Anaemia and iron deficiency disease in children

Transcription

1 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 Correspondence to: Manuel Olivares, Institute of Nutrition and Food Technology (INTA), University of Chile, Macul 5540, Casilla 138, Santiago 11, Chile 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 pregnancy 1. 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 due mainly to a low intake in bioavailable iron. However, in this setting, iron deficiency co-exists with other conditions such as, protein/energy malnutrition, vitamin A deficiency, folate deficiency, and infection 2 " 5. In tropical regions, parasitic infestation and haemoglobinopathies are also common 3-5 The prevalence of these pathologies is higher in less British Medical Bulletin 1999; 55 (No. 3): C The British Council 1999

2 Iron deficiency in children 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 absorbed 6. 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) begins 7. 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. 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 British Medical Bulletin 1999;55 (No. 3) 535

3 Micronutrients in health and disease factors that affect iron absorption occur: the body iron stores and the rate of erythropoiesis 8. 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 ions 11. 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 iron 12. 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-iron 13. 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 diet 14. 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 countries 15. 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 536 British Medical Bulletin 1999,55 (No. 3)

4 Iron deficiency in children 260 D ie t A D ie t B Vit.A Vit.C F olate Iro n Zinc 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 Fola 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 formulae 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 corn 18. 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 British Medical Bulletin 1999;55 (No. 3) 537

5 Micronutrients in health and disease 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). 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 deficiency 20 " 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 concentration 22. 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 supplementation " 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 538 British Medial Bulletin 1999;55 (No. 3)

6 Iron deficiency in children 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 metabolism Kahn et al studied a group Pakistani children, of whom 16% had low serum vitamin A and 2% were deficient 21 : 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 metabolism 24. 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 infection 26. Garci'a-Casal et al have shown the enhancer effect of vitamin A and P- carotene on non-haem iron absorption from Venezuelan cereal-based diets 27. Vitamin A increased iron absorption up to 2-fold for rice, 0.8- fold 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. 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 allergy Alaskan natives have shown a high prevalence of iron British Medial Bulletin 1999;55 (No. 3) 539

7 Micronutrients in health and disease deficiency anaemia despite an adequate iron intake. This population has an increased frequency of elevated stool haem concentration 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 fish 30, or caused by chronic active gastritis associated Helicobacter pylori infection 31. In tropical areas, pathologic bleeding due to infestation with parasites is a contributing factor to nutritional iron deficiency 3 " 5. Hookworms (Necator atnericanus and Ancylostoma duodenale) are the most prevalent parasites related to iron deficiency 32. 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, respectively 33. In areas endemic for urinary schistosomiasis, blood loss due to haematuria is a cofactor to the development of iron deficiency 34. Iron, inflammation and infection Acute or chronic inflammatory diseases are a well-recognised cause of mild to moderate anaemia 35. This reduction in haemoglobin level is due to several factors 36 : (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 infection 36. 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 significantly 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 illness The modifications of laboratory indicators of iron status are related to the severity of the inflammatory process 40. Changes in iron status parameters are more prominent in subjects with increased C reactive protein, high band counts, or fever above 38 C Proper diagnosis of iron status is based primarily on multiple laboratory measures. However, in populations where infections are prevalent, classic 540 British Medical Bulletin 1999;55 (No. 3)

8 Iron deficiency in children Inflammation/infection (-) E u m IV (6-11 mo.) (12 mo.) (12-69 mo.) 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 al 3 *, 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 processes 38 ' 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 it 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. References 1 DeMacyer E, Adiels-Tegman M. The prevalence of anaemia in the world. World Health Stat Q 1985; 38: Florentino RF, Guirriec RM. Prevalence of nutritional anemia in infancy and childhood with emphasis on developing countries. In: Stekel A (Ed) Iron nutrition in infancy and childhood. Vevey/New York: Nestle/Raven Press, 1984: Fleming AF. Iron deficiency in the tropics. Clin Haematol 1982; 2: Masawe AEJ. Nutritional anaemias. Part 1. Tropical Africa. Clin Haematol 1981; 3: Baker SJ. Nutritional anaemias. Pan 2. Tropical Asia. Clin Haematol 1981; 3: Stekel A, Olivares M, Pizarro F, Chadud P, Lopez I, Amar M. Absorption of fortification iron from milk formulas in infants. Am J Clin tiutr 1986; 43: Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990; 75: Charlton RW, Bothwell TH. Iron absorption. Annu Rev Med 1983; 34: British Medical Bulletin 1999;55 (No. 3) 541

9 Micronutrients in health and disease 9 Rossander-Hulthen L, Hallberg L. Dietary factors influencing iron absorption - an overview. In: Hallberg L, Asp N-G (Eds) Iron Nutrition in Health and Disease. London: John Libbey, 1996; Hallberg L, Brunt M, Rossander L. Iron absorption in man: ascorbic acid and dose dependent inhibition by phytate. Am J Clin Nutr 1989; 49: Wood JR, Han O. Recently identified molecular aspects of intestinal iron absorption. / Nutr 1998; 128: Olivares M, Hertrampf E, Pizarro F. Effect of iron stores on heme iron absorption. Nutr Res 1993; 13: Hallberg L, Bjorn-Rasmussen E, Howard L. Dietary haem iron absorption. A discussion of possible mechanisms for the absorption-promoting effect of meat and for the regulation of iron absorption. Scand ] Gastroenterol 1979; 14: Pizarro F, Yip R, Dallman PR, Olivares M, Hertrampf E, Walter T. Iron status with different feeding regimens: relevance to screening and prevention of iron deficiency. / Pediatr 1991; 118: Yip R, Walsh KM, Goldfarb MG, Binkin NJ. Declining prevalence of anemia in childhood in a middle-class setting: a pediatnc success story? Pediatrics 1987; 80: Hertrampf E, Olivares M, Pizarro F, Walter T. High absorption of fortification iron from current infant formulas. / Pediatr Gastroenterol Nutr 1998; 27: Walter T, Pino P, Pizarro F, Lozoff B. Prevention of iron-deficiency anemia: comparison of highand low-iron formulas in term healthy infants after six months of life. / Pediatr 1998; 132: 635^*0 18 Uauy R, Oyarziin MT. Food based approaches to meet vitamin and mineral needs: possibilities and limitations. Background paper to Joint FAO/WHO consultation on human vitamin and mineral requirements. Bangkok, Thailand, September 21-30, FAO/WHO. Preparation and use of food-based dietary guidelines. Report of a Joint FAO/WHO consultation. Nicosia, Cyprus: WHO, Suharno D, West CE, Muhilal B et al. Cross-sectional study on the iron and vitamin A status of pregnant women in West Java, Indonesia. Am ] Clin Nutr 1992; 56: Khan I, Baseer A. Hematologic effect of vitamin A supplementation in anemic Pakistani children. / Pak Med Assoc 1996; 46: Roodenburg AJ, West CE, Hovenier R, Beynen AC. Supplemental vitamin A enhances the recovery from iron deficiency in rats with chronic vitamin A deficiency. Br J Nutr 1996; 75: Mejia LA, Chew F. Hematological effect of supplementing anemic children with vitamin A alone and in combination with iron. Am J Cltn Nutr 1988; 48: Bloem MW, Wedel M, van Agtmaal EJ et al. Vitamin A intervention: short-term effects of a single, oral, massive dose on iron metabolism. Am] Clin Nutr 1990; 51: Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet 1993; 342: Northrop-Clewes CA, Paracha PI, McLoone UJ, Thurnham DI. Effect of improved vitamin A status on response to iron supplementation in Pakistani infants. Am J Clin Nutr 1996; 64: Garria-Casal MN, Layrisse M, Solano L, et al. Vitamin A and [}-carotene can improve nonheme iron absorption from rice, wheat and corn by humans. / Nutr 1998; 128: Ziegler EE, Fomon SJ, Nelson SE et al. Cow milk feeding in infancy: further observations on blood loss from the gastrointestinal tract./ Pediatr 1990; 116: Walter T, Hertrampf E, Arredondo M. Gastrointestinal iron losses in infancy: effect of the diet. In: Hercberg S, Galan P, Dupin H (Eds) Recent Knowledge on Iron and Folate Deficiencies in the World. Colloque INSERM Vol 197, Paris: INSERM, 1990; Petersen KM, Parkinson AJ, Nobmann ED, Bulkow L, Tip R, Mokdad A. Iron deficiency anemia among Alaska natives may be due to fecal loss rather than inadequate intake. / Nutr 1996; 126: Yip R, Limburg PJ, Ahlquist DA et al. Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency. Role of Helicobacter pylori gastritis. JAMA 1997; 277: British Medical Bulletin 1999;55 (No. 3)

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