Dietary or Supplemental Vitamin A (1 |xg)
Supplemental ß-carotene (2 |ig)
Dietary ra-carotene or ß-cryptoxanthin (24 |jg)
ß-carotene a-carotene or ß-cryptoxanthin
Retinol (1 ng)
FIGURE 4-2 Absorption and bioconvcrsion of ingested provitamin A carotenoids to retinol based on new equivalency factors (retinol activity equivalency ratio).
TABLE 4-3 Comparison of the 1989 National Research Council and 2001 Institute of Medicine Intcrconvcrsion of Vitamin A and Carotcnoid Units
1 retinol equivalent (|ig RE) = 1 (ig of all-iram-retinol = 2 Hg of supplemental all-irans-ß-carotene
= 6 M-g of dietary all-iraw.s-ß-carolerie = 12 (J.g of other dietary provitamin A carotenoids
1 retinol activity equivalent (|ig RAE) = 1 ng of all-iram-retinol = 2 Hg of supplemental all-irans-ß-carotene
= 12 |J.g of dietary all-ir-ans-ß-caroleiie = 24 |ig of other dietary provitamin A carotenoids
NOTE: 1 |ig retinol = 3.33 IU vitamin A activity from retinol (WHO, 1966); 10 IU p-carotene = 3.33 IU retinol (WHO, 1966); 10 IU is based on 3.33 IU vitamin A activity X 3 (the relative vitamin activity of |3-caroLene in supplements versus in diets). Thus, when converting from IU P-carotcne from fruits or vegetables to |ig RAE, IU is divided by 20 (2 x 10).
VITAMIN A 93
Example: A diet contains 1,666 IU of rctinol and 3,000 IU of p-carotcnc.
Example: A supplement contains 5,000 IU of vitamin A (20 percent as p-carotcne).
The use of |j.g RAE rather than |ag RE or international units (IU) is preferred when calculating and reporting the amount of the total vitamin A in mixed foods or assessing the amount of dietary and supplemental vitamin A consumed. Given the need to be able to calculate the intake of carotenoids, food composition data tables should report food content in amounts of each carotcnoid whenever possible.
Metabolism, Transport, and Excretion
Rctinyl esters and carotenoids arc transported to the liver in chylomicron remnants. Apoprotein E is required for the uptake of chylomicron remnants by the liver. Some rctinyl esters can also be taken up directly by peripheral tissues (Goodman et al., 1965). Several specific hepatic, membrane receptors (low density lipoprotein [LDL] receptor, LDL receptor-related protein, lipolysis-stimulated receptor) have been proposed to also be involved with the uptake of chylomicron remnants (Cooper, 1997). The hydrolysis of rctinyl ester to rctinol is catalyzed by rctinyl ester hydrolase following endo-cytosis. To meet tissue needs for retinoids, rctinol binds to rctinol-binding protein (RBP) for release into the circulation. In the blood, holo-RBP associates with transthyretin (a transport protein) to form a trimolccular complex with rctinol in a 1:1:1 molar ratio. Rctinol is transported in this trimolccular complex to various tissues, including the eye. The mechanism through which rctinol is taken up from the circulation by peripheral cells has not been conclusively established. Rctinol that is not immediately released into circulation by the liver is rccstcrificd and stored in the lipid-containing stellate (Ito) cells of the liver until needed to maintain normal blood rctinol concentrations.
Carotenoids arc incorporated into very low density lipoproteins (VLDL) and exported from the liver into the blood. VLDL arc converted to LDL by lipoprotein lipase on the surface of blood vessels.
Plasma membrane-associated rcccptors of peripheral tissue cells bind apolipoprotcin B100 on the surface of LDL, initiating receptor-mediated uptake of LDL and their lipid contents. The liver, lung, adipose, and other tissues possess carotene 15, 15'-dioxygcnase activity (Goodman and Blaner, 1984; Olson and Hayaishi, 1965), and thus it is presumed that carotenes may be converted to vitamin A as they arc delivered to tissues. The major end products of the enzyme's activity arc retinol and retinoic acid (Napoli and Race, 1988). It is unclear, however, whether carotcnoids stored in tissues other than the intestinal mucosa cells arc cleaved to yield retinol. Thatcher ct al. (1998) demonstrated that (3-carotcne stored in liver is not utilized for vitamin A needs in gcrbils.
Typically, the majority of vitamin A metabolites arc excreted in the urine. Saubcrlich ct al. (1974) reported that the percentage of a radioactive dose of vitamin A recovered in breath, feces, and urine ranged from 18 to 30 percent, 18 to 37 percent, and 38 to 60 percent, respectively, after 400 days on a vitamin A-deftcient diet. Almost all of the excreted metabolites arc biologically inactive.
Retinol is metabolized in the liver to numerous products, some of which arc conjugated with glucuronic acid or taurine for excretion in bile (Sporn ct al., 1984). The portion of excreted vitamin A metabolites in bile increases as the liver vitamin A exceeds a critical concentration. This increased excretion has been suggested to serve as a protective mcchanism for reducing the risk of excess storage of vitamin A (Hicks ct al., 1984).
The hepatic, vitamin A concentration can vary markedly depending on dietary intake. When vitamin A intake is adequate, over 90 percent of total body vitamin A is located in the liver (Raica ct al., 1972) as retinyl ester (Schindlcr ct al., 1988), where it is concentrated in the lipid droplets of pcrisinusoidal stellate cells (Hendriks ct al., 1985). The average concentration of vitamin A in postmortem livers of American and Canadian adults is reported to range from 10 to as high as 1,400 M-g/g liver (Furr ct al., 1989; Hoppner ct al., 1969; Mitchell ct al., 1973; Raica ct al., 1972; Schindlcr ct al., 1988; Underwood ct al., 1970). In developing countries where vitamin A deficiency is prevalent, the vitamin A concentration in liver biopsy samples is much lower (17 to 141 |J.g/g) (Abedin ct al., 1976; Flores and dc Araujo, 1984; Haskell ct al., 1997; Olson, 1979; Suthutvora-voot and Olson, 1974). A concentration of at least 20 jxg rctinol/g of liver in adults is suggested to be the minimal acceptable reserve
(Locrch ct al., 1979; Olson, 1982). The mean liver stores of vitamin A in children (1 to 10 years of age) have been reported to range from 171 to 723 M-g/g (Florcs and dc Araujo, 1984; Mitchcll ct al., 1973; Money, 1978; Raica ct al., 1972; Underwood ct al., 1970), whereas the mean liver vitamin A stores in apparently healthy infants is lower, ranging from 0 to 320 M-g/g of liver (Florcs and dc Araujo, 1984; Huquc, 1982; Olson ct al., 1979; Raica ct al., 1972; Schindlcr ct al., 1988).
With use of radio-isotopic methods, the efficiency of storage (retention) of vitamin A in liver has been estimated to be approximately 50 pcrccnt (Bausch and Rict/., 1977; Kusin ct al., 1974; Saubcrlich ct al., 1974). More recently, stablc-isotopic. methods have shown an cfficicncy of storage of 42 pcrccnt for individuals with concentrations greater than or equal to 20 jxg rctinol/g of liver (Haskell ct al., 1997). The cfficicncy of storage was lower in those with lower vitamin A status. The percentage of total body vitamin A stores lost per day was approximately 0.5 pcrccnt in adults consuming a vitamin A-frcc diet (Saubcrlich ct al., 1974).
The most specific, clinical effect of inadequate vitamin A intake is xerophthalmia. It is estimated that 3 to 10 million children, mostly in developing countries, bccomc xerophthalmia and 250,000 to 500,000 go blind annually (Sommcr and West, 1996; WHO, 1995). The World Health Organization (WHO, 1982) classified various stages of xerophthalmia to includc night blindness (impaired dark adaptation due to slowed regeneration of rhodopsin), conjunctival xerosis, Bitot's spots, corncal xerosis, corncal ulceration, and scarring, all related to vitamin A dcficicncy. Night blindness is the first ocular symptom to be observed with vitamin A dcficicncy (Dowling and Gibbons, 1961), and it responds rapidly to treatment with vitamin A (Sommcr, 1982). High-dose (60 mg) vitamin A supplementation reduced the incidcncc of night blindness by 63 pcrccnt in Ncpalcsc children (Katz ct al., 1995). Similarly, night blindness was reduced by 50 pcrccnt in women after weekly supplementation with cither 7,500 |j.g RF of vitamin A or (3-c.arotcnc (Christian ct al., 1998b).
An association of vitamin A dcficicncy and impaired embryonic, development is well documented in animals (Morriss-Kay and Sokolova, 1996; Wilson ct al., 1953). In laboratory animals, fetal resorption is common in severe vitamin A dcficicncy, while fetuses that survive have characteristic, malformations of the eye, lungs, urogenital tract, and cardiovascular system. Similar abnormalities arc
observed in rat embryos lacking nuclear retinoid receptors (Wcndling ct al., 1999). Morphological abnormalities associated with vitamin A deficiency arc not commonly found in humans; however, functional defects of the lungs have been observed (Chytil, 1996).
Because of the role of vitamin A in maintaining the structural integrity of epithelial cells, follicular hyperkeratosis has been observed with inadequate vitamin A intake (Chase ct al., 1971; Saubcrlich ct al., 1974). Men who were made vitamin A deficient under controlled conditions were then supplemented with cither rctinol or (3-carotcnc, which caused the hyperkeratosis to gradually clear (Saubcrlich ct al., 1974).
Vitamin A deficiency has been associated with a reduction in lymphocyte numbers, natural killer cells, and antigcn-spccific. immunoglobulin responses (Cantorna ct al., 1995; Nauss and Ncwbcrnc, 1985). A decrease in leukocytes and lymphoid organ weights, impaired T cell function, and decreased resistance to immunogenic, tumors have been observed with inadequate vitamin A intake (Dawson and Ross, 1999; Wicdcrmann ct al., 1993). A generalized dysfunction of humoral and cell-mediated immunity is common in experimental animals and is likely to exist in humans.
In addition to xerophthalmia, vitamin A deficiency has been associated with increased risk of infectious morbidity and mortality in experimental animals and humans, especially in developing countries. A higher risk of respiratory infection and diarrhea has been reported among children with mild to moderate vitamin A deficiency (Sommcr ct al., 1984). Mortality rates were about four times greater among children with mild xerophthalmia than those without it (Sommcr ct al., 1983). The risk of severe morbidity and mortality decreases with vitamin A repletion. In children hospitalized with measles, case fatality (Barclay ct al., 1987; Husscy and Klein, 1990) and the severity of complications on admission were reduced when they received high doses (60 to 120 mg) of vitamin A (Coutsoudis ct al., 1991; Husscy and Klein, 1990). In some studies, vitamin A supplementation (30 to 60 mg) has been shown to reduce the severity of diarrhea (Barrcto ct al., 1994; Donncn ct al., 1998) and Plasmodium falciparum malaria (Shankar ct al., 1999) in young children, but vitamin A supplementation has had little effect on the risk or severity of respiratory infections, except when associated with measles (Humphrey ct al., 1996).
In developing countries, vitamin A supplementation has been shown to reduce the risk of mortality among young children (Ghana VAST Study Team, 1993; Muhilal ct al., 1988; Rahmathullah ct al., 1990; Sommcr ct al., 1986; West ct al., 1991), infants (Humphrey ct
al., 1996), and pregnant and postpartum women (Westetal., 1999). Meta-analyses of the results from these and other community-based trials arc consistent with a 23 to 30 percent reduction in mortality of young children beyond 6 months of age after vitamin A supplementation (Beaton ct al., 1993; Faw/.i ct al., 1993, Glas/.iou and Mackcrras, 1993). WHO recommends broad-based prophylaxis in vitamin A-dcficicnt populations. It also recommends treating children who suffer from xerophthalmia, measles, prolonged diarrhea, wasting malnutrition, and other acute infections with vitamin A (WHO, 1997). Furthermore, the American Acadcmy of Pediatrics (AAP, 1993) recommends vitamin A supplementation for children in the United States who arc hospitalized with measles.
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