Anaemia and iron deficiency disease in children

Manuel Olivares, Tomds Walter, Eva Hertrampf and Fernando Pizarro

Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile

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Iron deficiency is the single most common nutritional disorder world-wide and the main cause of anaemia in infancy, childhood and pregnancy. It is prevalent in most of the developing world and it is probably the only nutritional deficiency of consideration in industrialised countries. In the developing world the prevalence of iron deficiency is high, and is due mainly to a low intake of bioavailable iron. However, in this setting, iron deficiency often co-exists with other conditions such as, malnutrition, vitamin A deficiency, folate deficiency, and infection. In tropical regions, parasitic infestation and haemoglobinopathies are also a common cause of anaemia. In the developed world iron deficiency is mainly a single nutritional problem. The conditions previously mentioned might contribute to the development of iron deficiency or they present difficulties in the laboratory diagnosis of iron deficiency.

Iron deficiency is the single most common nutritional disorder world-wide and the main cause of anaemia in infancy, childhood and pregnancy. It is prevalent in most of the developing world and it is probably the only nutritional deficiency of consideration in industrialised countries. Because of their high iron requirements, the most commonly affected groups are infants, children, adolescents, and women of childbearing age and pregnancy1. In the developing countries, the prevalence is usually greatest in infants and to a lesser extent in women; in contrast, in industrialised countries, it is present mainly in women due to the additional iron requirements imposed by menstruation and pregnancy. In the developing world, the prevalence of iron deficiency is high, and is Correspondence to: Manuel Olivares, due mainly to a low intake in bioavailable iron. However, in this setting, Institute of Nutrition and iron deficiency co-exists with other conditions such as, protein/energy Food Technology (INTA), malnutrition, vitamin A deficiency, folate deficiency, and infection2"5. In University of Chile, Macul 5540, Casilla 138, tropical regions, parasitic infestation and haemoglobinopathies are also 3-5 Santiago 11, Chile The prevalence of these pathologies is higher in less common
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developed countries than in areas with intermediate development. In the developed world iron deficiency is mainly a single nutritional problem. The conditions previously mentioned might contribute to the development of iron deficiency or they present difficulties in the laboratory diagnosis of iron deficiency.

Aetiology and pathogenesis of iron deficiency

Nutritional factors are the most frequent causes of iron deficiency in infancy and childhood. The main aetiologies of iron deficiency at this period of the life cycle are: (i) decreased iron stores at birth (preterm infants, twins, perinatal bleeding, early clamping of umbilical cord) (ii) inadequate iron supply (reduced dietary iron and/or low bioavailability of dietary iron); (iii) increased iron requirements imposed by growth; and (iv) increased iron losses (gastrointestinal blood loss, diarrhoea). Iron requirements of infants are not covered by their usual diet, which is mainly based on milk. This problem is more severe in children fed cows' milk, where the iron present is poorly absorbed6. Infants who are fed cows' milk starting in early infancy and those who are fed milk that is not iron fortified are at highest risk for the development of iron deficiency. The situation becomes critical when iron stores at birth are reduced. In older children, because of their slower growth rate and their more varied diet, nutritional iron deficiency anaemia is less prevalent (when present it is usually carry-over from earlier infancy) while other aetiologies become more prevalent, gastrointestinal blood loss among them. When dietary iron cannot fulfil the requirements, a fall in body stores occurs (iron depletion), which is characterised by a drop in serum ferritin (SF) below 12 ng/1. If this negative balance persists, iron tissue availability is compromised (iron deficient erythropoiesis). At this stage, an early progressive rise in the concentration of serum transferrin receptor (TfR) values occurs, followed by an increase in free erythrocyte protoporphyrin (FEP), a decrease in transferrin saturation (Sat), and the slow fall in haemoglobin (Hb) begins7. If the iron deficit continues, the last stage becomes evident when Hb falls below -2 standard deviations for that given population, i.e. iron deficiency anaemia.

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Dietary iron absorption

The amount of iron absorbed from the diet is dependent on three factors: (i) the quantity of iron; (ii) the composition of the diet; and (iii) the behaviour of the mucosa of the upper small bowel where two major
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factors that affect iron absorption occur: the body iron stores and the rate of erythropoiesis8. The effect of the composition of the diet is based on: the type of iron (haem or non-haem); amount of haem iron, specially as meat, the content of calcium in the meal, food preparation (time, temperature), iron status of the individual, amount of potentially available non-haem iron (adjustment for fortification iron and contamination iron) and the balance between enhancing (ascorbic acid, meat/poultry/fish, fermented foods) and inhibiting factors (phytate, polyphenols, calcium, soy protein). There are two kinds of iron in the diet with respect to the mechanism of absorption haem iron and non-haem iron utilising two different receptors on the mucosal cells. After the uptake of haem iron into the mucosal cells, the porphyrin ring is split by the haem-oxygenase within the cells and its iron is released. Non-haem and haem iron then have a common pathway and leave the mucosal cells in the same chemical form, utilising the same transfer system to the serosal side of the mucosal cells. Receptors on the luminal side probably compete for non-haem iron with complexing luminal ligands for the iron ions11. Haem iron in meat and meat products constitute about 5-10% of the daily iron intake in most industrialised countries. In developing countries, the haem iron content of diets is usually negligible. Its absorption is less influenced by body iron stores than non-haem iron12. The average absorption of haem iron in meat containing meals is about 25%, calcium being the only dietary factor that negatively influences the absorption of haem-iron13. Non-haem iron is the main form of dietary iron. The main sources are cereals, vegetables, pulses, beans, fruits, etc. The absorption of iron from iron fortificants and contamination iron is influenced by the same host and dietary factors as the native iron. Studies of iron absorption from various representative meals have been done primarily in adults, but the results are also pertinent to the mixed diet in late infancy. Absorption of non-haem iron from a mixed meal is about 4 times greater when the major protein source is meat, fish or chicken in comparison to the dairy products, milk, cheese or eggs. Term infants are protected from iron deficiency by their endowment at birth and the iron supply from breast milk during the first 6 months of life. The basis for the excellent absorption of iron from human milk is not known. From this age on, iron status is mainly dependent on iron sources in the diet14. The increasing use of iron fortified formulae and iron rich weaning foods have determined a decrease of iron deficiency anaemia among infants in highly developed countries15. The appropriate level of iron to fortify formulae is still under discussion. Recent evidence shows a high iron bioavailability in these products, which is a compelling argument for lowering the level of iron fortification in North
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260

D ie t A D ie t B

Vit.A

Vit.C

F olate

Iro n

Zinc Downloaded from http://bmb.oxfordjournals.org/ by guest on January 29, 2012

Fig. 1 White rice based diets: percentage of recommended nutrient density per 1000 kcal. Diet A composition: white rice 598 g and vegetable oil 25 g. Diet B composition: white rice 428 g, vegetable oil 25 g, carrots 21 g, orange 60 g, beef 35 g, spinach raw 50 g, and lentils 45 g. Recommended nutrient density of micronutrients was based on the recommendations of the FAO/WHO".
D ie t A D ie t B

Vit.A

Vit.C

F o l a te

Iron

Zinc

Fig. 2 Corn-tortilla based diets: percentage of recommended nutrient density per 1000 kcal. Diet A composition: corn-tortilla 368 g and vegetable oil 25 g. Diet B composition: corn-tortilla 266 g, vegetable oil 20 g, carrots 21 g, orange 60 g, beef 55 g, spinach raw 50 g, and black beans 45 g. Recommended nutrient density of micronutrients was based on the recommendations of the FAO/WHO".

American formulae1617. Home prepared complementary foods, based on cereals and legumes fed to weanlings in the less developed world where most of the children younger than 2 years reside, contain relatively high levels of phytic acid and negligible amounts of ascorbic acid or meat. School-age children and adolescents at a global level are affected by several micronutrient deficiencies, because at presently staple foods such as wheat, rice, corn or potatoes make up the largest proportion of the food supply. Uauy and Oyarzun explored the adequacy of food patterns based predominantly in rice and corn18. Theoretical diets were developed and complemented with low cost micronutrient rich foods. The food portion size considered in this exercise represent the usual amount eaten
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in a meal or provided by a 1000 kcal food tray. Vitamin A, vitamin C, folate, iron and zinc were selected. The nutrient density of plain rice and corn plus a regular portion of vegetable oil as a fat source was analysed. The content of selected micronutrients was computed per 1000 kcal. As shown in Figures 1 and 2 in terms of percentage recommended nutrient density, both diets provide no vitamins A or C, and very low levels of folates, iron and zinc. Following a food based approach to improve the micronutrient content of the diets, small portions of carrots, orange, beef, spinach, and lentils or black beans were added. In both cases, all micronutrient needs were covered (Figs 1 & 2).
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Interactions between iron and vitamin A

Vitamin A is important not only for visual function but also for normal differentiation of various tissues. Early reports demonstrated anaemia and reduction in haemopoietic tissue in severe vitamin A deficiency. Thereafter, an array of epidemiological studies have shown that vitamin A deficiency and anaemia often co-exist and that there is significant association between retinol and biochemical indicators of iron deficiency20"21. There are several hypotheses to explain this interrelation: (i) that improving vitamin A status improves mobilisation of iron from the tissue stores; (ii) that vitamin A decreases infection and thus improves iron status; and (iii) that vitamin A improves iron absorption. It is of interest to note that interactions are found only in vitamin A deficient populations and no demonstration of these effects has been shown in vitamin A sufficient subjects. Animal experiments show that supplemental vitamin A enhances the recovery from iron deficiency in rats with chronic vitamin A deficiency. Vitamin A supplementation during the period of iron treatment produced a depletion of spleen and tibia iron concentration22. Other authors found also decreased liver iron in a similar experiment. Supplemental vitamin A also produced a reduction of Hb probably explained by a decrease in the degree of haemoconcentration seen in vitamin A deficiency. These studies in experimental animals suggest that supplemental vitamin A during iron repletion contributes to optimum erythropoeisis and iron mobilisation when baseline vitamin A status is impaired. Several studies in anaemic children and pregnant women in endemic vitamin A deficient regions have shown a beneficial effect on iron status with vitamin A supplementation21-23"25. Mejfa and Chew in Guatemala studied 99 children, 1-8 years of age, divided in 4 groups 23 . Each group was supplemented for 2 months with: (i) vitamin A; (ii) iron; (iii) vitamin A plus iron; or (iv) placebo. Vitamin
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A elevated retinol, Hb, serum iron (Fe) and Sat. Iron alone did not affect retinol but improved haematological and iron nutrition indicators including total iron binding capacity (TIBC) and SF. The concomitant supplementation of vitamin A and iron resulted in a better response of Fe and Sat saturation than either alone. This study suggested that vitamin A benefits haematological condition and iron metabolism. Two studies showed the effect of a single oral massive dose of vitamin A on iron metabolism21-24. Kahn et al studied a group Pakistani children, of whom 16% had low serum vitamin A and 2% were deficient21: 42 children were supplemented with a single oral vitamin A dose and 53 children received placebo. After 6 weeks, there were significant differences between the 2 groups for retinol, retinol binding protein and haematocrit (Htc). However, no significant difference could be found for Hb, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin concentration, Fe, transferrin, and SF. In the another study, a group of 134 school children, with signs of conjunctival xerosis, from Thailand were selected for a controlled study on the short-term effect of a single, oral high dose of vitamin A on iron metabolism24. Children within villages were randomly assigned to receive the vitamin A or serve as control subjects. Two weeks after supplementation, significant increases of retinol, retinol binding protein, Hb, Htc, Fe, and Sat were found in the supplemented group. SF concentrations did not change significantly. These two studies provide further evidence of a causal association between vitamin A and iron metabolism. The anti-infective properties of vitamin A are well known, and there is some suggestion that the benefits of vitamin A on iron status may be do to reduced level of infection26. Garci'a-Casal et al have shown the enhancer effect of vitamin A and Pcarotene on non-haem iron absorption from Venezuelan cereal-based diets27. Vitamin A increased iron absorption up to 2-fold for rice, 0.8fold for wheat and 1.4-fold for corn; |3-carotene increased absorption more than 3-fold for rice and 1.8-fold for wheat and corn. The authors suggested that both compounds prevented the inhibitory effect of phytates and polyphenols on iron absorption, because both compounds may form a complex with iron, keeping it soluble in the intestinal lumen.

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Pathological blood loss

The digestive tract is the most frequent source of occult bleeding. Gastrointestinal blood loss may occur during the first months of life when infants are fed fresh or pasteurised cows' milk, or during repeated episodes of acute diarrhoea, or less frequently, in cows' milk protein allergy28-29. Alaskan natives have shown a high prevalence of iron
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deficiency anaemia despite an adequate iron intake. This population has an increased frequency of elevated stool haem concentration30-31. The gastrointestinal blood loss has been attributed to an altered platelet function due probably a high intake of (n-3) fatty acid from marine mammals and fish30, or caused by chronic active gastritis associated Helicobacter pylori infection31. In tropical areas, pathologic bleeding due to infestation with parasites is a contributing factor to nutritional iron deficiency3"5. Hookworms (Necator atnericanus and Ancylostoma duodenale) are the most prevalent parasites related to iron deficiency32. These haematophagous intestinal parasites produce intestinal blood loss that is proportional to the parasitic load. When faeces contain 1000 eggs/g, daily blood loss is 2 ml (1 mg of iron) if the infection is due to N. atnericanus, the corresponding figures for A. duodenale and Trichiuris trichiura infestations are 4 ml and 0.25 ml, respectively33. In areas endemic for urinary schistosomiasis, blood loss due to haematuria is a cofactor to the development of iron deficiency34.

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Iron, inflammation and infection

Acute or chronic inflammatory diseases are a well-recognised cause of mild to moderate anaemia35. This reduction in haemoglobin level is due to several factors36: (i) a block in iron release from the reticuloendothelial system and a reduction in iron intestinal absorption, with the consequent reduction on iron available for erythropoiesis; (ii) inhibition of erythropoiesis; (iii) inappropriate erythropoietin production; and (iv) reduction of erythrocyte survival. Immunoactivation releases cytokines that are mainly responsible for the changes on iron metabolism, inhibition of eythropoiesis and lower erytropoietin production observed in inflammation or infection36. Acute infections are very frequent in childhood, especially in subjects of low socio-economic strata of developing countries. Even mild infections that do not warrant medical consultation induce a significant decrease in Hb, Fe, TIBC, and Sat, whereas, FEP and SF increase significantly37-38. Most of the changes in iron laboratory indices persist for 2-3 weeks after the appearance of fever, and some measures may become abnormal even during the incubation period of the illness37-39. The modifications of laboratory indicators of iron status are related to the severity of the inflammatory process40. Changes in iron status parameters are more prominent in subjects with increased C reactive protein, high band counts, or fever above 38C38-40. Proper diagnosis of iron status is based primarily on multiple laboratory measures. However, in populations where infections are prevalent, classic

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Inflammation/infection

(-)

E u m

IV
(6-11 mo.) (12 mo.) ( 1 2 - 6 9 mo.)

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Studies
Fig. 3 Prevalence of anaemia in children with and without inflammations/infections. Data of studies I, II, III, and IV were taken from Olivares et al3*, Jansonn et al*\ Reeves et at*2, and Freire et a/*3, respectively.

iron measures might underestimate or overestimate the prevalence of iron deficiency depending on the measure used. Figure 3 shows the results of several studies in which the prevalence of anaemia in subjects with and without inflammation/infection was studied. The prevalence of anaemia was overestimated in subjects with clinical and/or laboratory evidence of inflammatory or infectious processes38'41"43. TfR assay has been shown to be useful in evaluating iron status in these populations, since acute or chronic infection or inflammation does not affect it44-45. In the absence of this indicator, the interpretation of iron status measures should be made with caution in populations or individuals during or shortly after an inflammatory process.

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