contents
Abstract ... 142 Overview ... 142 Iron ... 143 Iron Status ... 144 Zinc ... 144 Zinc Status ... 145 Selenium ... 146 Selenium Status ... 147 Thiamin ... 147 Thiamin Status ... 148 Folic Acid ... 148 Folic Acid Status ... 150 Vitamin B12... 150 Vitamin B12 Status ... 151 Vitamin A ... 151 Vitamin A Status ... 153 Vitamin D ... 153 Vitamin D Status ... 154 Other Nutrients ... 154 Nutrient Interactions ... 155 Malnutrition ... 156 Reductive Adaptation ... 156 Stunting ... 157 Wasting ... 157 Edematous Malnutrition ... 158 Global Burden of Disease ... 158 Conclusions ... 159 Study Topics ... 159 Note ... 160 References ... 160
AbstRAct
Essential nutrients vary enormously in their body content and requirements. They are each crucial for normal metabolism, they interact with one another, and they act differently when metabolism is altered by either nutrient deficiencies or excesses or by disease. Their deficiencies can also affect the metabolism of invading microor-ganisms. In poverty, numerous nutrient deficiencies and numerous infections coexist and are synergistic, forming a vicious spiral that leads to malnutrition. The most common form of this, affecting about half the children living in poverty in the devel-oping world, is chronic stunting. It is preventable. This chapter focuses on nutri-ent deficiencies and their effects. Specific micronutrinutri-ents, important to health, are included: iron, zinc and vitamin A, which have deficiencies that together appear to be responsible for nearly 20% or 2 million deaths a year in young children; folic acid and vitamin B12, which also contribute to the ubiquitous problem of anemia;
and selenium, thiamin, and vitamin D as examples for which we have learned much from history and geography. For each nutrient, advice is given on estimation of nutri-ent status. For several nutrinutri-ents, however, the tests available are not yet sufficinutri-ently specific. Zinc is an example; we still have no reliable measure of its status for either clinical use or population studies. Finally, the major problem of childhood malnutri-tion is outlined. Our knowledge and understanding of nutrient metabolism is sparse, but still progressing.
oveRvIew
Among other challenges, poverty means inadequate intakes of monotonous diets of poor quality (imbalance of essential nutrients, excessive antinutrients or toxins).
One meal may be the only meal possible. If it is breast milk for a young infant, then dietary quality is excellent for the first 6 months. However, in poverty in much of the developing world, the meal may only be maize meal porridge for all age groups.
This represents poor quality, being deficient in several essential nutrients (e.g., lysine and zinc) and rich in antinutrients (e.g., phytate). Poverty also dictates that meals are often contaminated, especially when fed from a bottle to an infant.
The almost inevitable consequence is frequent infections and malnutrition. These become a vicious spiral: Malnutrition reduces barriers and resistance to infections, and the consequent increased severity and duration of infections exacerbates malnutrition.
What has this to do with micronutrient deficiencies? It is obvious to all that mal-nourished children receive too little dietary energy and protein. However, not so obvious are the needs for and roles of individual essential nutrients, including micro-nutrients, the vitamins and essential trace elements (Geissler and Powers 2006).
When a diet is of good quality and adequate quantity and provided hygienically to an individual in good health, then the risks of deficiencies or toxicities of ents are minimized. In the face of poverty, the risks of deficiency of many micronutri-ents are enormous. However, our knowledge of the world population’s micronutrient status is poor, as is our diagnosis and management of individual deficiencies. This is, among other reasons, because of:
ignorance of risk factors for specific micronutrient deficiencies
•
ignorance and lack of reliable tests for status of specific micronutrients
•
inability to interpret such tests
•
lack of understanding of factors affecting supply and distribution of
micro-•
nutrients within the body
lack of understanding of needs and roles of micronutrients and how these
•
change with nutritional status and disease
reductive adaptation, by which nutrient deficiency limits growth and
there-•
fore nutrient requirements (World Health Organization 1999a)
The chapter is devoted mainly to a few micronutrient deficiencies for which we have some knowledge and less understanding. Our knowledge comes from historical writ-ings, geographic differences, scientific basic studies, and human intervention studies.
IRon
Iron, in humans, is the most abundant of the essential trace elements, comprising around 5 g of an adult. It is mainly in hemoglobin in red blood cells. Iron deficiency is purported to be the most prevalent of all deficiencies. This is because anemia, as we define it, based on blood concentration of hemoglobin, is very common, espe-cially in late infancy and pregnancy. Are our definitions of anemia correct? Are the low hemoglobins all because of iron deficiency? We know the answer to the second question is “No.” In large-scale studies in infants and young children, much of the anemia was not associated with low iron stores (Duque et al. 2007).
Malaria is common and causes hemolytic anemia. Hemoglobin is not lost; its iron is retrieved and reused. Thus, iron available for hemoglobin synthesis may be adequate even though the anemia may be severe. Other infections are also associated with a decrease in blood hemoglobin concentration without loss of iron.
Folic acid, vitamin B12, and vitamin A deficiencies (discussed separately) are rela-tively common causes of anemia in young children.
In severely malnourished children, the red blood cell picture tends to be mixed, showing signs of multiple deficiencies often compounded by malaria and other infec-tions. Less-malnourished children comprise the vast majority of children living in poverty. Their anemias tend also to be less severe but probably no less complex, affected by multiple nutrient deficiencies and infections.
In pregnancy, hemodilution and major changes in nutrient transport and metabo-lism occur; anemia is common even using a lower cutoff for hemoglobin concentra-tion. Lactation is more clearly a drain on iron reserves.
Anemia in the elderly, as in malnourished children, tends to show a mixed pic-ture, often with less evidence of iron than vitamin deficiencies.
Thus, all anemia is not due to iron deficiency but there is little doubt that it is com-mon. Why? There is no shortage of iron in the Earth’s crust. However, inorganic iron and ferric salts are very poorly absorbed by humans. The form of iron that is most bioavailable to us is that found in animal tissues, within heme. Most of the world’s children consume very little in the way of animal tissues. Most today have not been exclusively breastfed—breast milk iron is also absorbed well. Iron in plants is mostly
as ferric salts. Thus, it is likely that iron deficiency is very common in young children and detrimental to their health and development (see Chapters 11 and 12).
Iron toxicity is usually considered only from iron overdose, as in toddlers con-suming their mother’s iron supplements or patients on excess oral or parenteral iron or having numerous blood transfusions. Iron absorption is normally highly con-trolled at the intestinal level. However, hemochromatosis is an inherited disorder in which iron absorption is increased, and the resultant excess stored iron causes organ damage, particularly in the liver, pancreas, testis and heart. Surprisingly, it was found that plasma ferritin, a measure of iron stores, was very high in severely malnourished children, especially those with edematous malnutrition and those who died (Srikantia 1958). This could be due to an acute-phase response in which iron is normally sequestered in the liver. However, there is little evidence of such a host response to infection in these ill children. The high plasma ferritin is more likely to reflect genuine iron overload. This implies the risk of “free” iron available for both the growth of pathogens and to act as a prooxidant, possibly responsible for general-ized cell damage, via lipid peroxidation of membranes (Golden and Ramdath 1987).
Therefore, iron therapy is contraindicated in the early management of severely mal-nourished children (World Health Organization [WHO] 1999a).
iron status
Anemia prevalence is not a good measure of the extent of the problem. The same is true for plasma iron concentration. This is affected, more often than not, by the presence of an acute-phase response, usually to invasion by bacteria, viruses, and the like as described. As part of this, circulating iron is bound to proteins within the liver so plasma iron decreases. Iron stores, mainly in the liver, can be estimated indi-rectly by measuring plasma ferritin concentration. However, this increases during an acute-phase response. Thus, a “normal” value may have been a low value before the child developed pneumonia, for example. Finally, another indirect measure of iron status is the plasma concentration of transferrin receptor. An increase in this protein implies that the iron supply for hemoglobin synthesis in the bone marrow is deficient.
It is supposed to be independent of an acute-phase response, but this is unlikely.
In conclusion, iron status is probably best assessed today by measuring iron stores (plasma ferritin) when there is no evidence of an acute-phase response.
zInc
Zinc is half as abundant as iron in the body. Whereas iron is required for a few pro-teins, zinc is ubiquitous: It is required for the structure or function of at least 200 metalloenzymes, within cytoplasm, nucleus, and membranes (Hallberg et al. 2000).
Without zinc, neither cell hyperplasia, requiring DNA synthesis, nor hypertrophy, requiring protein synthesis, can occur.
When a zinc-deficient diet is fed to rats, they experience fluctuating anorexia, with spells of reasonable intake separated by spells of very poor intake; their growth is severely restricted. When such a diet is force-fed to rats, they die within only a few days.
In human diets, zinc accompanies protein; it is almost impossible to provide a protein-deficient diet that is not zinc deficient (Golden and Golden 1981). Zinc is highly available from breast milk and animal protein. Before the cause of acroder-matitis enteropathica, an inherited defect of intestinal zinc absorption, was discov-ered, it was treated effectively with breast milk.
In poverty, most of the monotonous plant-based diets contain little zinc but much phytate, which further reduces intestinal absorption of zinc. Many millions of infants and children grow less quickly than their genetic potential for many reasons. One reason is zinc deficiency; the extent of its contribution is unclear but may be consid-erable in, for example, rural India. When it limits growth, the children are smaller and require less zinc. This is an example of reductive adaptation. Providing zinc as a supplement allows growth to resume, but this can only continue while there is suf-ficient energy and all other essential nutrients to sustain it. As the child grows, more of everything is required.
The effects of zinc deficiency are, like zinc itself, ubiquitous. They appear first in tissues with normally high turnover rates. Thus, intestinal mucosal function suffers:
Malabsorption is general and permeability is increased. Diarrhea, or enteropathica, is the clinical outcome. Skin epithelium, the epidermis, thins, and it becomes less effective as a barrier. Wound healing is also impaired. Minor trauma, which tends to occur around orifices and on extremities, leads to chronic skin lesions, or acro-dermatitis. These features manifest themselves late; before this, the child will have
“adapted” to a low-zinc diet by not growing and hence not requiring so much. There are other costs of this adaptation. Not only are the barriers to infection reduced, but also the ability to exhibit either nonspecific immunity, in the form of inflammation or an acute-phase response, or specific immunity, especially cell-mediated immu-nity, is reduced. Infections pass unnoticed because of the lack of clinical signs (of the child’s response); they are not treated, and the child suffers severe, prolonged morbidity and much increased mortality from infections that were initially relatively innocuous. Zinc deficiency is rarely diagnosed in such circumstances.
zinC status
One of the most important and fascinating aspects of zinc in human health is that even today, it is almost impossible to assess zinc status reliably “in the field.” It cannot be done on clinical grounds because the effects of its deficiency are nonspecific, growth failure, until very advanced. It cannot be done easily in the laboratory. Kinetic studies using stable isotopes are probably the gold standard but are confined to the research laboratory. Hair zinc analysis is fraught with methodological difficulties, and neither plasma nor cell zinc concentrations inform zinc status reliably. A retrospective diag-nosis of zinc deficiency can be made following a positive effect of a period of zinc supplementation. This has led to large-scale zinc supplementation studies of infants and children with various infections. In most, a positive effect has been demonstrated (Umeta et al. 2000, Brooks et al. 2005). However, it is clear that, as with studies of several other micronutrients, effects are seen if deficiencies are made good, but not if the subjects are not deficient in the first place. Indeed, although zinc toxicity
effects are rare, in one study these may have accounted for increased mortality in the supplemented group (Doherty et al. 1998). More is not necessarily better.
selenIum
Selenium was a little-known trace element in human health until recently, when two questions came under scrutiny: the role of oxidative stress in disease and the cause of Keshan disease.
Selenium is essential for the pivotal antioxidant glutathione peroxidase. This enzyme helps protect cells from the damaging effects of oxidation, for example, by ultraviolet radiation of skin, by exogenous toxins in the liver, or from any excess of
“normal” oxidative processes that are used, for example, to damage and kill invading bacteria. Glutathione peroxidase acts on lipid peroxides and hydrogen peroxide to produce harmless hydroxy acids and water, respectively (Geissler and Powers 2006).
In the 1980s, the “free-radical” theory of the etiology of edematous malnutrition was supported by evidence of deficiencies in several antioxidant systems, including glutathione peroxidase (Golden and Ramdath 1987). Since then, evidence has accu-mulated for a role of oxidative stress in several other common, chronic diseases, such as atherosclerosis and arthritis.
Keshan disease was described to the Western world also in the 1980s. It is charac-terized by a cardiomyopathy present in thousands of youngish women and children living in a specific region in southwest China in which soil selenium is particu-larly low. In large studies, selenium supplements appeared to prevent, although not treat, the disease. Later, it was observed that there were temporal fluctuations in Keshan disease (Geissler and Powers 2006). Enteroviruses were implicated, espe-cially Coxsackie virus B4. This led to mouse experiments in which it was shown that increased oxidative stress, induced by deficiency of either selenium or vitamin E in mice infected with nonvirulent Coxsackie virus (B3/0), could induce mutations in the virus, causing it to become virulent (Beck et al. 2003). Indeed, high intakes of polyunsaturated fatty acids (PUFAs) or iron had similar effects, also explained by increased oxidative stress. Thus, it appears that Keshan disease is not a direct effect of selenium deficiency; rather, it is due to the effect of oxidative stress on infecting viruses. This shows how complex interactions are, not only between micronutrients themselves, but also between micronutrients and human metabolism and even the metabolism of invading microorganisms.
Another pair of interesting selenoenzymes are thyrodoxin and iodothyronine deiodinase. Both are involved in thyroid metabolism, which of course is also highly dependent on iodine supply.1 Selenium deficiency exacerbates the effects of iodine deficiency (Geissler and Powers 2006). In the face of both deficiencies, giving iodine without selenium does not adequately treat the features of iodine deficiency disor-ders (IDD). This was also observed in south China, where the iodine-deficient belt overlaps the selenium-deficient belt.
Another important role of selenium, also related to its antioxidant function, is in prevention of a variety of malignancies, including the increasingly common pros-tate cancer.
Thus, this micronutrient is indeed essential for optimal health. However, its physi-ological range of intake is small. Intakes only three to four times higher are associ-ated with physical signs of toxicity. Excess selenium is excreted in breath as dimethyl selenide, and hair, skin, and nail lesions occur (Geissler and Powers 2006). This suggests that at lower intakes, closer to physiological, metabolism may also be dis-turbed. Thus, yet again, it is important that the public are not led to believe that more is necessarily better in terms of selenium supplements.
seLenium status
Selenium status is best estimated from red blood cell selenium concentration or glu-tathione peroxidase activity or content. They are generally closely related to one another and reflect status over the previous few months, the average life of red blood cells. Plasma selenium tends to fluctuate widely in relation to meals.
thIAmIn
Clinical thiamin deficiency, or beriberi, was probably first described in 2600 B.C.
However, it came to the fore relatively recently, at the end of the nineteenth century, mainly in Eastern and South Eastern Asia, when rice was first effectively milled, yielding polished white rice. This became the sole diet of poor, laboring populations in China and Japan, and epidemics of beriberi followed. It was not a problem in Africa while traditional root crops or maize remained the staple (WHO 1999b).
Studies were performed in several isolated groups, including sailors and those in mental institutes and labor camps. They were fed largely rice and developed beriberi.
It was shown that this could be prevented by providing either other foods as well as rice, or unpolished rice, or just by adding the otherwise discarded polishings them-selves. Thus, it became clear that an essential nutrient was in the discarded polish-ings. Thereafter, in 1926, the water-soluble, heat-labile vitamin was isolated and 10 years later was given its chemical formula and name, thiamin (Williams 1961).
Since then, there have continued to be many outbreaks of thiamin deficiency from which we have learned much. Usually, they have been in poor communities living mainly on polished rice. However, the same disease has occurred in other isolated groups living mainly on white bread made from highly milled wheat. Wernicke-Korsakov syndrome, which was initially described in the 1880s, occurs in a small proportion of thiamin-deficient alcoholics, those who have an inherited abnormal-ity of the enzyme transketolase, which prevents its binding to thiamin diphosphate (WHO 1999b). An alcohol diet means a high carbohydrate diet, and this requires a higher-than-usual thiamin intake; alcohol also inhibits the intestinal absorption of thiamin. Recently, beriberi was diagnosed in northeastern Thailand, but thiamin intake appeared to be adequate; however, antithiamin factors, in the raw, fermented fish that they ate and the betel nuts that they chewed, tipped the balance toward deficiency (Vimokesant et al. 1975). There have also been several recent outbreaks of beriberi in refugee camps. Again, the underlying problem has been a monoto-nous diet of poor quality, with inadequate thiamin relative to other nutrients. Finally, although breastfeeding provides the best-quality diet for an infant, when that infant’s
mother is thiamin deficient, her breast milk does not supply sufficient thiamin for her infant, and the consequence is beriberi.
Beriberi varies considerably in presentation. Chronic low-grade beriberi is easily overlooked. It is probably common in malnourished communities in which many
Beriberi varies considerably in presentation. Chronic low-grade beriberi is easily overlooked. It is probably common in malnourished communities in which many