From 1954 to 1968, more than 30 nutritional and medical surveys were conducted around the world using methods developed by the ICNND (Interdepartmental Committee on Nutrition for National Defense 1963; Hodges et al, 1978). In the nutrition survey from Paraguay, hemoglobin and plasma retinol concentrations were highly correlated, with a correlation coefficient of 0.90 (Interdepartmental Committee on Nutrition for National Defense 1967). Pooled data from surveys conducted in Vietnam, Chile, Brazil, Uruguay, Ecuador, Venezuela, Guatemala and Ethiopia showed a high correlation (r=0.77, P<0.0001) between hemoglobin and plasma retinol concentrations (Hodges et al, 1978). A correlation between hemoglobin and plasma or serum retinol concentrations has been described in many studies, including studies of preschool children from Pakistan (r=0.367, P<0.0001; Molla et al, 1993b), school-aged children in Central America (r=0.209, P<0.05, Majía et al, 1977), school-aged children from Bangladesh (r=0.31, P<0.001; Ahmed et al, 1993), children in India (r=0.52, P<0.001, Mohanram et al, 1977), adolescent girls in Malawi (r=0.161, P=0.08; Fazio-Tirrozzo et al, 1998), and older adults in Vienna (r=0.56, P<0.001)( Wenger et al, 1979). During the second trimester of pregnancy, pregnant women in Malawi had a correlation between plasma vitamin A and hemoglobin concentrations (r=0.256, P<0.0001; Figure 1, Semba et al, unpublished data).
More recent epidemiological studies of vitamin A deficiency and anemia that have been published within the last 15 y are shown in Table 1. Most of the surveys used serum retinol concentrations to assess the presence of vitamin A deficiency in the study population. A high proportion of children in these studies from Brazil, Pakistan, Ethiopia, Micronesia, South Africa, Mexico, Honduras, Bangladesh and Malawi show a relatively high prevalence of vitamin A deficiency. In the same populations, a high prevalence of anemia was also present. Few of the studies actually stated the proportion of subjects with both vitamin A deficiency and anemia. In Honduras, 15.5% of children in a national survey had both vitamin A deficiency and anemia, leading the investigators to conclude that intervention programs targeted exclusively at either vitamin A deficiency or anemia would fail to reach a large proportion of children who had the non-targeted condition (Albalak et al, 2000). Vitamin A deficiency was also common among pregnant women in Malawi and Nepal and, in the same populations, a high prevalence of anemia was found.
Several clinical trials or intervention studies have been conducted which assessed the impact of improved vitamin A status upon hemoglobin and anemia (Table 2). The impact of improving vitamin A status through fortification was addressed in a community-based trial in Indonesia by Muhilal et al (1988). Villages were randomly allocated to receive either unfortified monosodium glutamate (MSG) or vitamin A-fortified MSG for 5 months. In the villages receiving fortified and unfortified MSG, mean hemoglobin concentrations of preschool children changed by +10 and −2 g/l, respectively. In a controlled trial of iron, vitamin A or vitamin A plus iron to anemic children, aged 1–8 y, vitamin A supplementation significantly increased hemoglobin, hematocrit, serum iron, and percentage transferrin saturation, but had no apparent effect on total iron binding capacity or serum ferritin (Mejía & Chew, 1988).
In northeast Thailand, children who received high dose vitamin A, 60 mg retinol equivalent (RE), had higher serum iron and percentage transferrin saturation compared with control children at 2 months post-supplementation, but these differences disappeared by 4 months post-supplementation (Bloem et al, 1989). Further investigation involving school children with conjunctival xerosis showed that children who received 60 mg RE vitamin A had a significant increase in hemoglobin, hematocrit, serum iron and percentage transferrin saturation at 2 weeks following supplementation, whereas no changes of these indicators occurred in the control group (Bloem et al, 1990). In a controlled, clinical trial involving preschool children in Indonesia with clinical and subclinical vitamin A deficiency, vitamin A supplementation, 60 mg RE, was associated with a significant increase of 21 g/l hemoglobin and a significant increase in plasma ferritin among those children who were anemic at enrollment (Semba et al, 1992). A recent study among anemic school children in Tanzania showed that daily vitamin A supplementation was associated with an increase in hemoglobin of 13.5 g/l at 3 months following enrollment, and a larger increase of 22.1 g/l was observed in children who received both vitamin A and iron (Mwanri et al, 2000).
In a study conducted in Bangladesh, women of childbearing age were randomly allocated to receive iron, vitamin A plus iron or vitamin A plus iron and zinc (Kolsteren et al, 1999). Significant increases in hemoglobin were observed only among women who received vitamin A, iron and zinc. The lack of an effect of vitamin A alone upon hemoglobin was attributed to the relative lack of vitamin A deficiency among women in this population. In two parallel clinical trials involving 120 human immunodeficiency virus (HIV)-infected and 120 HIV-negative adult, injection drug users in Baltimore, Maryland, two consecutive doses of vitamin A, 60 mg RE, had no impact upon hemoglobin concentrations (Deloria-Knoll et al, unpublished data). In this population, HIV-positive and HIV-negative subjects had a low prevalence of anemia and vitamin A deficiency and the lack of an effect might also be attributed to the relative lack of anemia and vitamin A deficiency in this population.
Studies conducted among pregnant women suggest that vitamin A supplementation alone during pregnancy can increase hemoglobin concentrations (Suharno et al, 1993). In West Java, Indonesia, 251 anemic pregnant women were randomly allocated to receive iron, 60 mg/day, vitamin A, 2.4 mg RE/day, iron, 60 mg/day plus vitamin A, 2.4 mg RE/day, or placebo for 8 weeks. After supplementation, the proportion of women who were not anemic in the iron, vitamin A, vitamin A plus iron and placebo groups was 68, 35, 97 and 16%, respectively. Other studies have also explored the use of vitamin A combined with iron and or folate (Panth et al, 1990; Chawla & Puri, 1995). In a population with a high prevalence of iron deficiency anemia, weekly vitamin A supplementation reduced anemia by 9% during pregnancy and postpartum compared with controls. A study conducted in Tanzania suggests that daily multivitamins, but not vitamin A, increased hemoglobin concentrations among HIV-positive pregnant women (Fawzi et al, 1998). In Indonesia, pregnant women who received weekly vitamin A and iron supplementation had a greater increase in hemoglobin that women who received weekly iron or daily iron (Muslimatun et al, 2001). There was an accompanying decrease in serum ferritin among women who received vitamin A and iron, suggesting to the investigators that vitamin A supplementation increased the utilization of iron for hematopoiesis.
There are many potential biological mechanisms by which vitamin A deficiency could cause anemia, and a conceptual model is shown in Figure 2 These mechanisms fall into three general categories: (1) modulation of erythropoiesis, (2) modulation of immunity to infectious diseases and the anemia of infection, and (3) modulation of iron metabolism. There is probably some overlap between these mechanisms, as erythropoiesis and iron metabolism are modulated by infection.
The process of red blood cell formation involves the differentiation of pluripotent stem cells into multipotent (colony-forming unit granulocyte erythroid macrophage mixed (CFU-GEMM) cells, and differentiation and commitment of CFU-GEMM into erythroid burst-forming units (BFU-E) and then into erythroid colony-forming units (CFU-E; Gregory & Eaves, 1978). Development of BFU-E into erythroblasts requires stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) and erythropoietin. Development of CFU-E into proerythroblasts requires erythropoietin alone (Migliaccio et al, 1988). Proerythroblasts mature through several stages to orthochromatic erythroblasts, at which stage the nucleus undergoes pyknotic degeneration, and after the nucleus is extruded, the cell is known as a reticulocyte. Hemoglobin synthesis occurs during the differentiation of CFU-E into erythrocyte precursors (Bondurant et al, 1985) and continues until the reticulocyte matures into a mature erythrocyte (Izak et al, 1971). Reticulocytes are released from the bone marrow about 18–36 h prior to final maturation into erythrocytes. Control of erythropoiesis is regulated by erythropoietin, a 34 kDa glycoprotein that is produced by the renal cortical cells in response to hypoxia, and erythropoietin induces erythroid progenitor cells to differentiate into proerythroblasts (Erslev, 1991). In the erythrocyte lineage, CFU-E have the highest density of erythropoietin receptors on their surface and depend upon erythropoietin for their survival (Daniels & Green, 2000).
Retinoids and erythropoiesis
The effects of retinoids on erythroid progenitors has been studied in CD34+ hematopoietic progenitor cells, which consist of a heterogeneous population of CFU-GEMM, BFU-E and CFU-E, and in CD36+ cells, which consist of intermediate and late erythroid progenitors (late BFU-E and CFU-E) in purified erythrocyte systems (Van Schravendijk et al, 1992; Zermati et al, 2000). All-trans retinoic acid was shown to stimulate human BFU-E colony formation, suggesting that retinoids were involved in erythropoiesis (Douer & Koeffler, 1982). All-trans retinol did not enhance growth of erythroid progenitors in this in-vitro culture system that involved fetal calf serum, a rich source of vitamin A (Douer & Koeffler, 1982). Subsequent studies using progenitor cells from human peripheral mononuclear cells in serum free media showed that both retinyl acetate and all-trans retinoic acid stimulated d16 (early) erythroid colonies, and a synergism was noted between retinoids, erythropoietin, and insulin-like growth factor I (IGF-I; Correa & Axelrad, 1992). The impact of retinoids on erythropoiesis is complex and depends upon the stage of erythrocyte development (Perrin et al, 1997).
Retinoids appear to regulate apoptosis, or programmed cell death, in erythropoietic progenitor cells, but the nature of this interaction may be bidirectional (Rusten et al, 1996). All-trans retinoic acid appears to stimulate the survival of purified CD34+ cells obtained from mid-trimester fetal blood (Zauli et al, 1995). In CD34+ hematopoietic progenitor cells isolated from normal adult human bone marrow, all-trans retinoic acid induced apoptosis of CD34+ cells and CD34+CD71+ cells stimulated with erythropoietin (Josefsen et al, 1999). By using selective ligand agonists, it was noted that both RARs and RXRs were involved in RA-mediated apoptosis of erythroid progenitor cells. The effects of retinoids on hematopoiesis are complex and depend on culture conditions, maturation stage of the cells and cytokines used for stimulation. Whether vitamin A status in humans has any influence upon apoptosis of erythropoietic progenitor cells has not been determined. As noted in many of the studies in Table 2, vitamin A supplementation has been generally shown to increase hemoglobin concentrations. Whether retinol, all-trans retinoic acid, and related retinoids mediate their effects in vivo on erythroid progenitor cells is not known.
Modulation of erythropoietin production by retinoids
The 3′-enhancer region for the erythropoietin gene contains a sequence homologous to DR-2, a steroid-responsive element that appears to be regulated by retinoic acid (Okano et al, 1994). In vitamin A-depleted rats, intragastric administration of all-trans retinoic acid was associated with an increase in serum erythropoietin concentrations within 4 h of dosing, but within 24 h, serum erythropoietin concentrations returned to original levels (Okano et al, 1994). Vitamin A, but not vitamin E or vitamin C, was shown to have a dose-related effect on the production of erythropoietin in human hepatoma cell lines HepG2 and Hep3B (Jelkmann et al, 1997). Experimental observations of the modulation of erythropoietin by vitamin A have currently been limited because a renal cell culture model has not been established, and current in-vitro models utilize human hepatoma cell lines. Alternatively, modulation of erythropoietin production by vitamin A has been studied in isolated, perfused rat kidneys, and perfusion with vitamin A or the antioxidant desferrioxamine was shown to increase renal erythropoietin synthesis (Neumcke et al, 1999). Regulation of erythropoietin gene expression appears to involve both hypoxia and reactive oxygen species (Dahgman et al, 1999). Studies in embryonal carcinoma cells suggest that retinoic acid stimulates erythropoietin gene transcription in an oxygen-dependent manner (Kambe et al, 2000).
Recently, a clinical trial was conducted to determine whether vitamin A supplementation would modulate plasma erythropoietin concentrations in pregnant women in Malawi (Semba et al, 2001). Two hundred and three women in the second trimester of pregnancy were randomly allocated to receive daily vitamin A (3 mg retinol equivalent), iron (30 mg), and folate (400 µg) vs iron (30 mg) and folate (400 µg; control). At enrollment, 50% of the women were anemic (hemoglobin <110 g/l). Mean±s.d. change in hemoglobin from enrollment to 38 weeks was 5±12 g/l (P=0.003) and 7±16 g/l (P=0.003) in the vitamin A and control groups, respectively. There were no significant differences between vitamin A and control groups in the slope of the regression line between log10 erythropoietin and hemoglobin at enrollment or 38 weeks, and between enrollment and follow-up within either group. We concluded from this trial that vitamin A supplementation did not influence erythropoietin production and is not a biological mechanism by which vitamin A modulates anemia.
The anemia of infection
The anemia of infection refers to the anemia observed in individuals in the setting of chronic infection, and it is considered a syndrome within the broader category of the ‘anemia of chronic disease’ (Means, 2000). The anemia of infection is a hypoproliferative anemia in which hypoferremia is found despite adequate reticuloendothelial iron stores, and the anemia is usually normocytic and normochromic. Human immunodeficiency virus infection (Semba & Gray, 2001) and tuberculosis (Morris et al, 1989) are two well-known causes of the anemia of infection. Anemia is also common in children with acute infections ( Jansson et al, 1986). Inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interferon gamma (IFN-α) have been implicated in the anemia of infection, as they appear to interfere with erythropoiesis (Murphy et al, 1988). TNF-α and IFN-γ also appear to induce hypoferremia and increase ferritin production (Feelders et al, 1998). Human recombinant TNF-α inhibited CFU-E from bone marrow mononuclear cells but not CFU-E generated from human peripheral mononuclear cells, suggesting that TNF-α inhibited CFU-E through an accessory cell in bone marrow, and marrow fractionation studies suggested that a bone marrow stromal cell was responsible for the inhibitory effect of TNF-α on CFU-E (Means et al, 1990).
Other biological mechanisms that may contribute to the anemia of infection include shortened red cell survival, impaired erythropoietin production in response to anemia, inhibited response of erythroid progenitors to erythropoietin, and increased apoptosis of erythroid progenitors (Means et al, 2000). Iron mobilization from reticuloendothelial iron stores is reduced during the anemia of infection, and decreased serum iron in the setting of infection is well known and implicated in the host response against infection (Kluger & Rothenburg, 1979). As described below, decreased mobilization of iron from the liver and spleen also occurs during vitamin A deficiency, and it is not entirely clear whether the same phenomenon during the anemia of infection is related (Thurnham, 1993; Bloem, 1995). Although it has been hypothesized that vitamin A may modulate the acute phase response, and thus retinol-binding protein and transferrin, a controlled clinical trial in Indonesia did not show any effect any effect of vitamin A supplementation, 60 mg RE, on acute phase proteins (α1-acid glycoprotein and C-reactive protein) when given to preschool children with clinical and subclinical vitamin A deficiency (Semba et al, 2000b).
Vitamin A and immune modulation
Vitamin A plays an important role in immune function (Semba, 1998) and in reducing the morbidity and mortality of some infectious diseases, such as diarrheal disease, measles, tuberculosis and malaria (Semba, 1999a). Thus, a potential mechanism by which vitamin A could reduce anemia is through an impact upon the anemia of infection. Recent clinical trials have examined the impact of vitamin A supplementation or fortification on infectious disease morbidity and mortality (Villamor & Fawzi, 2000), but less attention has been given to anemia as a clinical outcome. A recent randomized, placebo-controlled clinical trial was conducted in Papua New Guinea to examine the effects of vitamin A supplementation, 60 mg RE every 3 months, on malarial morbidity in preschool children (Shankar et al, 1999). Vitamin A supplementation reduced the incidence of malaria attacks by 20–50%, but the impact of vitamin A supplementation on anemia was unclear, as the study did not address the point prevalence of anemia within the first few weeks of vitamin A supplementation. Although it seems reasonable to speculate that vitamin A enhances immunity, reduces infection and hence the anemia of infection, there is little data available to support this hypothesis directly.
Vitamin A and iron metabolism
There are several lines of evidence to show that vitamin A modulates iron metabolism (West & Roodenburg, 1992). In experimental animal models, vitamin A deficiency increased iron concentrations in the liver (Mejia et al, 1979; Staab et al, 1984; Sklan et al, 1987; Beynen et al, 1992; Sijtsma et al, 1993) spleen (Mejia et al, 1979; Roodenburg et al, 1994), and femur (Beynen et al, 1992). During vitamin A deficiency, iron absorption appeared to be enhanced (Roodenburg et al, 1994; Sijtsma et al, 1993) and bone marrow uptake of iron impaired (Sijtsma et al, 1993). In vitamin A-deficient rats, the incorporation of 59Fe in erythrocytes was reduced by 40–50% compared with control animals, suggesting that during vitamin A deficiency, iron is trapped in the liver and spleen and not effectively released for erythropoiesis by bone marrow (Mejia et al, 1979; Gardner et al, 1979). Vitamin A repletion in deficient rats stimulated the utilization of iron stores in spleen and bone (Roodenburg et al, 1996). Vitamin A deficiency did not affect the osmotic fragility of erythrocytes in vitamin A-deficient rats, providing some evidence against increased hemolysis as a mechanism for anemia during vitamin A deficiency (Gardner et al, 1979; Hodges, 1978), and recent studies show that erythropoiesis and erythrocyte turnover were not affected by mild vitamin A deficiency in rats (Roodenburg et al, 2000).
Poor vitamin A status has been associated with low iron binding capacity and percent transferrin saturation (Mejia & Arroyave, 1983; Bloem et al, 1989), but not low circulating transferrin concentrations (Mejia & Arroyave, 1983). Iron metabolism was examined in a large study of preschool children, age 1–5 y, before and after a program of vitamin A-fortified sugar (Mejia & Arroyave, 1982). Two years after vitamin A fortification, indicators of iron status, such as serum iron, percentage transferrin saturation and ferritin concentrations, increased. A recent study suggests that gut integrity in infants, as measured by a urinary lactulose:mannitol excretion test, is influenced by vitamin A supplementation (Thurnham et al, 2000), and these findings suggest another mechanism by which vitamin A status could affect the absorption of nutrients involved in erythropoiesis. In studies using cereal-based diets with labelled 59Fe or 55Fe, both vitamin A and beta-carotene enhanced the absorption of nonheme iron in human adults (García-Casal et al, 1998).
Many developing countries have adopted programs aimed at reducing vitamin A deficiency (World Health Organization, 1995), but the impact of these programs on anemia has not been addressed. Nutritional surveys clearly indicate that a high prevalence of vitamin A deficiency and a high prevalence of anemia usually occur together in the same population. What would be the global impact of improving vitamin A status on anemia? From the data from the Honduras survey, it appears that interventions targeted at vitamin A deficiency alone may only eliminate a proportion of the anemia (Albalak et al, 2000), given the proportion of children with anemia but no vitamin A deficiency. In the same populations at risk for vitamin A deficiency, there are likely to be other concomitant vitamin deficiencies that may cause anemia (Fishman et al, 2000). With the current, available data, it is not possible to make a good estimate of how the elimination of vitamin A deficiency would impact the prevalence of anemia in developing countries.
The evidence that vitamin A deficiency causes anemia through modulation of iron metabolism is strong and supported by observations from both experimental animal models and human studies. The hypothesis that vitamin A deficiency contributes to anemia through depressed immunity to infection and an increase in the anemia of chronic disease is reasonable, but there is a paucity of data to support this idea directly. Most of the controlled clinical trials of disease-targeted vitamin A supplementation have not examined anemia as a outcome measure and, in retrospect, measurement of hemoglobin, hematocrit and iron status indicators would have been fairly easy to include. It is unclear whether vitamin A supplementation modulates circulating proinflammatory cytokines that are known to have a negative effect on erythropoiesis, such as TNF-α and IFN-γ.
The laboratory picture of the anemia of vitamin A deficiency has not been fully characterized and has been described as hypochromic (Bloem, 1995) or microcytic and hypochromic (Oski, 1995). The red cell indices may not be consistent during the anemia of vitamin A deficiency because of other factors, including iron deficiency, malaria, other infections and medications. Severe vitamin A deficiency alone in rats produced a microcytic, hypochromic polycythemia, whereas simultaneous vitamin A and iron deficiencies produced a normocytic, hypochromic anemia (Amine et al, 1970). The anemia of acute malaria is generally a normocytic, normochromic anemia (Wickramasinghe & Abdalla, 2000). Medications that may complicate the interpretation of red cell indices include trimethoprim, a widely used antibiotic that can cause a megaloblastic anemia (Magee et al, 1981), isoniazid and pyrazinamide, tuberculosis medications that can cause a sideroblastic anemia (Sharp et al, 1990), and chloroquine, which may suppress erythropoietin production (El Hassan et al, 1997).
Although vitamin A deficiency is a cause of anemia, further work is needed to characterize both the pathogenesis and public health importance of ‘vitamin A deficiency anemia’. Nutritional surveys should address the prevalence of concomitant vitamin A deficiency and anemia, and surveys are needed to gain insight into other underlying social, behavioral and economic factors that contribute to vitamin A deficiency and anemia. The consequences of vitamin A deficiency and anemia on the household, community, and country level need clarification. Further basic hematological studies are needed to characterize the red cell indices in different populations with vitamin A deficiency and anemia. In disease-targeted vitamin A interventions, the potential modulation of TNF-α, IFN-γ and other cytokines needs to be addressed. It may be useful for vitamin A program evaluations to include anemia as an outcome measure. Finally, consideration should be given to community-based trials of multi-micronutrient supplementation as a strategy to reduce anemia in both children and women in developing countries.
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Financial support for this study came from: The National Institute of Child Health and Human Development (HD32247, HD30042), the National Institute of Allergy and Infectious Diseases (AI41956), and the Fogarty International Center, the National Institutes of Health, and the United States Agency for International Development (Cooperative Agreement HRN A-0097-00015-00).
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Semba, R., Bloem, M. The anemia of vitamin A deficiency: epidemiology and pathogenesis. Eur J Clin Nutr 56, 271–281 (2002). https://doi.org/10.1038/sj.ejcn.1601320
- retinoic acid
- vitamin A
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