Vitamin A is a nutrient of global importance. Shortages in its consumption are estimated to affect as many as 140 million children worldwide, some 90% of whom live in Southeast Asia and Africa. Vitamin A deficiency results in a clinical eye disease (xerophthalmia) and whilst the incidence has declined in recent years it is estimated that around five million children remain affected by night blindness. If untreated, two-thirds of those children die within months of going blind owing to their increased susceptibility to infections enhanced by the deficiency. Hence, Vitamin A deficiency still remains the single most important cause of childhood blindness in developing countries. But deficiency is not simply a condition of childhood as it is estimated that of the 19 million pregnant women in developing countries are also vitamin A-deficient; a third are affected by night blindness. Subclinical vitamin A deficiency in this population is also associated with increased child morbidity and mortality, with recent intervention trials suggesting that providing vitamin A can reduce child mortality by about 25%, and birth-related maternal mortality by 40% (1).
Deprivation of vitamin A also impairs vital functions that can be life-threatening (e.g., corneal destruction, infection, stunted growth). Collectively, these vital functions have been referred to as the systemic functions in which vitamin A acts much like a hormone. Chief among the systemic functions of vitamin A is its role in the differentiation of epithelial cells. It is well documented that vitamin A-deficient individuals (humans or animals) experience replacement of normal mucus-secreting cells by cells that produce keratin, particularly in the conjunctiva and cornea of the eye, the trachea and the skin. It appears that retinoids affect cell differentiation through actions analogous to those of the steroid hormones.
Most of the preformed vitamin A in the diet is in the form of retinyl esters which are hydrolyzed in the lumen of the small intestine to yield retinol. The retinyl esters, as well as the carotenoids, are hydrophobic, and thus depend on incorporation of micelles for their dispersion in the aqueous environment of the small intestine. For this reason, vitamin A is poorly utilized from low-fat diets. The major sources of vitamin A activity for most populations are the provitamin A carotenoids. Their utilization involves three steps:
Release from food matrices-A major factor limiting the utilization of carotenoids from food sources is their release from physical food matrices. Carotenoids can occur in complexes where they can be associated with proteins, polysaccharides, fibres, and phenolic compounds. Many carotenoid complexes are resistant to digestion without heat treatment.
Micelle formation in the intestine-The absorption of carotenoids depends on their incorporation into micelles, the formation of which requires the consumption and digestion of lipids. Absorption, particularly of the less water soluble carotenoids, can be impaired by the presence of undigested lipids or sucrose polyesters in the intestine. Gastric acidity may also be a factor, as patients taking omeprazole showed reduced blood responses to test doses of β-carotene.
Uptake by the intestinal mucosa- The process appears to be impaired by soluble dietary fibre and, likely, other factors that interfere with the contact of the micelle with the mucosal brush border. Limited evidence suggests that carotenoids may be mutually competitive during absorption. For example, high doses of canthoxanthin or lycopene have been shown to reduce the absorption of β-carotene.
In healthy individuals, plasma retinol is maintained within a narrow range in spite of widely varying intakes of vitamin/provitamin A. The liver and kidneys appear to play important roles in this process. Indeed, renal dysfunction has been shown to increase plasma retinol levels. Serum retinol levels can also be affected by nutrition status with respect to zinc. Plasma levels of carotenoids, in contrast, do not appear to be regulated; they reflect intake of carotenoid-rich foods. Careful studies have revealed, however, cyclic changes of up to nearly 30% in the plasma β-carotene concentrations during the menstrual cycles of women. Whether these fluctuations are physiologically meaningful or whether they relate to fluctuations in plasma lipids is not clear.
The appreciable storage of vitamin A in the body tends to mitigate against the effects of low dietary intakes of the vitamin, as tissue stores are mobilized in response to low-vitamin A conditions. However, because there are effectively two pools of vitamin A in the body, the rate of mobilization varies between tissues according to their respective proportions of fast-turnover and slow-turnover pools. Vitamin A deficiency can occur either because of a lack of both provitamins A and preformed vitamin A in diets (primary vitamin A deficiency), or because of failures in their physiological utilization (secondary vitamin A deficiency). Primary vitamin A deficiency can occur among children and adults who consume diets composed of few servings of yellow and green vegetables and fruits, and of liver. Secondary vitamin A deficiency can occur in several ways. Either chronically impaired enteric absorption of lipids, such as in pancreatitis, cystic fibrosis, nutritional selenium deficiency or bile production and release, or due to the consumption of diets containing very low amounts of fat. Chronic exposure to oxidants can also induce vitamin A depletion; an example is benzo(α)pyrene in cigarette smoke. Nutritional deficiencies of zinc can also impair the absorption, transport, and metabolism of vitamin A, as zinc is essential for the synthesis of RBP4 in the liver. Malnourished populations, which typically have low intakes of several essential nutrients, including vitamin A and zinc, are at risk of vitamin A deficiency.
Vitamin A functions in many organs of the body. However, the only unequivocal signs of vitamin A deficiency are the ocular lesions and xerophthalmia. The lesions cause a disorder of dark adaptation of the retina that can take a year to develop after the initiation of a vitamin A-deficient diet, but responds rapidly to vitamin A treatment. The latter disorder involves permanent changes of the anterior segment of the eye that are not correctable without scarring. Early intervention is very important in cases of xerophthalmia in order to interrupt the progressive lesions in early stages before permanent blindness occurs.
Because vitamin A is stored in appreciable amounts in the liver, it can be administered in relatively large, infrequent doses with efficacy. In cases of clear or suspected xerophthalmia, particularly in communities in which the deficiency is prevalent, vitamin A is administered orally in large doses, followed by an additional dose the next day and a third a few weeks later. Night blindness due to vitamin A deficiency responds within hours to days upon the administration of vitamin A, although full recovery of visual function may take weeks, and the fading of retinal lesions may take up to three months.
Four aspects of vitamin A metabolism tend to protect against hypervitaminosis:
- Relatively inefficient conversion of the provitamins A in the gut
- The unidirectional oxidation of the vitamin to a form (retinoic acid) that is rapidly catabolized and excreted
- A relative excess capacity to bind retinol
- Accelerated vitamin A catabolism.
Hypervitaminosis A therefore requires high exposures. Chronic hypervitaminosis A occurs with recurrent exposures exceeding 12,500 IU (infants) to 33,000 IU (adult).
Retinoids can be toxic to maternally exposed embryos – a fact that limits their therapeutic uses and raises concerns about the safety of high-level vitamin A supplementation for pregnant animals and humans. This is especially true for 13-cis-retinoic acid, which is very effective in the treatment of acne but can cause severe birth.
The critical period for foetal exposure to maternally derived retinoids is when organogenesis is occurring – i.e., before many women suspect they are pregnant. Foetal malformations of cranial–neural crest origin have been reported in cases of oral use of all-trans-retinoic acid in treating acne vulgaris and of regular prenatal vitamin A supplements in humans. The latter have generally been linked to daily exposures at or above 20,000–25,000 IU. A retrospective epidemiologic study reported an increased risk of birth defects associated with an apparent threshold exposure of about 10,000 IU of preformed vitamin A per day; however, the elevated risk of birth defects was observed in a small group of women whose average intake of the vitamin exceeded 21,000 IU/day.
The toxicities of carotenoids are considered low, and circumstantial evidence suggests that β-carotene intakes of as much as 30 mg/day are without side effects other than the accumulation of the carotenoid in the skin, with consequent yellowing of the skin (carotenodermia). Regular, high intakes of β-carotene can lead to accumulation in fatty tissues, and thus to this condition. An intervention study with a small number of subjects showed that a daily intake of 30 mg of β-carotene from carotene-rich foods produced carotenodermia within 25–42 days of exposure; the effect persisted for at least 14 days, and in some cases for more than 42 days, after cessation of carotene exposure. It appears that under highly oxidative conditions β-carotene can yield oxidative breakdown products that can diminish retinoic acid signalling by interfering with the binding of retinoic acid to RAR. This effect has been proposed as the basis for the finding that a regular daily dose of β-carotene increased lung cancer risk among smokers.
Sources of Vitamin A
Vitamin A exists in natural products in many different forms. It exists as preformed retinoids, which are stored in animal tissues, and as provitamin A carotenoids, which are synthesized as pigments by many plants and are found in green, orange, and yellow plant tissues. In milk, meat, and eggs, vitamin A exists in several forms, mainly as long-chain fatty acid esters of retinol, the predominant one being retinyl palmitate. Carotenoid pigments are widespread among diverse animal species, with more than 500 different compounds estimated. About 60 of these have provitamin A activity, i.e., those that can be cleaved by animals to yield at least one molecule of retinol. In practice, however, only five or six of these provitamins A are commonly encountered in foods.
Owing to the fact that vitamin A exists in foods in many different preformed retinoids and provitamin A carotenoids, the reporting of vitamin A activity in foods requires some means of standardization. Two systems are used for this purpose: retinol equivalents (RE) for food applications, and international units (IU) for pharmaceutical applications. It is clear that β-carotene from plant foods is utilized with much poorer efficiency than has been previously thought. This appears to be especially the case in resource-poor countries in which children rely almost entirely on the conversion of β-carotene from fruits and vegetables for their vitamin A. In such circumstances, several factors may reduce that bioconversion efficiency: low fat intakes, intestinal roundworms, recurrent diarrhoea, and these factors may reduce by more than half the expected bioconversion of plant carotenoids. Although several foods contain vitamin A activity; relatively few are rich dietary sources, the best being green and yellow vegetables, liver, oily fishes, and vitamin A-fortified products such as margarine. It should be noted that, for vitamin A and other vitamins that are susceptible to breakdown during storage and cooking, values given in food composition tables are probably high estimates of amounts actually encountered in practical circumstances.
The bioconversion of carotenoids to vitamin A has been found experimentally to vary considerably from around 10% to 90%. Variation has also been apparent in practical circumstances, as not all interventions with vegetables have produced improvements in vitamin A status of deficient individuals (2).
Retinol is transferred from mother to infant through milk. The retinol A content of milk is a function of two factors: the stage of lactation, and the vitamin A status of the mother. Human breast milk from well nourished, vitamin A-adequate mothers typically drops by a third from that in colostrum compared to mature milk. These levels are enough to meet the infant’s immediate metabolic needs while also supporting the development of adequate vitamin A stores. Such an infant will consume, over the first 6 months of life, nearly 60 times as much vitamin A from breast milk than it accumulated throughout gestation.
VITAMIN A IN HEALTH AND DISEASE
Retinoids play fundamental roles as differentiating agents in morphogenesis (3). It now appears that the embryo has multiple areas with different responsiveness to retinoic acid caused by local differences in the production and binding of, and sensitivity to, retinoic acid. These differences appear to vary among tissues during development.
Vitamin A is essential for eye health. In the eye the visual functions of rhodopsin and the iodopsins are affected by the rapid, light-induced isomerization of 11-cis-retinal to the all-trans form. This results in the dissociation of the retinoid from the opsin complex. This process (bleaching) is a complex series of reactions, involving progression of the pigment through a series of unstable intermediates of differing conformations which ultimately dissociate to all-trans-retinal and opsin. The dissociation of all-trans-retinal and opsin is coupled to nervous stimulation of the vision centres of the brain via a change in membrane potential transmitted as a nervous impulse along the optic neurons. The visual process is a cyclic one, in that its constituents are regenerated.
The role of vitamin A in protecting against xerophthalmia and night blindness is discussed above.
There is evidence to suggest that Vitamin A may also have a beneficial effect in preventing cataracts and glaucoma (4,5)
Vitamin A has an essential role in the normal metabolism of bone (6). The metabolic role of vitamin A in bone is not clear. Retinoids are thought to be involved in regulating the expression of bone-mobilizing cells, osteoclasts, which are reduced in vitamin A deficiency (7).
Because chronic deprivation of vitamin A leads to anaemia, a role for the vitamin in iron metabolism has been suggested (87). Supplemental vitamin A has been shown to increase iron status in anaemic, vitamin A-deficient animals and humans (9). Clinical trials have shown intervention with both iron and vitamin A to be more effective in correcting anaemia than intervention with iron alone.
The metabolic basis of the role of vitamin A appears to involve the mobilization and transport of iron from body stores, as well as the enhancement of non-haeme-iron bioavailability. The presence of vitamin A or β-carotene has been found to increase the enteric absorption of iron from both inorganic and plant sources; this has been explained on the basis of the formation of complexes with iron that are soluble in the intestinal lumen, thus blocking the inhibitory effects of iron absorption of such antagonists as phytates and polyphenols (10).
Vitamin A-deficient animals and humans are typically more susceptible to infection than are individuals of adequate vitamin A intake. Epidemiologic studies have found that low vitamin A status is frequently associated with increased incidences of morbidity and mortality (11). Many studies have found positive associations between mild xerophthalmia and risks of diarrhoea, respiratory infection, and measles among children. Vitamin A deficiency leads to changes providing environments conducive to bacterial growth and secondary infection. Underlying these effects are roles of vitamin A in inducing heightened primary immune responses.
Active infection appears to alter the utilization or, at least, the distribution of vitamin A among tissues. Plasma retinol concentrations drop during malarial attacks, chickenpox, diarrhoea, measles, and respiratory disease (12). Episodes of acute infection have been found to be associated with substantive (e.g., eight-fold) increases in the urinary excretion of retinol. That such insults to vitamin A status can be of clinical significance is indicated by the fact that vitamin A treatment can greatly reduce the case morbidity and mortality rates in measles and respiratory diseases.
Stimulation of immunity and resistance to infection are thought to underlie the observed effects of vitamin A supplements in reducing risks of mortality and morbidity from some forms of diarrhoea, measles, HIV infection, and malaria in children (13,14). Night-blind women have a five-fold increased risk of dying from infections, and low doses of vitamin A have been found to reduce peri- and post-partum mortality in women, presumably due to reduction in the severity of infections. Indeed, vitamin A supplementation has been found to reduce the incidence of uncomplicated malaria by more than 30%.
Restoration of adequate vitamin A status of deficient children can reduce morbidity rates, particularly for diarrhoea and measles. Meta-analyses of community-based vitamin A intervention studies indicate an average 23% reduction in pre-school mortality (15). Vitamin A supplementation of children with active, severe, complicated measles has been shown to reduce in-hospital mortality by at least 50%.
Vitamin A has a role in the normal health of the skin. Its vitamers, as well as carotenoids, are typically found in greater concentrations in the subcutis, the dermis and epidermis. Vitamin A deficiency impairs the differentiation of human keratinocytes and causes the skin to be thick, dry and scaly. It also results in obstruction and enlargement of the hair follicles.
13-cis-retinoic acid is used for the treatment of acne vulgaris, as it affects all of the major pathogenic mechanisms. It decreases sebum production, inhibits the development of blackheads, reduces bacterial numbers in both the ducts and at the surface, and reduces inflammation. Topical treatment with all-trans-retinoic acid has been found to protect against photoaging signs by stimulating collagen synthesis, thereby increasing collagen replacement. The action of retinoids in psoriasis appears to involve thinning of the stratum corneum, reduced keratinocyte proliferation, and reduced inflammation.
Adipose tissue is a major storage site of carotenoids, which partition into fat (16). Carotenoid concentrations tend to be inversely related to percentage body fat, due to the fact that the caloric excesses that drive adiposity tend to be unrelated to the intake of carotenoid-rich foods (fruits, vegetables). Therefore, body fat would appear to be a determinant of the tissue distribution of carotenoids, including those with pro-vitamin A potential.
It has been suggested that actions of vitamin A in supporting the health of the skin and immune systems may involve effects on systems that provide protection against the adverse effects of pro-oxidants. Yet it is unlikely that vitamin A itself is physiologically significant in this regard, as retinol and retinal have only weak capacities to scavenge free radicals. It can, however, affect tissue levels of other antioxidants; deprivation of vitamin A leads to marked increases in the concentrations of α-tocopherol in the liver and plasma, whereas high intakes of retinyl esters can enhance the bioavailability of selenium, an essential constituent of several glutathione-dependent peroxidases. Several carotenoids, on the other hand, have been shown to have direct antioxidant activities. These include β-carotene, lycopene, and some oxycarotenoids (zeaxanthin, lutein), which can quench free radicals in the lipid membranes into which they partition. Carotenoids can also participate in the reduction of free radicals; xanthophyll carotenoids (lutein, lycopene, and β-cryptoxanthin) are more effective than β-carotene and more efficient than α-tocopherol in vitro. Despite these differences, the carotenoids tend to be less plentiful in tissues, for which reason their contributions to physiologic antioxidant protection are likely to be less important than those of the tocopherols except, perhaps, in cases of high carotenoid intake.
Epidemiologic investigations have repeatedly found inverse relationships between the level of consumption of provitamin A-containing fruits and vegetables and risks of cardiovascular disease. Indeed, plasma retinol levels have been found to be related inversely to the risk of ischemic stroke, and low plasma β-carotene concentrations are associated with increased risk of myocardial infarction (17-19).
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Keywords, Vitamin A, retinoids, carotenoids, eye health, xerophthalmia, Glaucoma, Cataracts, pregnancy, reproduction, bone, immunity, skin, obesity, antioxidant, cardiovascular disease