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Populations at risk for, and consequences of, vitamin A deficiency 2.2.1 Definition of vitamin A deficiency VAD is not easily defined. WHO defines it as tissue concentrations of vitamin A low enough to have adverse health consequences even if there is no evidence of clinical xerophthalmia (16). In addition to the specific signs and symptoms of xerophthalmia and the risk of irreversible blindness, nonspecific symptoms include increased morbidity and mortality, poor reproductive health, increased risk of anaemia, and contributions to slowed growth and development. However, these nonspecific adverse effects may be caused by other nutrient deficits as well, making it difficult to attribute non-ocular symptoms specifically to VAD in the absence of biochemical measurements reflective of vitamin A status. 2.2.2 Geographic distribution and magnitude In 1995, WHO estimated the global distribution of VAD (Table 2.1) and categorized countries according to the seriousness of VAD as a public health problem on the basis of both clinical and moderate and severe subclinical (prevalence of low blood levels of retinol) indicators of deficiency (16, 17). It was estimated that about 3 million children have some form of xerophthalmia and, on the basis of blood levels, another 250 million are subclinically deficient (17). The magnitude of the subclinical estimate is currently being re-evaluated to establish quantitatively a benchmark for measuring prevalence trends. The actual number of subclinical deficiencies based on the prevalence of low serum levels of retinol, however, remains uncertain because P017-044 3/12/05 16:56 Page 20 of the confounding and poorly quantified role of infections (see section 2.2.5). Epidemiological studies repeatedly report clustering of VAD, presumably resulting from concurrent occurrences of several risk factors. This clustering may occur among both neighbourhoods and households (18). 2.2.3 Age and sex VAD can occur in individuals of any age. However, it is a disabling and potentially fatal public health problem for children under 6 years of age. VADrelated blindness is most prevalent in children under 3 years of age (19). This period of life is characterized by high requirements for vitamin A to support rapid growth, and the transition from breastfeeding to dependence on other dietary sources of the vitamin. In addition, adequate intake of vitamin A reduces the risk of catching respiratory and gastrointestinal infections. The increased mortality risk from concurrent infections extends at least to 6 years of age and is associated with both clinical and subclinical VAD (20). There is little information regarding the health consequences of VAD in school-age children. The prevalence of Bitot’s spots (i.e. white foamy patches on the conjunctiva) may be highest in this age group but their occurrence may reflect past more than current history of VAD (21). Women of reproductive age are also thought to be vulnerable to VAD during pregnancy and lactation because they often report night blindness (22, 23) and because their breast milk is fre2. VITAMIN A 21 TABLE 2.1 Estimates of clinical and subclinical vitamin A deficiency in preschool children, by WHO regiona Subclinical (severe Clinical and moderate) Prevalence Region (millions) (millions) (%) Africa 1.04 52 49 The Americas 0.06 16 20 South-East Asia 1.45 125 69 Europe NA NA NA Eastern Mediterranean 0.12 16 22 Western Pacific 0.13 42 27 Subtotal 2.80 251 Total 254 NA, not applicable. a Based on a projection for 1994 from those countries in each region where data were available. Source: adapted from reference (17). P017-044 3/12/05 16:56 Page 21 VITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION 22 quently low in vitamin A (24, 25). Not all night blindness in pregnant women, however, responds to vitamin A treatment (23). There is no consistent, clear indication in humans of a sex differential in vitamin A requirements during childhood. Growth rates, and presumably the need for vitamin A, from birth to 10 years for boys are consistently higher than those for girls (26). In the context of varied cultural and community settings, however, variations in gender-specific child-feeding and care practices are likely to subsume a small sex differential in requirements to account for reported sex differences in the prevalence of xerophthalmia. Pregnant and lactating women require additional vitamin A to support maternal and fetal tissue growth and lactation losses, additional vitamin A which is not needed by other post-adolescent adults (27). 2.2.4 Risk factors VAD is most common in populations consuming most of their vitamin A needs from provitamin carotenoid sources and where minimal dietary fat is available (28). About 90% of ingested preformed vitamin A is absorbed, whereas the absorption efficiency of provitamin A carotenoids varies widely, depending on the type of plant source and the fat content of the accompanying meal (29). Where possible, an increased intake of dietary fat is likely to improve the absorption of vitamin A in the body. In areas with endemic VAD, fluctuations in the incidence of VAD throughout the year reflect the balance between intake and need. Periods of general food shortage (and specific shortages in vitamin A-rich foods) coincide with peak incidence of VAD and common childhood infectious diseases (e.g. diarrhoea, respiratory infections, and measles). Seasonal food availability influences VAD prevalence directly by influencing access to provitamin A sources; for example, the scarcity of mangoes in hot arid months followed by the glutting of the market with mangoes during harvest seasons (30). Seasonal growth spurts in children, which frequently follow seasonal post-harvest increases in energy and macronutrient intakes, can also affect the balance. These increases are usually obtained from staple grains (e.g. rice) and tubers (e.g. lightcoloured yams) that are not, however, good sources of some micronutrients (e.g. vitamin A) to support the growth spurt (31). Food habits and taboos often restrict consumption of potentially good food sources of vitamin A (e.g. mangoes and green leafy vegetables). Culturespecific factors for feeding children, adolescents, and pregnant and lactating women are common (28, 32–34). Illness- and childbirth-related proscriptions of the use of specific foods pervade many traditional cultures (35). Such influences alter short- and long-term food distribution within families. However, P017-044 3/12/05 16:56 Page 22 some cultural practices can be protective of vitamin A status and they need to be identified and reinforced. 2.2.5 Morbidity and mortality The consequences of VAD are manifested differently in different tissues. In the eye, the symptoms and signs, together referred to as xerophthalmia, have a long, well-recognized history and have until recently been the basis for estimating the global burden from the disease (19). Although ocular symptoms and signs are the most specific indicators of VAD, they occur only after other tissues have impaired functions that are less specific and less easily assessed. The prevalence of ocular manifestations (i.e. xerophthalmia or clinical VAD) is now recognized to far underestimate the magnitude of the problem of functionally significant VAD. Many more preschool-age children, and perhaps older children and women who are pregnant or lactating, have their health compromised when they are subclinically deficient. In young children, subclinical deficiency, like clinical deficiency, increases the severity of some infections, particularly diarrhoea and measles, and increases the risk of death (20, 36). Moreover, the incidence (37) and prevalence (38) of diarrhoea may also increase with subclinical VAD. Meta-analyses conducted by three independent groups using data from several randomized trials provide convincing evidence that community-based improvement of the vitamin A status of deficient children aged 6 months to 6 years reduces their risk of dying by 20–30% on average (20, 39, 40). Mortality in children who are blind from keratomalacia or who have corneal disease is reported to be from 50% to 90% (19, 41), and measles mortality associated with VAD is increased by up to 50% (42). Limited data are available from controlled studies of the possible link between morbidity history and vitamin A status of pregnant and lactating women (43). There are discrepancies in the link between incidence and severity of infectious morbidity of various etiologies and vitamin A status. A great deal of evidence supports an association of VAD with severity of an infection once acquired, except for respiratory diseases, which are non-responsive to treatment (16, 36–38, 44). The severity of pneumonia associated with measles, however, is an exception because it decreases with the treatment of vitamin A supplementation (42, 45). Infectious diseases depress circulating retinol and contribute to vitamin A depletion. Enteric infections may alter the absorptive surface area, compete for absorption-binding sites, and increase urinary loss (7, 46, 47). Febrile systemic infections also increase urinary loss (6, 48) and metabolic utilization 2. VITAMIN A 23 P017-044 3/12/05 16:56 Page 23 VITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION 24 rates and may reduce apparent retinol stores if fever occurs frequently (49). In the presence of latent deficiency, disease occurrence is often associated with precipitating ocular signs (50, 51). Measles virus infection is especially devastating to vitamin A metabolism, adversely interfering with both efficiencies of utilization and conservation (42, 51, 52). Severe protein–energy malnutrition affects many aspects of vitamin A metabolism, and even when some retinyl ester stores are still present, malnutrition—often coupled with infection—can prevent transport-protein synthesis, resulting in immobilization of existing vitamin A stores (53). The compromised integrity of the epithelium, together with the possible alteration in hormonal balance at severe levels of deficiency, impairs normal reproductive functions in animals (9, 14, 15, 24, 54, 55). Controlled human studies are, of course, lacking. In animals and humans, congenital anomalies can result if the fetus is exposed to severe deficiency or large excesses of vitamin A at critical periods early in gestation (first trimester) when fetal organs are being formed (24, 56). Reproductive performance, as measured by infant outcomes, in one community-based clinical intervention trial, however, was not influenced by vitamin A status (43). The growth of children may be impaired by VAD. Interventions with vitamin A only have not consistently demonstrated improved growth in community studies because VAD seldom occurs in isolation from other nutrient deficiencies that also affect growth and may be more limiting (57). A lack of vitamin A can affect iron metabolism when deficiencies of both nutrients coexist and particularly in environments that favour frequent infections (58). Maximum haemoglobin response occurs when iron and vitamin A deficiencies are corrected together (59). VAD appears to influence the availability of storage iron for use by haematopoietic tissue (59, 60). However, additional research is needed to clarify the mechanisms of the apparent interaction. 2.3 Units of expression In blood, tissues, and human milk, vitamin A levels are conventionally expressed in mg/dl or mmol/l of all-trans-retinol. Except for postprandial conditions, most of the circulating vitamin A is retinol whereas in most tissues (such as the liver), secretions (such as human milk), and other animal food sources, it exists mainly as retinyl esters, which are frequently hydrolysed before analytical detection. To express the vitamin A activity of carotenoids in diets on a common basis, a Joint FAO/WHO Expert Group (61) in 1967 introduced the concept P017-044 3/12/05 16:56 Page 24 of the retinol equivalent (RE) and established the following relationships among food sources of vitamin A: 1 mg retinol = 1 RE 1 mg b-carotene = 0.167 mg RE 1 mg other provitamin A = 0.084 mg RE. carotenoids These equivalencies were derived from balance studies to account for the less efficient absorption of carotenoids (at that time thought to be about one third that of retinol) and their bioconversion to vitamin A (one half for b-carotene and one fourth for other provitamin A carotenoids). It was recognized at the time that the recommended conversion factors (i.e. 1:6 for vitamin A:bcarotene and 1:12 for vitamin A:all other provitamin carotenoids) were only best approximations for a mixed diet, which could under- or overestimate bioavailability depending not only on the quantity and source of carotenoids in the diet, but also on how the foods were processed and served (e.g. cooked or raw, whole or puréed, with or without fat). In 1988, a Joint FAO/WHO Expert Consultation (62) confirmed these conversion factors for operational application in evaluating mixed diets. In reaching its conclusion, the Consultation noted the controlled depletion–repletion studies in adult men using a dark adaptation endpoint that reported a 2:1 equivalency of supplemental bcarotene to retinol (63), and the range of factors that could alter the equivalency ratio when dietary carotenoids replaced supplements. Recently there has been renewed interest in re-examining conventional conversion factors by using more quantitative stable isotope techniques for measuring whole-body stores in response to controlled intakes (64–66) and by following post-absorption carotenoids in the triacylglycerol-rich lipoprotein fraction (67–70). The data are inconsistent but suggest that revision toward lower absorbability of provitamin A carotenoids is warranted (64, 68, 69). These studies indicate that the conditions that limit carotenoids from entering enterocytes rather than conversion once in the enterocyte are more significant than previously thought (71). Other evidence questions the validity of factors used earlier, which suggests that 6mg of food-sourced b-carotene is equivalent to 2mg pure bcarotene in oil, and equivalent to 1mg dietary retinol. Currently, however, only one study has used post-absorptive serum carotenoids to directly compare, in healthy, adequately nourished adult humans in Holland, the absorption of carotene in oil with that of dietary b-carotene from a mixed diet predominately containing vegetables (72). The investigators reported that 2. VITAMIN A 25 P017-044 3/12/05 16:56 Page 25 VITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION 26 about 7mg of b-carotene from the mixed predominately vegetable diet is equivalent to 1mg pure b-carotene when it is provided in oil. Assuming that 2mg b-carotene in the enterocyte is equivalent to 1mg retinol, the conversion factor would be 1:14 for b-carotene and 1:28 for other provitamin A carotenoids. Other researchers using a similar methodology have reported factors from a variety of specific food sources that fall within this range. Lowest bioavailability is reported for leafy green vegetables and raw carrots and highest for fruit/tuber diets (68, 73–75). In view of the data available to date, conversion factors from usual mixed vegetable diets of 1:14 for bcarotene and 1:28 for other provitamin A carotenoids as suggested by Van het Hof et al. (72) are recommended. Where green leafy vegetables or fruits are more prominent than in the usual diet in Holland, adjustment to higher or lower conversion factors could be considered. For example, in the United States of America where fruits constitute a larger portion of the diet, the Food and Nutrition Board of the Institute of Medicine suggests retinol activity equivalency (RAE) factors of 12:1 for b-carotene and 24:1 for other provitamin A carotenoids (76). Retinol equivalents in a diet are calculated as the sum of the weight of the retinol portion of preformed vitamin A plus the weight of b-carotene divided by its conversion factor, plus the weight of other provitamin A carotenoids divided by their conversion factor (62). Most recent food composition tables report b-carotene and, sometimes, other provitamin A carotenoids as mg/g edible portion. However, older food composition tables frequently report vitamin A as international units (IUs). The following conversion factors can be used to calculate comparable values