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7
Fat-Soluble Vitamins

VITAMIN A

Vitamin A designates a group of compounds essential for vision, growth, cellular differentiation and proliferation, reproduction, and the integrity of the immune system (Goodman, 1984b; Moore, 1957; Olson, 1984; Sporn et al., 1984). Retinol, retinaldehyde, and retinoic acid, naturally occurring compounds with some vitamin A activity, and a large number of synthetic analogs with or without vitamin A activity are collectively termed retinoids. Retinoids vary qualitatively as well as quantitatively in vitamin A activity. Dietary retinoic acid, for example, does not fulfill all the metabolic needs for vitamin A, since it does not protect against night blindness or reproductive dysfunction. The body's need for vitamin A can be met by dietary intake of preformed retinoids with vitamin A  activity (usually in animal products) or by consumption of carotenoid precursors of vitamin A such as ß-carotene, a-carotene, and cryptoxanthin formed by plants and present in some animal fats.

The structural requirements for vitamin A biological activity are very strict and apply both to retinoids and to carotenoids (Wolf and Johnson, 1960). Of more than 500 carotenoids found naturally, only about 50 are precursors of retinol (i.e., have provitamin A activity) (Isler, 1971; Olson, 1983, 1984). All-trans ß-carotene is the most active on a weight basis and makes the most important quantitative contribution to human nutrition (Bauernfeind, 1972; Moore, 1957; Underwood, 1984)

Preformed vitamin A is present in foods of animal origin mainly as retinyl ester (Goodman and Blaner, 1984). In the small intestine,



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Page 78 7 Fat-Soluble Vitamins VITAMIN A Vitamin A designates a group of compounds essential for vision, growth, cellular differentiation and proliferation, reproduction, and the integrity of the immune system (Goodman, 1984b; Moore, 1957; Olson, 1984; Sporn et al., 1984). Retinol, retinaldehyde, and retinoic acid, naturally occurring compounds with some vitamin A activity, and a large number of synthetic analogs with or without vitamin A activity are collectively termed retinoids. Retinoids vary qualitatively as well as quantitatively in vitamin A activity. Dietary retinoic acid, for example, does not fulfill all the metabolic needs for vitamin A, since it does not protect against night blindness or reproductive dysfunction. The body's need for vitamin A can be met by dietary intake of preformed retinoids with vitamin A  activity (usually in animal products) or by consumption of carotenoid precursors of vitamin A such as ß-carotene, a-carotene, and cryptoxanthin formed by plants and present in some animal fats. The structural requirements for vitamin A biological activity are very strict and apply both to retinoids and to carotenoids (Wolf and Johnson, 1960). Of more than 500 carotenoids found naturally, only about 50 are precursors of retinol (i.e., have provitamin A activity) (Isler, 1971; Olson, 1983, 1984). All-trans ß-carotene is the most active on a weight basis and makes the most important quantitative contribution to human nutrition (Bauernfeind, 1972; Moore, 1957; Underwood, 1984) Preformed vitamin A is present in foods of animal origin mainly as retinyl ester (Goodman and Blaner, 1984). In the small intestine,

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Page 79 retinyl esters are hydrolyzed; the products are associated first with lipid globules and then with bile salt-containing mixed micelles in the upper part of the small intestine. These mixed micelles contain carotenoids as well as retinol. However, absorption of retinol and carotenoids, especially ß-carotene, differs in several ways. For example, in physiological amounts, retinol is more efficiently absorbed than are most carotenoids, e.g., 70 to 90% compared to 20 to 50% (Bauernfeind, 1972; Reddy and Sivakumar, 1972). However, carotenoids present in oils are well absorbed (Rao and Rao, 1970). As the amount ingested increases, the efficiency of retinol absorption usually remains high (60 to 80%), whereas carotenoid absorption falls markedly to levels as lowas 10% or less (Bauernfeind, 1972; Olson, 1972). Absorbed retinol is largely esterified in intestinal mucosal cells and incorporated into chylomicrons, as is the portion of absorbed ß-carotene and other biologically active carotenoids that is not cleaved in intestinal cells. Most absorbed ß-carotene normally is converted to retinol (and then to retinyl esters) in mucosal cells. The retinyl esters and carotenoids are taken up from the blood with chylomicron remnants, mainly in the liver by hepatocytes (Blomhoff et al., 1982; Goodman and Blaner, 1984). Studies in animals have shown that when liver reserves of vitamin A are adequate, much of the newly absorbed retinol is transferred from hepatocytes to stellate cells of the liver and stored as retinyl esters (Blomhoff et al., 1982, 1985). In well-nourished individuals, the storage efficiency of ingested vitamin A in the liver is more than 50% (Sauberlich et al., 1974), and the liver contains =90% of the total body stores of the vitamin (Underwood, 1984). In vitamin A-depleted rats, liver stores are reduced and the kidneys and other tissues contain an appreciable percentage (10 to 50%) of the small amount of total body reserve. In humans, carotenoids are deposited more widely, including localization in adipose tissues and adrenals; relatively small amounts are found in the liver (Raica et al., 1972). Retinol circulates in the blood as a 1: 1:1 trimolecular complex with retinol-binding protein (RBP) and transthyretin (TTR) (Goodman, 1984a). RBP is released from the liver in combination with retinol, and the holo-RBP complex combines with TTR in the blood. Subsequently, retinol is slowly metabolized in the liver to numerous products, some of which are conjugated with glucuronic acid or taurine, and eliminated in the bile (Sporn et al., 1984). Of the total retinol metabolized, approximately 70% of the metabolic products appear in the feces and 30% are excreted in the urine. Almost all these excreted products are biologically inactive metabolites. For a more detailed review of retinol metabolism, see Goodman and Blaner (1984).

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Page 80 General Signs of Deficiency Vitamin A deficiency is found most commonly in children under 5 years of age and is usually due to an insufficient dietary intake. Deficiency also occurs as a result of chronic fat malabsorption. Prominent clinical signs are ocular, and range—in increasing severity—from night blindness and conjunctival xerosis to corneal xerosis, ulceration, and sometimes liquefaction. Collectively, these symptoms and signs are referred to as xerophthalmia (Sommer, 1982). Irreversible corneal lesions associated with partial or total blindness are termed keratomalacia. Other less specific deficiency signs may include loss of appetite, hyperkeratosis, increased susceptibility to infections, and metaplasia and keratinization of epithelial cells of the respiratory tract and other organs. Although rare in the United States, vitamin A deficiency is a major nutritional problem in some parts of the nonindustrialized world, causing a number of the more than 500,000 new cases of active corneal lesions that occur annually in children (FAO, 1988). The Nutritional Relationship Between Preformed Vitamin A, Biologically Active Retinoids, and Carotenoids Vitamin A activity is often expressed as international units (IU), derived both from preformed vitamin A and from carotenoids. This has led to confusion, since the term IU was based on studies that did not take into account the poor absorption and bioavailability of carotenoids. Solely on the basis of growth-promoting action in rats under controlled conditions, 1 IU of vitamin A activity has been defined as equal either to 0.30 µg of all-trans retinol or to 0.60 µg of all-trans ß-carotene. In studies in humans, the same relationship held when small oral doses of synthetic all-trans retinyl acetate and of synthetic all-trans ß-carotene were used to cure vitamin A deficiency (i.e., 1 µg of retinol was equivalent to about 2 µg of ß-carotene) (Sauberlich et al., 1974). The bioavailability of carotenoids in many foods is not as great as that of retinol or of pure carotenoid supplements. As noted above, pure carotenoids are absorbed from the intestine less well than retinol. Furthermore, provitamin A carotenoids other than ß-carotene yield only half the vitamin A activity of ß-carotene. On the basis of all these considerations, the assumed relationship between the biological effectiveness of ß-carotene and retinol was changed, so that 6 µg of dietary ß-carotene was assumed to be nutritionally equivalent to l µg of retinol (FAO/WHO, 1967; NRC, 1980). The vitamin A

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Page 81 activity in foods is thus currently expressed as retinol equivalents (RE): 1 RE is defined as 1 µg of all-trans retinol, 6 µg of all-trans ß-carotene, or 12 µg of other provitamin A carotenoids. This definition of retinol equivalent is now generally accepted throughout the world (Bieri and McKenna, 1981) and has been included, together with IU, in the recent revision of Agriculture Handbook Series 8 of the U.S. Department of Agriculture (USDA, 1976-1989). Dietary Sources and Usual Intakes The richest sources of preformed retinol are liver and fish liver oils, and appreciable quantities are also present in whole and fortified milk and in eggs. Biologically active carotenoids are found in abundance in carrots and in dark-green leafy vegetables such as spinach (USDA, 1976-1989). Because only a few carotenoids serve as provitamin A compounds and because many other yellow and orange carotenoid and other pigments are present in plants, the color intensity of a fruit or vegetable is not a reliable indicator of its content of provitamin A. Data from the second (1976-1980) National Health and Nutrition Examination Survey (NHANES II) indicate that the major contributors of vitamin A or provitamin A in the U.S. diet are liver, carrots, eggs, vegetable-based soups, and whole-milk products (Block et al., 1985). Fortified food products also contribute substantially to the dietary intake of vitamin A in the United States. In addition, recent surveys indicate that approximately one-third of the U.S. adult population consumes vitamin supplements regularly, including vitamin A in doses often meeting or exceeding the 1980 RDAs (McDonald, 1986; Stewart et al., 1985). In view of the incomplete data on the carotenoid content of foods, it is not possible to state precisely what percentage of vitamin A activity in the diet is contributed by carotenoids. With improved methodology, current studies of the carotenoid content of vegetables should yield more reliable figures (Khachik et al., 1986). Using available food composition data, the USDA found the average vitamin A intake of adult men to be 1,419 RE (USDA, 1986). The corresponding intakes for adult women and children 1 to 5 years of age were 1,170 RE and 1,049 RE, respectively (USDA, 1987). Less than one-third of total vitamin A activity in the diets of these groups came from carotenoids. Recommended Allowances Adults Estimates of vitamin A intakes have been based on the amounts needed (1) to correct impaired dark adaptation, abnormal

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Page 82 electroretinograms, and follicular hyperkeratosis among vitamin Adepleted subjects; (2) to increase the concentration of retinol in the plasma of depleted subjects to the normal range; and (3) to maintain a normal plasma concentration of retinol in well-nourished subjects (Rodriguez and Irwin, 1972). Some studies in humans suggest that at liver storage concentrations above 20 µg/g, an adequate supply of retinol is available to maintain normal plasma levels and to meet tissue needs (Amedee-Manesme et al., 1984, 1987, 1988). By contrast, average liver concentrations were 149 µg/g in specimens obtained from humans at autopsy (Raica et al., 1972). In a human vitamin A depletion-repletion study, initial body pools of vitamin A were estimated to range from 315 to 877 mg. At the time vitamin A deficiency signs appeared, the body vitamin A pool was reduced by approximately one-half (Sauberlich et al., 1974). Induced vitamin A depletion and repletion have been conducted only in a few adult males in two studies. During World War II, Hume and Krebs (1949) in Sheffield, England, investigated the human requirements for vitamin A. Vitamin A deficiency symptoms included dryess of skin, impaired dark adaptation, eye discomfort, and low plasma retinol levels (< 15 µg/dl). Of the 16 subjects studied, only three had changes in dark adaptation of sufficient magnitude to serve as a criterion to investigate the curative ability of varying amounts of retinol or ß-carotene. One subject was given 390 µg of retinol per day—an amount sufficient to improve his dark adaptation but to improve his low plasma retinol levels only transiently. Supplementation with 780 µg of retinol per day for 45 days had little further effect on the subject's plasma retinol level (an initial level of 17 µg/ dl was increased to 21 µg/dl). However, daily retinol supplements of 7,200 µg returned his plasma retinol level to his initial level of 33 µg/dl and higher. Two other subjects were repleted with two different levels of ß-carotene. One received 768 µg daily but did not improve until the dose was increased to 1,500 µg of ß-carotene daily. The other subject, who had a milder vitamin A deficiency, promptly improved with daily ß-carotene supplements of 1,500 µg. From the results of the one subject, Hume and Krebs (1949) concluded that a daily retinol intake of 390 µg represented the minimum protective dose. They recommended, however, that a daily intake of 750 µg of retinol be considered as the vitamin A requirement of the adult human. This figure should be raised by 20% to 900 µg to correct for an error in the conversion factor used in the analytical measurements of Hume and Krebs (Leitner et al., 1960).

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Page 83 In the study by Sauberlich et al. (1974), eight volunteer adult males were depleted of vitamin A. There was considerable variation among them in the time of occurrence of vitamin A deficiency signs. Abnormal electroretinograms occurred at plasma retinol levels of 4 to 11 µg/dl and impaired dark adaptation was observed at plasma retinol levels of 3 to 25 µg/dl, whereas follicular hyperkeratosis was found at plasma retinol levels of 7 to 37 µg/dl. Plasma levels below 30 µg/ dl were associated with a mild degree of anemia that responded only to vitamin A supplementation (Hodges et al., 1978). Daily retinol supplements of 300 µg partially corrected the abnormal electroretinograms, whereas supplements of 600 µg/day corrected the condition completely in one subject and to a great extent in two others. This suggests that 600 µg/day is the minimum physiological need for retinol to prevent eye changes in adult men. However, the skin lesions failed to clear promptly with this level of intake. The skin lesions were among the earliest manifestations of vitamin A deficiency, occurring in some subjects with plasma retinol levels higher than 30 µg/dl. Hence, maintenance of a plasma retinol level above 30 µg/dl in adult men appears desirable to prevent vitamin A deficiency manifestations and to ensure modest body stores of the vitamin. After 103 days of vitamin A depletion, the plasma vitamin A levels ranged from 29 to 34 µg/dl. Radioisotopic labeling of the body pool of vitamin A indicated that the average rate of utilization at this state of depletion was 910 µg of vitamin A per day (range, 570 to 1,250 µg). This suggests that a daily retinol intake of 900 µg would maintain a plasma retinol level of 30 µg/dl and provide a modest body pool of vitamin A in most adult men. For women, the requirement would be reduced in proportion to body weight. The amount of ß-carotene necessary to meet the vitamin A requirement of adult men was approximately twice that of retinol, although in some instances the amount required appeared to be less than double. A ß-carotene intake of 1,200 µg/day was comparable to a retinol intake of 600 µg/day. The ß-carotene was provided to the subjects under optimal conditions for absorption (dissolved in corn oil); under normal dietary states, the bioavailability of ß-carotene (in vegetables and fruits) would be considerably less. An international committee (FAO, 1988) analyzed the data obtained in this study of Sauberlich et al. (1974) and interpreted these results differently. They calculated the mean dietary intake of retinol required to maintain a minimal reserve in adult males to be 526 µg/ day. Given the limited number of subjects in the Sauberlich study,

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Page 84 the large observed variation in the depletion rate of body stores, and the assumptions required for the calculation, it is difficult to accept 526 µg/day as a basis for establishing the allowance for vitamin A. Furthermore, none of the data provide a valid basis for estimating the population variance of the requirement of adults or children. Other earlier studies suggest that the daily vitamin A requirement for adult men ranges from 750 to 1,200 µg of retinol. For instance, Jeghers (1937) reported a minimal retinol intake of 1,200 µg/day; Basu and De (1941) concluded that 900 µg of retinol per day was needed to prevent impaired dark adaptation in adults; and Wagner (1940) reported that 750 µg of retinol per day was required to produce visual normality. In a recent population-based study of Gambian women whose vitamin A intake came almost entirely from provitamin A carotenoids, Villard and Bates (1987a) found that vitamin A adequacy was achieved with daily intakes as low as 500 RE. However, the actual provitamin A activity of dietary carotenoids and the applicability of this study to women in the U.S. population are uncertain. Clinical observations, radiometric findings on body pools of vitamin A, and vitamin A utilization rates suggest that the maintenance of a plasma retinol level above 20 µg/dl appears to be essential, while a plasma level above 30 µg/dl would be desirable to ensure modest body stores of the vitamin. These plasma levels would be associated with utilization rates of vitamin A of 570 to 1,250 µg/day found for the eight adult men in the study of Sauberlich et al. (1974). Hence, 600 pg of retinol per day represents a minimal intake that would not necessarily support optimal levels of liver stores of retinol or plasma retinol levels. Since the data are limited, and the study of Sauberlich et al. (1974) suggests that the individual requirement for adult men varies considerably, it is the judgment of the subcommittee that there is no reason to alter the RDA for adult men from the value of 1,000 RE recommended in the ninth edition of the RDAs. The RDA for adult women is set at 800 RE on the basis of their lower body weight. Healthy elderly Americans (65 years of age and older) ingest the same average amounts of vitamin A as do other adults (DHEW, 1979; USDA, 1984) and have normal plasma vitamin A levels (DHEW, 1974; Garry et al., 1987). Although diseases that adversely affect vitamin A absorption, storage, and transport may be more common among the elderly than among other age groups, the vitamin A status of otherwise healthy elderly people does not appear to require special attention.

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Page 85 Pregnancy and Lactation Vitamin A is required for growth, for cellular differentiation, and for the normal development of fetuses. Most, if not all, vitamin A transferred to the fetus is derived from holo-RBP in maternal plasma. The median retinol concentration in fetal liver is low (<25 µg/g) and does not increase appreciably, even when the mother is given vitamin A supplements (Wallingford and Underwood, 1986). During the last trimester, the total body pool of vitamin A in the fetus increases only by approximately 1.3 mg (Montreewasuwat and Olson, 1979). In contrast, the total body pool would be 209 mg in a 63-kg woman whose liver contains a vitamin A concentration of 100 µg/g (Mitchell et al., 1973; Raica et al., 1972). If the mean fetal utilization of vitamin A for the last 13 weeks (91 days) were 200 µg/day, 18 mg of vitamin A, or only 9% of the total mean maternal stores, would be required. For most women in our society, therefore, no increment of vitamin A intake is necessary during pregnancy. The range of vitamin A in human milk from well-nourished women in the United States and Europe is about 0.4 to 0.7 µg of retinol per milliliter (Wallingford and Underwood, 1986). If the mean daily milk volume is 750 ml, the daily secretion of vitamin A in the milk would be 300 to 525 µg. Over a 6-month period, 54 to 95 mg of vitamin A would be secreted, i.e., 26 to 45% of the total mean maternal reserve of 209 mg. To maintain maternal liver reserves, account for normal variation in milk volume, and provide a margin of safety, therefore, a daily increment of 500 RE is recommended during the first 6 months of lactation. Inasmuch as the mean daily human milk volume falls to 600 ml after 6 months, a daily increment of 400 RE should suffice during this later period. The efficiency with which vitamin A ingested by a well-nourished mother is transferred to the milk is not readily defined. In vitamin A-depleted lactating women and those chronically ingesting low intakes, however, dietary supplements increase the concentration of vitamin A in the milk (Venkatachalam et al., 1962; Villard and Bates, 1987b). Infants and Children As noted above, the milk of well-nourished U.S. and European women contains 40 to 70 µg/dl retinol and 20 to 40 µg/dl of carotenoids (mainly as ß-carotene). In terms of retinol equivalents, carotenoids contribute approximately 10% of the vitamin A value of milk. If a retinol concentration of 40 µg/dl and a milk consumption of 750 ml/day are accepted as adequate, the intake of vitamin A for an infant would be 300 µg of retinol per day. The coefficient of variation in the vitamin A content of human milk is

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Page 86 48% (Gebre-Medhin et al., 1976). The relevance of this variance to the actual requirement of the infant is unclear, primarily because signs of vitamin A deficiency, and reduced growth rate are not generally apparent in children receiving as little as 100 to 200 µg of retinol a day (Batista, 1969; Patwardhan, 1969; Reddy, 1971) and because infants who are breastfed by well-nourished women in the United States (do not show signs of vitamin A deficiency. Thus, a daily intake of 375 µg of retinol (300 µg + 2 SDs) seems sufficient to meet the needs of essentially all healthy infants. Because the need for vitamin A during rapid growth greatly exceeds that for the maintenance of adequate reserves in adults (Underwood, 1984), the RDA remains relatively constant as the growth rate falls but the body weight increases. In the absence of specific data on the needs of children, the retinol allowance of 375 µg seems adequate from birth to about 1 year of age. Thereafter, RDA values are extrapolated to the adult level on the basis of body weight. Allowances of 400, 500, and 700 RE daily are recommended for the age groups of 1 to 3, 4 to 6, and 7 to 10 years, respectively, with no distinction between males and females. The 11- to 14-year group and older age groups are considered separately by sex because of differences in lean body mass that occur during this period of development and the different hormonal influences on blood values of the vitamin independent of vitamin A status (Pilch, 1987). Recommended intakes during the adolescent years are similar to those for adults. Other Factors Affecting Recommended Allowances The absorption and utilization of carotenoids and vitamin A are enhanced by dietary fat, protein, and vitamin E, and are depressed by the presence of peroxidized fat and other oxidizing agents in the food. The absorption of carotenoids and vitamin A is markedly reduced when diets contain very little =5 g/day) fat. At low carotenoid intakes, conversion of ß-carotene to retinol may, however, be more efficient. Deficiencies of a variety of other nutrients, including protein, a-tocopherol, iron, and zinc, also adversely affect vitamin A transport, storage, and utilization. (For review and references, see Underwood, 1984.) The ability of retinoids to prevent, suppress, or retard some experimentally produced cancers at sites such as the skin, bladder, and breast in animal models is well established. However, neither intake of foods rich in preformed vitamin A nor concentration of retinol in plasma appears to be associated with the risk of any type of cancer

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Page 87 in humans (NRC, 1989). On the other hand, most carotenoids, unlike vitamin A, trap free radicals (Burton and Ingold, 1984) and quench singlet oxygen, which can cause neoplastic changes in cells. Because only about 10% of carotenoids in nature show provitamin A activity, any anticancer effects that carotenoids possess might be related more to their rather unique antioxidant or other properties than to their conversion into vitamin A (Bendich and Shapiro, 1986; Olson, 1986; NRC, 1989). This possibility is supported by a report that the ingestion of carrots and squash was not associated with any protection against neoplasia, whereas the intake of tomatoes, containing some ß-carotene but mainly lycopene with no provitamin A activity, was protective (Colditz et al., 1985). In addition, a recent epidemiological study correlated the dietary intake of carotenoid-rich vegetables with a lowered risk of lung cancer among white men in New Jersey (Ziegler et al., 1986). This subject has been reviewed in the National Research Council reports on Diet, Nutrition, and Cancer (NRC, 1982) and Diet and Health (NRC, 1989). At this time, it is not possible to draw any conclusions about how this information relates to setting RDAs for vitamin A, but it does suggest that a generous intake of carotenoid-rich foods may be of benefit. Excessive Intakes and Toxicity When ingested in very high doses, either acutely or chronically, preformed vitamin A causes many toxic manifestations, including headache, vomiting, diplopia, alopecia, dryness of the mucous membranes, desquamation, bone abnormalities, and liver damage (Bauernfeind, 1980). Signs of toxicity usually appear only with sustained daily intakes, including both foods and supplements, exceeding 15,000 µg of retinol (50,000 IU) in adults and 6,000 µg of retinol (20,000 IU) in infants and young children (Bauernfeind, 1980). These doses are more than 10 times higher than the RDA and usually cannot be obtained from foods, except by the sustained ingestion of large amounts of liver or fish liver oils, which are particularly rich in vitamin A. A high incidence (= 20%) of spontaneous abortions and of birth defects, including malformations of the cranium, face, heart, thymus, and central nervous system, has been observed in the fetuses of women ingesting therapeutic doses (0.5 to 1.5 mg/kg) of 13-cis retinoic acid (isotretinoin) during the first trimester of pregnancy (Lammer et al., 1985). Large daily doses of retinyl esters or retinol (³ 6,000 RE or 20,000 IU) may cause similar abnormalities (Costas et al., 1987; Miller et al., 1987; Stange et al., 1978).

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Page 88 A single oral dose of 60 mg of retinol in oil (60,000 RE or 200,000 IU) is well tolerated by children and has been successfully used prophylactically in preschool Asian children (Bauernfeind, 1980). Transient symptoms of acute toxicity with no lasting effects have, however, occurred in 1 to 3% of children given the high dose supplement (WHO, 1982). Single doses of vitamin A up to 300 mg (300,000 RE or 1 million IU) administered to adults have resulted in only minor, transient toxic signs (Olson, 1983) Carotenoids, even when ingested in very large amounts for weeks to years, are not known to be toxic (Bauernfeind, 1980; Miller et al., 1987; Olson, 1983). The main reasons for their lack of toxicity are their markedly reduced efficiency of absorption at high doses and relatively limited conversion to vitamin A in the intestine, liver, and other organs (Brubacher and Weiser, 1985). On the other hand, carotenoids taken in large doses for several weeks are absorbed well enough to color the adipose tissue stores, including the subcutaneous fat. Thus, the skin, especially the palms of the hands and the soles of the feet, appears yellow. This coloration gradually disappears when the high intake is discontinued. For food products containing large quantities of carotenoids, it would be advisable in nutritional labeling to distinguish between retinol, which in large amounts is toxic, and carotenoids, which are not. References Amedee-Manesme, O., D. Anderson, and J.A. Olson. 1984. Relation of the relative dose response to liver concentration of vitamin A in generally well-nourished surgical patients. Am. J. Clin. Nutr. 39:898-902. Amedee-Manesme, O., M.S. Mourey, A. Hanck, and J. Thearasse. 1987. Vitamin A relative dose response test: validation by intravenous injection in children with liver disease. Am. J. Clin. Nutr. 46:286-289. Amedee-Manesme, O., R. Luzeau, J.R. Wittepen, A. Hanck, and A. Sommer. 1988. Impression cytology detects subclinical vitamin A deficiency. Am. J. Clin. Nutr. 47:875-878. Basu, N. M., and N.K. De. 1941. Assessment of vitamin A deficiency amongst Bengalees and determination of the minimal and optimal requirements of vitamin A by a simplified method for measuring visual adaptation in the dark. Indian J. Med. Res. 29:591. Batista, M. 1969. Consideracoes—sobre o problema da Vitamina A no Nordeste Brasileiro. Hospital (Rio de Janeiro) 75:817-832. Bauernfeind, J.C. 1972. Carotenoid vitamin A precursors and analogs in foods and feeds. J. Agric. Food Chem. 20:456-473. Bauernfeind, J.C. 1980. The Safe Use of Vitamin A. International Vitamin A Consultative Group. The Nutrition Foundation, Washington, D.C. Bendich, A., and S.S. Shapiro. 1986. Effect of ß-carotene and canthaxanthin on the immune responses of the rat. J. Nutr. 116:2254-2262.

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Page 104 about the tocopherol concentration of human milk (Jansson et al., 1981), by assuming a 750 ml estimated daily volume of milk ingestion, and by adding a coefficient of variation of 12.5%, which raises average intake by 25%. Although human milk has been shown to contain all the expected isomers of tocopherol, vitamers other than a-tocopherol account only for approximately 2% of the vitamin E activity. Human milk provides about 6% of calories as PUFA (Lammi-Keefe and Jensen, 1984). When smaller volumes of milk are consumed by breastfed babies during the first week of life, sufficient tocopherol is provided by colostrum, which has a threefold higher concentration compared to mature milk (Jansson et al., 1981). The relatively high intake of PUFA by infants fed human milk or formula should be adequately met by 3 mg of vitamin E per day. For infants older than 6 months, the RDA has been increased to 4 mg in proportion to growth. These RDAs provide approximately 0.5 mg of a-TEs per kilogram infant body weights. Premature infants present problems somewhat different from those of full-term infants of normal weight. Because of their low body stores of tocopherol, their reduced intestinal absorption (Gross and Melhorn, 1972), and the relatively greater growth rates associated with prematurity, it is more difficult for these infants to achieve and maintain normal vitamin E status (Bieri and Farrell, 1976). Thus, oral supplementation of 17 mg of vitamin E (all-rac-a-tocopherol) per day may be required by premature infants up to 3 months of age (Farrell et al., 1985). Children  The requirements for vitamin E increase with increasing body weight until adulthood, but not as rapidly as during the first year of life. Thus, during the steady growth of early childhood, an intake increasing from 6 mg for the reference child of 13 kg body weight at 1 to 3 years of age to 7 mg at 7 to 10 years (28 kg) should be satisfactory for the average diet. During the adolescent growth spurt, an increase to 8 mg for females and 10 mg for males is recommended, i.e., the same amount as for adults. Excessive Intakes and Toxicity Compared with other fat-soluble vitamins, vitamin E is relatively nontoxic when taken by mouth. Most adults appear to tolerate oral doses of 100 to 800 mg/day (Bendich and Machlin, 1988; Farrell and Bieri, 1975) without gross signs or biochemical evidence of toxicity. In view of the lack of evidence of any definitive benefits of vitamin

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Page 105 E supplements for normal individuals, the subcommittee does not encourage supplementation, except as specifically noted. References Anonymous. 1987. Nomenclature policy: generic descriptors and trivial names for vitamins and related compounds. J. Nutr. 117:7-14. Anonymous. 1988. Vitamin E supplementation of premature infants. Nutr. Rev. 46:122-123. Bauernfeind, J. 1980. Tocopherols in foods. Pp. 99-167 in L.J. Machlin, ed. Vitamin E: A Comprehensive Treatise. Marcel Dekker, New York. Behrens, W.A., J.N. Thompson, and R. Madére. 1982. Distribution of a-tocopherol in human plasma lipoproteins. Am. J. Clin. Nutr. 35:691-696. Bendich, A., and L.J. Machlin. 1988. Safety of oral intake of vitamin E. Am. J. Clin. Nutr. 48:612-619. Bieri, J.G., and R.P. Evarts. 1973. Tocopherols and fatty acids in American Diets. The recommended allowance for vitamin E. J. Am. Diet. Assoc. 62:147-151. Bieri, J.G., and P.M. Farrell. 1976. Vitamin E. Vitam. Horm. 34:31-75. Bieri, J.G., L. Corash, and V.S. Hubbard. 1983. Medical uses of vitamin E. N. Engl. J. Med. 308:1063-1071. Bunnell, R.H., J. Keating, A. Quaresimo, and G.K. Parman. 1965. Alpha-tocopherol content of foods. Am. J. Clin. Nutr. 17: 1-10. Bunyan, J., D. McHale, J. Green, and S. Marcinkiewicz. 1961. Biological potencies of epsilon- and zeta-l-tocopherol and 5-methyltocol. Br. J. Nutr. 15:253-257. Catignani, G.L. 1975. An a-tocopherol binding protein in rat liver cytoplasm. Biochem. Biophys. Res. Commun. 67:66-72. Dam, H. 1962. Interrelations between vitamin E and polyunsaturated fatty acids in animals. Vit. Horm. 20:527-540. Dicks, M.W. 1965. Vitamin E Content of Foods and Feed for Human and Animal Consumption. Agricultural Experimental Station Bulletin No. 435. University of Wyoming, Laramie. Dillard, C.J., V.C. Gavino, and A.L. Tappel. 1983. Relative antioxidant effectiveness of a-tocopherol and g-tocopherol in iron-loaded rats. J. Nutr. 131:2266-2273. Diplock, A.T. 1985. Vitamin E. Pp. 154-224 in A.T. Diplock, ed. Fat-Soluble Vitamins: Their Biochemistry and Applications. Technomic Publications Co., Lancaster, Pa. Elias, E., D.P. Muller, and J. Scott. 1981. Association of spinocerebellar disorders with cystic fibrosis or chronic childhood cholestasis and very low serum vitamin E. Lancet 2:1319-1321. Farrell, P.M. 1980. Deficiency states, pharmacological effects, and nutrient requirments. Pp. 520-620 in L.J. Machlin, ed. Vitamin E: A Comprehensive Treatise. Basic and Clinical Nutrition, Vol. 1. Marcel Dekker, New York. Farrell, P.M., and J.G. Bieri. 1975. Megavitamin E supplementation in man. Am. J. Clin. Nutr. 28:1381-1386. Farrell, P.M., P.M. Zachman, and G.R. Gutcher. 1985. Fat soluble vitamins A, E, and K in the premature infant. Pp. 63-98 in R.S. Tsang, ed. Vitamin and Mineral Requirements in Preterm Infants. Marcel Dekker, New York. Gallo-Torres, H.E. 1980. Absorption: Transport and Metabolism. Pp. 170-267 in L.J. Machlin, ed. Vitamin E: A Comprehensive Treatise. Marcel Dekker, New York.

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Page 106 Gross, S., and D.K. Melhorn. 1972. Vitamin E, red cell lipids and red cell stability in prematurity. Ann. N.Y. Acad. Sci. 203: 141-162. Guggenheim, M.A., S.P. Ringel, A. Silverman, B.F. Grabert, and H.E. Neville. 1982. Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency: clinical and muscle biopsy findings and treatment with atocopherol. Ann. N.Y. Acad. Sci. 393:84-93. Hassan, H., S.A.  Hashim,  T.B. Van Itallie, and W.H. Sebrell. 1966. Syndrome in premature infants associated with low plasma vitamin E levels and high polyunsaturated fatty acid diet. Am. J. Clin. Nutr. 19:147-157. Hoekstra, W.G. 1974. Biochemical role of selenium.  Pp. 61-77 in W.G. Hoekstra, J.W. Suttic. H.F. Ganther, and W. Mertz, eds. Trace Element Metabolism  in Animals, 2. Proceedings of the Second International Symposium. University Park Press, Baltimore, Md. Horwitt, M.K.  1960. Vitamin  E and lipid metabolism  in man. Am. J. Clin. Nutr. 8:451-461. Horwitt, M.K. 1962. Interrelations between vitamin E and polyunsaturated fatty acids in adult men. Vitam. Horm. 20:541-558. Horwitt, M.K. 1974. Status of human requirements for vitamin E. Am. J. Clin. Nutr. 27:1182-1193. Horwitt,  M. K., C.C. Harvey C.H. Dahm, Jr., and M.T. Searcy. 1972. Relationship between tocopherol and serum lipid levels for determination of nutritional adequacy. Ann. N.Y  Acad. Sci. 203:223-236. Jansson, L., B. Akesson, and L.  Holmberg. 1981. Vitamin E and fatty acid composition of human milk. Am. J. Clin. Nutr. 34:8-13. Jeffrey, G.P., D.P.R. Muller, A.K. Burroughs, S. Matthews, C. Kemp, O. Epstein, T.A.  Metcalfe, F. Southam, M. Tazir-Melboucy, P.K. Thomas, and N. McIntyre. 1987. Vitamin E deficiency and its clinical significance in adults with primary biliary cirrhosis and other forms of liver disease.  Hepatol.  4:307-317. Kelleher, J.M.G. Miller J. M. Littlewood, A.M. McDonald, and M.S. Losowsky. 1987. The clinical effect of correction of vitamin E depletion in cystic fibrosis. Int. J. Vitam. Nutr. Res. 57:253-259. Kitabchi, A.F., and J. Wimalasena.  1982. Specific binding sites for D-a-tocopherol on human erythrocytes. Biochim. Biophys. Acta 684:200-206. Lammi-Keefe, C.J., and R.G. Jensen. 1984. Lipids in human milk: a review. 2. Composition and fat-soluble vitamins. J. Pediatr. Gastroenterol. Nutr. 3:172-198. Leonard, P.J., and M.S. Losowsky. 1971. Effect of alpha-tocopherol administration on red cell survival in vitamin E-deficient human subjects. Am. J. Clin. Nutr. 24:388-393. Levine, S.L., A.J. Adams, M.D. Murphy, and P.M. Farrell. 1976. Survey of vitamin E status in children. Pediatr. Res. 10:356. Muller, D.P. 1986. Vitamin E-its role in neurological function. Postgrad. Med. J. 62:107-112. NRC (National Research Council). 1974. Recommended Dietary Allowances, 8th ed. Report of the Committee on Dietary Allowances, Committee on the Interpretation of the Recommended Dietary Allowances, Food and Nutrition Board. National Academy of Sciences, Washington, D.C. 128 pp. NRC (National Research Council). 1980. Recommended Dietary Allowances, 9th ed. Report of the Committee on Dietary Allowances, Division of Biological Sciences, Assembly of  Life Sciences, Food and  Nutrition Board. National Academy of Sciences, Washington, D.C. 185 pp.

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Page 107 Oski, F.A., and I,.A. Barness. 1967. Vitamin E deficiency: a previously unrecognized cause of hemolytic anemia in the premature infant. J. Pediatr. 70:21 1-220. Quaife, M.L., and M.Y. Dju. 1949. Chemical estimation of vitamin E in tissue and tocopherol content of some normal human tissues. J. Biol. Chem. 180:263-272. Sokol, R.J. 1984. Vitamin E deiciency in adults (letter). Ann. Int. Med. 100:769. Thurnham. D.I.,J.A. Davies, B.J. Crump, R.D. Situnayake, and M. Davis. 1986. The use of different lipids to express serum  tocopherol: lipid ratios for the measurement of vitamin E status. Ann. Clin. Biochem. 23:514-520. Traber, M.G., K.U. Ingold, G.W. Burton, and H.J. Kayden. 1988. Absorption and transport of deuterium-substituted 2R,4'R,8'R-a-tocopherol in human lipoproteins. Lipids 23:791-797. USDA (U.S. Department of Agriculture). 1984. Oil Crops: Outlook and Situation Report. OCS-4. Economic Research Service, U.S. Department of Agriculture, Washington, D.C. 25 pp. USDA (U.S. Department of Agriculture). 1986. CSFII. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp. USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp. Vandewoude, M.F., and M.G. Vandewoude. 1987. Vitamin E status in a normal population: the influence of age. J. Am. Coll. Nutr. 6:307-311. Witting, L.A., and I.. Lee. 1975. Dietary levels of vitamin E and polyunsaturated fatty acids and plasma vitamin E. Am. J. Clin. Nutr. 28:571-576. VITAMIN K Vitamin  K  is the name for a group of compounds, all of which contain  the 2-methyl-1,4-naphthoquinone  moiety. In plants (phylloquinone), the substituent at C-3 is a 20-carbon phytyl group; in bacteria (menaquinones), it is a polyisoprenyl side chain with 4 to 13 5-carbon isoprenyl units. Animal tissues contain both phylloquinone and  menaquinones. Menadione, a fat-soluble synthetic compound that contains no side chain, and its water-soluble derivatives are alkylated in the liver to biologically active menaquinones in humans in vivo (Suttie, 1985). Compounds with vitamin K activity are essential for the formation of prothrombin and at least five other proteins (factors VII, IX, and X, and proteins C and S) involved in the regulation of blood clotting. Although  vitamin  K  is also required  for the biosynthesis of some other proteins found in the plasma, bone, and kidney, defective coagulation of the blood is the only major sign of vitamin K deficiency (Olson, 1984; Suttie, 1985).

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Page 108 Metabolism Under normal conditions, vitamin K is moderately (40 to 70%) well absorbed from thejejunum and ileum, but very poorly absorbed from the colon (Shearer et al., 1974). As with other lipid-soluble vitamins, absorption depends on a normal flow of bile and pancreatic juice and is enhanced by dietary fat. Consequently, the absorption of vitamin K in fat malabsorption syndromes is very poor. Absorbed vitamin K is transported primarily via the lymph in chylomicrons. It is initially concentrated in the liver and is then distributed widely among body tissues. Within cells, vitamin K is associated primarily with membranes, especially with those of the endoplasmic reticulum and mitochondria. Under normal physiological conditions, 30 to 40% of absorbed vitamin K is excreted via the bile into the feces as partially degraded, conjugated, water-soluble metabolites, whereas approximately 15% is excreted as water-soluble metabolites in the urine (Shearer et al., 1974). In humans, the total body pool of vitamin K is small, and its turnover is rapid (Bjornsson et al., 1980; Olson, 1984). Liver stores of vitamin K appear to consist of only about 10% phylloquinone and approximately 90% of various menaquinones, which are probably synthesized by intestinal bacteria (Shearer et al., 1988). It appears, however, that the total need for vitamin K cannot be supplied from synthesis of menaquinones by intestinal bacteria, since simple restriction of dietary vitamin K can result in alterations in clotting factors (Suttie et al., 1988). In the liver, vitamin K plays an essential role in the posttranslational carboxylation of glutamic acid to y-carboxyglutamyl residues in prothrombin (coagulation factor II) and in factors VII, IX, and X, and proteins C, S, and Z (Magnusson et al., 1974; Nelsestuen et al., 1974; Stenflo et al., 1974). In the absence of vitamin K, these proteins are still synthesized but are nonfunctional because they lack the g-carboxyglutamyl residues. During the incorporation of carbon dioxide into g-carboxyglutamyl residues, reduced vitamin K is oxidized to an epoxide intermediate and is then recycled back to the reduced vitamin by the action of several membrane-bound enzymes (Friedman et al., 1979; Hall et al., 1982; Larson et al., 1981). Other vitamin K-dependent proteins that contain g-carboxyglutamyl residues have also been identified in bone, kidney, and other tissues. These proteins, like the clotting proteins, bind calcium ions and seem to be related to bone crystal formation and possibly to synthesis of some phospholipids (Lev and Sundaram, 1988; Price, 1988).

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Page 109 Dietary Sources and Usual Intakes The vitamin K content of commonly consumed foods is not known with precision and therefore is not given in food composition tables. Early data, mainly from bioassays, were summarized by Olson (1988). In more recent studies in which high pressure liquid chromatography was used, the phylloquinone content of common vegetables often differed by as much as threefold (higher or lower) from values found using chick bioassays (Shearer et al., 1980). Green leafy vegetables, which provide 50 to 800 µg of vitamin K per 100 g of food, are clearly the best dietary sources. Small but significant amounts of vitamin K (1 to 50 µg/100 g) are also present in milk and dairy products, meats, eggs, cereals, fruits, and vegetables. Human milk is relatively low in vitamin K (approximately 2 µg/ liter). Thus, breastfed infants may ingest only about 1 µg/day, which amounts to only 20% of the presumed requirement of 5 µg/day, or to an even smaller portion of the rather generous recommended content of 4 µg/100 kcal in infant formulas (AAP, 1976). Cow's milk contains 4 to 18 µg of vitamin K per liter (Haroon et al., 1982; Shearer et al., 1980). Another potentially important source of vitamin K is the bacterial flora in the jejunum and ileum. The extent of utilization of menaquinones synthesized by gut microorganisms is not clear, however. A normal mixed diet consumed daily by a healthy adult in the United States has been estimated to contain an average of 300 to 500 µg of vitamin K (Olson, 1988), although more recent studies suggest that these estimates may be too high (Suttie et al., 1988). Green leafy vegetables were consumed by only 1 of 12 persons in the United States on a specific day in 1977 (USDA, 1980); however, the average daily intake of vitamin K by surveyed individuals still seems to be adequate. The vitamin K intake in a single day is not a reliable indicator of its average intake by an individual over an extended period, and diets largely free of green leafy vegetables may still contain adequate amounts of vitamin K. Recommended Allowances Adults The major criterion for assessing the adequacy of vitamin K status in adult humans is the maintenance of plasma prothrombin concentrations in the normal range, i.e., from 80 to 120 µg/ml (Blanchard et al., 1981). Although prothrombin levels are commonly based on assays that determine clotting time, both normal and

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Page 110 abnormal (des-g-carboxyglutamyl) prothrombin in the plasma can now be measured directly. The ratio of the two may be a useful indicator of marginal or incipient vitamin K deficiency in the absence of an observable defect in blood clotting (Blanchard et al., 1981; Corrigan et al., 1981). The 24-hour urine excretion of y-carboxyglutamic acid along with plasma vitamin K concentration have also been used to assess vitamin K status (Sadowski et al., 1988). In vitamin K-depleted adult subjects fed a diet containing small amounts of vitamin K (10 µg/day) and treated with neomycin for 4 weeks, daily intravenous dosages of 1.5 µg of vitamin K per kilogram of body weight restored normal plasma prothrombin levels, whereas 0.1 µg/kg daily did not (Frick et al., 1967). In a study of four adults fed 0.4 µg/kg daily and treated with antibiotics for 5 weeks, plasma concentrations of prothrombin fell but remained at 70% or more of normal values (O'Reilly, 1971). Suttie et al. (1988) reported studies of 10 college-aged male subjects who consumed a self-selected diet that eliminated foods high in vitamin K (mainly green leafy vegetables and liver) for 21 days. Such a diet provided the subjects with an average of approximately 50 µg phylloquinone per day. Serum phylloquinone values decreased during this period, but prothrombin time remained in what was considered the normal range. By the end of the period of vitamin K restriction, however, there was a significant increase in the ratio of abnormal prothrombin to active prothrombin. Similarly, a decrease in urinary g-carboxyglutamic acid was observed during the period of reduced vitamin K consumption. Supplementation of the subjects with 50 or 500 µg of phylloquinone per day for 12 days eliminated the abnormal ratios of active to abnormal prothrombin and restored g-carboxyglutamic acid excretion to normal values. The supplement of 50 µg of phylloquinone did not raise plasma phylloquinone levels to prerestriction levels, although the 500 µg supplement was effective in raising serum phylloquinone levels to about double normal values. This study (Suttie et al., 1988) shows that simple elimination of foods high in vitamin K from a normal diet can result in signs of vitamin K inadequacy. It also suggests that bacterial synthesis of menaquinones was not sufficient to eliminate the need for dietary vitamin K in subjects consuming approximately 50 µg of phylloquinone per day. Given the results of Frick et al. (1967) and the more recent results of Suttie et al. (1988) discussed above, it appears that a dietary intake of about 1 µg/kg body weight per day should be sufficient to maintain normal blood clotting time in adults. Thus, the RDA for a 79-kg man is 80 µg per day, and for a 63 kg woman, it is 65 µg.

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Page 111 Elderly persons in good health are not known to have an increased need for vitamin K. On the other hand, 75% of an older hospitalbased population had a hypoprothrombinemia that was responsive to vitamin K treatment (Hazell and Baloch, 1970). Chronic disease, drug therapy, and poor diet may well have contributed to the hypoprothrombinemic condition of this group. Trauma, physical debilitation, renal insufficiency, and chronic treatment with large doses of broad-spectrum antibiotics increase the risk of vitamin K insufficiency (Ansell et al., 1977). Pregnancy and Lactation  Data are insufficient to establish an RDA for vitamin K during pregnancy. Because vitamin K consumed in usual diets generally exceeds the RDA established for adult women, additional increments to usual intake are not recommended. Lactation imposes little additional need, since vitamin K consumed in usual diets generally exceeds the RDA. Therefore, additional increments are not recommended. Infants and Children  The newborn infant has low plasma prothrombin levels. Although some hypoprothrombinemic infants respond to vitamin K treatment, other factors, including immaturity of the liver, may cause hypoprothrombinemia in the newborn (Suttie, 1984). Because human milk contains low levels of vitamin K (2 µg/ liter) and the intestinal flora are limited, exclusively breastfed infants who do not receive vitamin K prophylaxis at birth are at very real risk of developing fatal intracranial hemorrhage secondary to vitamin K deficiency (Lane et al., 1983). Home-delivered, breastfed infants require particular attention in this regard. A recommended range of total intake for infants is 5 µg of phylloquinone or menaquinone per day during the first 6 months of infancy and 10 µg during the second 6 months. Newborn infants are routinely given a supplement of vitamin K by intramuscular injection to prevent hemorrhage (AAP, 1985). The usual dose is 0.5-1.0 mg for full-term infants and at least 1 mg for preterm infants. Infant formulas should contain 4 µg of vitamin K per 100 kcal (AAP, 1985). In the absence of specific information about the vitamin K requirements of children, RDA values for them are set at about 1 µg/kg body weight. Other Considerations In persons treated with anticoagulant drugs, such as the 4-hydroxy coumarins, vitamin K status should be carefully monitored. Acci-

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Page 112 dental ingestion of large amounts of these compounds, e.g., in rat poisons, requires vitamin K therapy (Suttie, 1984). High intakes of vitamin E can produce a vitamin K-responsive hemorrhagic condition in laboratory animals and humans, particularly when humans are also being treated with anticoagulants (Olson, 1982; Suttie, 1984). Adults treated chronically with broad-spectrum antibiotics or on longterm hyperalimentation, and patients with chronic biliary obstruction or with lipid malabsorption syndromes, are particularly sensitive to vitamin K   deficiency (Olson, 1982, 1984; Olson and Suttie, 1977; Suttie, 1984). Excessive Intakes and Toxicity Even when large amounts of vitamin K are ingested over an extended period, toxic manifestations have not been observed (Owen, 1971). However, administered menadione, but not phylloquinone, may cause hemolytic anemia, hyperbilirubinemia, and kernicterus in the newborn (Owen, 1971), primarily because of its interaction with sulfhydryl groups. References AAP (American Academy of Pediatrics). 1985. Pediatric Nutrition Handbook, 2nd ed. American Academy of Pediatrics, Elk Grove Village, Ill. ASHP (American Society of Hospital Pharmacists). 1985. Phytonadione. Pp. 17091710 in American Hospital Formulary Service: Drug Information 85. American Society of Hospital Pharmacists, Bethesda, Md. Ansell, J., E. Kumar, and R.D. Deykin. 1977. The spectrom of vitamin K deficiency. J. Am. Med. Assoc. 238:40-42. Bjornsson, T.D., P.J. Meffin, S.E. Smezey, and T.F. Blaschke. 1980. Disposition and turnover of vitamin K1 in man. Pp. 328-332 in J.W. Suttie, ed. Vitamin K Metabolism and Vitamin K-dependent Proteins. University Park Press, Baltimore. Blanchard, R.A., B.C. Furie. M.Jorgensen, S.F. Kruger, and B. Furie. 1981. Acquired vitamin K-dependent carboxylation deficiency in liver disease. N. Engl. J. Med. 305:242-248. Corrigan, J.J., Jr., L.M. Taussig, R. Beckerman, and J.S. Wagener. 1981. Factor II (prothrombin) coagulant activity and immunoreactive protein detection of vitamin K deficiency and liver disease in patients with cystic fibrosis. J. Pediatr. 99:254-257. Frick, P.G., G. Riedler, and H. Brogli. 1967. Dose response and minimal daily requirement for vitamin K in man. J. Appl. Physiol. 23:387-389. Friedman, P.A., M.A. Shia, P.M. Gallop, and A.E. Griep. 1979. Vitamin K-dependent gamma-carbon-hydrogen bond cleavage and nonmandatory concurrent carboxylation of peptide-bound glutamic acid residues. Proc. Natl. Acad. Sci. U.S.A. 76:3126-3129.

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Page 113 Hall, A.L., R. Kloepper, R.K.-Y Zee-Cheng, Y.J.D. Chiu, F.C. Lee, and R.E. Olson. 1982. Mechanisms of action of tert-butyl hydroperoxide in the inhibition of vitamin K-dependent carboxylation. Arch. Biochem. Biophys. 214:45-50. Haroon, Y., M.J. Shearer. S. Rahim, W.G. Gunn, G. McEnergy, and P. Barkan. 1982. The content of phylloquinone (vitamin K1) in human milk, cow's milk and infant formula foods determined by high-performance liquid chromatography.J. Nutr. 112:1105-1117. Hazell, K., and K.H. Baloch. 1970. Vitamin K deficiency in the elderly. Gerontol. Clin. 12:10-117. Lane, P.A., W.E. Hathaway,J.H. Githens, R.D. Krugman, and D.A. Rosenberg. 1983. Fatal intracranial hemorrhage in a normal infant secondary to vitamin K deficiency. Pediatrics 72:562-564. Larson, A.E., P.A. Friedman. and J.W. Suttie. 1981. Vitamin K-dependent carboxylase: stoichiometry of carboxylation and vitamin K 2,2-epoxide formation. J. Biol. Chem. 256:11032-11035. Lev, M., and K.S. Sundaram. 1988. Modulation of glycosphingolipid synthesis by vitamin K depletion in bacteria and in brain. Pp. 211-220 in J.W. Suttie, ed. Current Advances in Vitamin K Research. Elsevier, New York. Magnusson, S., L. Sottrup-Jansen, T.E. Peterson, H.R. Morris, and A. Dell. 1974. Primary structure of the vitamin K-dependent part of prothrombin. FEBS Lett. 44:189-193. Nelsestuen, G.L., T.H. Zythovicz, and J.B. Howard. 1974. The mode of action of vitamin K. J. Biol. Chem. 249:6347-6350. Olson, R.E. 1982. Vitamin K. Pp. 582-594 in R.W. Colman, J. Hirsch, V.J. Marder, and W.W. Salzman, eds. Hemostasis and Thrombosis. Lippincott, New York. Olson, R.E. 1984. The function and metabolism of vitamin K. Annu. Rev. Nutr. 4:281-337. Olson, R.E. 1988. Vitamin K. Pp. 328-339 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia. Olson, R.E., and J.W. Suttie. 1977. Vitamin K and carboxyglutamate biosynthesis. Vit. Horm. 35:59-108. O'Reilly, R.A. 1971. Vitamin K in hereditary resistance to oral anticoagulant drugs. Am. J. Physiol. 221:1327-1330. Owen, C.A.,Jr. 1971. Pharmacology and toxicology of the vitamin K group. Pp. 492509 in W.H. Sebrell and R.S. Harris, eds. The Vitamins, Vol. III Academic Press, New York. Price, P.A. 1988. Bone Gla protein and matrix Gla protein: identification of the probable structures involved in substrate recognition by the g-carboxylase and discovery of tissue differences in vitamin K metabolism. Pp. 259-274 in J.W. Suttie, ed. Current Advances in Vitamin K Research. Elsevier, New York. Sadowski, J.A., D.S. Bacon, S. Hood, K.W. Davidson, C.M. Ganter, Y. Haroon, and D.C. Shepard. 1988. The application of methods used for the evaluation of vitamin K nutritional status in human and animal studies. Pp. 453-463 in J.W. Suttie, ed. Current Advances in Vitamin K Research. Elsevier, New York. Shearer, M.J., A. McBurney, and P. Barkhan. 1974. Studies on the absorption and metabolism of phylloquine (vitamin K) in man. Vit. Horm. 32:513-542. Shearer, M.J., V. Allan, Y. Haroon, and P. Barkhan. 1980. Nutritional aspects of vitamin K in the Human. Pp. 317-327 in J.W. Suttie, ed. Vitamin K Metabolism and Vitamin K-dependent Proteins. University Park Press, Baltimore. Shearer, M.J., P.T. McCarthy, and O.E. Crampton. 1988. The assessment of human vitamin K status from tissue measurements. Pp. 437-452 in J.W. Suttie, ed. Current Advances in Vitamin K Research. Elsevier, New York.

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Page 114 Stenflo, J., P. Fernlund, W. Egan, and P. Roepstorff. 1974. Vitamin K-dependent modifications of glutamic acid residues in prothrombin. Proc. Natl. Acad. Sci. U.S.A. 71:2730-2733. Suttie, J.W. 1984. Vitamin K. Pp. 147-198 in L.J. Machlin, ed. Handbook on Vitamins, Marcel Dekker, New York. Suttie, J.W. 1985. Vitamin K. Pp. 225-311 in A.T. Diplock, ed. The Fat Soluble Vitamins. William Heinemann, Ltd., London. Suttie, J.W., L.L. Mummah-Schendel, D.V. Shah, B.J. Lyle, and J.L. Greger. 1988. Vitamin K deficiency from dietary vitamin K restriction in humans. Am. J. Clin. Nutr. 47:475-480. USDA (U.S. Department of Agriculture). 1980. Nationwide Food Consumption Survey 1977-78. Food and Nutrient Intakes of Individuals in I Day in the United States, Spring 1977. Preliminary Report No. 2. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md.