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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 5 Vitamin K SUMMARY Vitamin K functions as a coenzyme during the synthesis of the biologically active form of a number of proteins involved in blood coagulation and bone metabolism. Because of the lack of data to estimate an average requirement, an Adequate Intake (AI) is set based on representative dietary intake data from healthy individuals. The AI for men and women is 120 and 90 μg/day, respectively. No adverse effect has been reported for individuals consuming higher amounts of vitamin K, so a Tolerable Upper Intake Level (UL) was not established. BACKGROUND INFORMATION Compounds with vitamin K activity are 3-substituted 2-methyl-1,4-naphthoquinones. Phylloquinone, the plant form of the vitamin, contains a phytyl group; “long chain” menaquinones (MK-n), produced by bacteria in the lower bowel, contain a polyisoprenyl side chain with 6 to 13 isoprenyl units at the 3-position (Suttie, 1992). A specific menaquinone, MK-4, is not a major bacterial product, but can be formed by the cellular alkylation of menadione (2-methyl-1,4-naphthoquinone). Recently, MK-4 has been shown to be produced from phylloquinone in germ-free animals and in tissue culture (Davidson et al., 1998).
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Function Vitamin K plays an essential role in the posttranslational conversion of specific glutamyl residues in a limited number of proteins to γ-carboxyglutamyl (Gla) residues (Suttie, 1993). These proteins include plasma prothrombin (coagulation factor II) and the plasma procoagulants, factors VII, IX, and X. Because under-γ-carboxylated forms of these proteins lack biological activity, the classical sign of a vitamin K deficiency has been a vitamin K-responsive increase in prothrombin time and, in severe cases, a hemorrhagic event. Two structurally related vitamin K-dependent proteins (Price, 1988), osteocalcin found in bone and matrix Gla protein originally found in bone but now known to be more widely distributed, have received recent attention as proteins with possible roles in the prevention of chronic disease (Ferland, 1998). No relationship between a decreased biological activity of any of the other vitamin K-dependent proteins and a disease-related physiological response has been postulated. Physiology of Absorption, Metabolism, and Excretion Phylloquinone, the major form of vitamin K in the diet, is absorbed in the jejunum and ileum in a process that is dependent on the normal flow of bile and pancreatic juice and is enhanced by dietary fat (Shearer et al., 1974). Absorption of free phylloquinone is nearly quantitative (Shearer et al., 1970), but recent studies (Garber et al., 1999; Gijsbers et al., 1996) suggest that the vitamin in food sources is less well absorbed. Absorbed phylloquinone is secreted into lymph as a component of chylomicrons and enters the circulation in this form. Circulating phylloquinone is present in the very low density triglyceride-rich lipoprotein fractions and chylomicrons (Kohlmeier et al., 1996; Lamon-Fava et al., 1998). A dependence of plasma phylloquinone concentrations (Kohlmeier et al., 1995) on the distribution of lipoprotein apoE isoforms suggests that the vitamin enters the liver through the endocytosis of chylomicron remnants. The liver rapidly accumulates ingested phylloquinone and contains the highest concentration. Skeletal muscle contains little phylloquinone, but significant concentrations are found in the heart and some other tissues (Davidson et al., 1998; Thijssen and Drittij-Reijnders, 1994). It is not known how or if hepatic phylloquinone is secreted and transported from the liver to peripheral tissues. The vitamin is rapidly catabolized and excreted from the liver, mainly in bile. A smaller amount appears in urine (Shearer et al.,
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 1974). The excretion products have not been extensively characterized but are known to proceed through the oxidative degradation of the phytyl side chain of phylloquinone, followed by glucuronide conjugation. Turnover in the liver is rapid and hepatic reserves are rapidly depleted when dietary intake of vitamin K is restricted (Usui et al., 1990). The human gut contains a large amount of bacterially produced menaquinones, but their contribution to the maintenance of vitamin K status has been difficult to assess (Suttie, 1995). Although the content is extremely variable, human liver contains about 10 times as much vitamin K as a mixture of menaquinones than as phylloquinone (Shearer, 1992; Thijssen and Drittij-Reijnders, 1996; Usui et al., 1990). Absorption of these very lipophilic membrane-associated compounds from the distal bowel has been difficult to demonstrate (Ichihashi et al., 1992). Evidence of vitamin K inadequacy in normal human subjects following dietary restriction of vitamin K also suggests that this source of the vitamin is not utilized in sufficient amounts to maintain maximal γ-carboxylation of vitamin K-dependent proteins. One specific menaquinone, MK-4, appears to have a unique yet unidentified role. MK-4 can be formed from menadione (2-methyl-1,4-naphthoquinone) but is also formed in animal tissues from phylloquinone (Davidson et al., 1998; Thijssen and Drittij-Reijnders, 1994). It is present in much higher concentrations than phylloquinone in tissues such as pancreas, salivary gland, brain, and sternum, and its concentration in these tissues is to some degree dependent on phylloquinone intake. Clinical Effects of Inadequate Intake A clinically significant vitamin K deficiency has usually been defined as a vitamin K-responsive hypoprothrombinemia and is associated with an increase in prothrombin time (PT) and, in severe cases, bleeding. Spontaneous cases have been rare and have usually been associated with various lipid malabsorption syndromes (Savage and Lindenbaum, 1983). There are numerous case reports of bleeding episodes in antibiotic-treated patients, and these have often been ascribed to an acquired vitamin K deficiency resulting from a suppression of menaquinone-synthesizing organisms. However, these reports are complicated by the possibility of general malnutrition in this patient population and by the antiplatelet action of many of the same drugs (Suttie, 1995). Reports of experimentally induced, clinically significant vitamin K deficiencies are scant. Udall (1965) fed 10 healthy subjects a diet
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc that probably contained less than 10 μg /day of phylloquinone. After 3 weeks, a statistically significant increase in the PT was observed, but it was still within the normal range. In another study, Frick and coworkers (1967) administered a parenteral nutrient solution to a small number of neomycin-treated adults for 4 weeks and observed prolonged PT that responded to the parenteral administration of phylloquinone. They concluded that the minimal daily requirement was between 0.3 and 1.05 μg per kg body weight of phylloquinone. In more recent studies (Allison et al., 1987; Ferland et al., 1993), feeding healthy individuals diets containing 5 to 10 μg/day of phylloquinone for 14- to 16-day periods failed to induce any change in PT measurements. These limited studies, conducted over a number of years, indicate that the simple restriction of vitamin K intake to levels almost impossible to achieve in any nutritionally adequate, self-selected diet do not impair normal hemostatic control in healthy subjects. Although there is some interference in the hepatic synthesis of the vitamin K-dependent clotting factors that can be measured by sensitive assays, standard clinical measures of procoagulant potential are not changed. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR VITAMIN K Various indicators have been used to assess vitamin K status in humans (Booth and Suttie, 1998). Of these, only one, prothrombin time (PT), has been associated with adverse clinical effects. All other indicators have been shown to respond to alterations in dietary vitamin K, but the physiological significance of these diet-induced changes is lacking. Therefore, these indicators have been used to assess relative changes in vitamin K status but do not provide, by themselves or collectively, an adequate basis on which to estimate an average requirement for vitamin K. Prothrombin Time The classical PT used to measure the procoagulant potential of plasma is not a sensitive indicator of vitamin K status because plasma prothrombin concentration must be decreased by approximately 50 percent before a value is outside of the “normal” range (Suttie, 1992). Furthermore, studies conducted thus far clearly indicate that PT does not respond to a change in dietary vitamin K in healthy
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc subjects (Allison et al., 1987; Bach et al., 1996; Binkley et al., 1999; Booth et al., 1999a; Suttie et al., 1988). Factor VII On the basis of its relatively short half-life (approximately 6 hours), factor VII activity has been used to assess vitamin K status. Allison and colleagues (1987) maintained 33 healthy subjects, some given antibiotics, for 2 weeks on a low vitamin K diet (less than 5 μg/day of phylloquinone) and observed a decrease from the normal range of plasma factor VII in seven of the subjects. However, in the absence of antibiotic treatment, factor VII activity is not a sensitive indicator of vitamin K status as it does not usually respond to changes in vitamin K intake in healthy individuals (Bach et al., 1996; Ferland et al., 1993). Plasma and Serum Phylloquinone Concentration Both phylloquinone and the menaquinones have been used to assess status, with phylloquinone as the vitamer usually studied because it is the primary source of dietary vitamin K in western countries (Booth and Suttie, 1998). Serum or plasma phylloquinone concentration reflects recent intakes and has been shown to respond to changes in dietary intake within 24 hours (Sokoll et al., 1997). However, given the distribution of vitamin K in the food supply, a single day plasma (serum) phylloquinone concentration may not reflect normal dietary intake. Positive correlations between circulating phylloquinone concentration and dietary intake have been reported, but the strength of this association has varied according to studies, possibly due to differences in intake assessment methodology (i.e., number of diet record days) (Booth et al., 1995, 1997b). In healthy individuals, phylloquinone concentrations are higher in older subjects than in younger subjects, irrespective of dietary intake (Booth et al., 1997b; Ferland et al., 1993; Sokoll and Sadowski, 1996). Strong positive correlations between plasma (serum) phylloquinone and triglyceride concentrations have been reported (Kohlmeier et al., 1995; Sadowski et al., 1989; Saupe et al., 1993), a finding that likely explains the higher vitamin K concentrations observed in older individuals (Sadowski et al., 1989). Normal ranges for plasma phylloquinone concentration in healthy adults aged 20 to 49 years (n = 131) was 0.25 to 2.55 nmol/L; for those aged 65 to 92 years (n = 195), 0.32 to 2.67 nmol/L (Sadowski et al., 1989).
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Urinary γ-Carboxyglutamyl Residues After protein catabolism, γ-carboxyglutamyl (Gla) residues contained in the vitamin K-dependent proteins are not further metabolized and are excreted via urine (Shah et al., 1978). As a result, urinary Gla excretion has been used as an indicator of vitamin K status. Urinary Gla responds to alterations in dietary intake, but periods of several days are needed before any change can be observed (Ferland et al., 1993; Suttie et al., 1988). In a study by Suttie and coworkers (1988), 10 college-age men were asked to eliminate the major sources of vitamin K from their diet, thereby reducing their intake to less than 40 μg/day of phylloquinone. Urinary Gla excretion decreased 22 percent after 3 weeks and returned to baseline values 12 days after supplementation with 50 or 500 μg of phylloquinone. In a recent study, increasing phylloquinone intakes from 100 μg/day to a range of 377 to 417 μg/day for 5 days did not induce significant changes in urinary Gla (Booth et al., 1999a). Response of urinary Gla to vitamin K intake alterations appears to be age-specific. In a study by Ferland and coworkers (1993), 32 subjects were divided into four groups of eight (men or women, 20 to 40 or 60 to 80 years old) and housed in a metabolic research unit. They were fed 80 μg of phylloquinone for 4 days followed by a low vitamin K diet (approximately 10 μg phylloquinone/day) for 16 days. At the end of the depletion period, urinary Gla excretion had decreased significantly in the younger, but not the older subjects. Short-term supplementation with 45 μg/day of phylloquinone reversed the decline to near baseline values. In another study involving 263 healthy individuals (127 men, 136 women) aged 18 to 55 years, urinary Gla/creatinine excretion ratios increased significantly with age in both men and women with values 20 percent higher in women over the age span (Sokoll and Sadowski, 1996). To date, there are insufficient data for using urinary Gla excretion for estimating an average requirement. Undercarboxylated Prothrombin In humans, an insufficiency of vitamin K leads to the secretion into plasma of biologically inactive, under-γ-carboxylated forms of the vitamin K-dependent clotting factors. These proteins are referred to as protein induced by vitamin K absence or antagonism (PIVKA). In reference to prothrombin (factor II), the term used is PIVKA-II. This protein has been measured by specific immunoassay (Blanchard et al., 1981), by thrombin generation after the removal
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc of normal prothrombin by adsorption to barium or calcium salts (Francis, 1988), or by an indirect assay that compares biologically active prothrombin to the amount of thrombin that can be generated by a nonphysiological activator (Allison et al., 1987). A number of immunochemical assays, which are very sensitive and are capable of measuring very small increases of this indicator of vitamin K insufficiency, are now commercially available. Typically, these kits will detect changes of a few ng/mL whereas plasma prothrombin concentration averages 100 μg/mL. Concentrations of PIVKA-II vary little with aging in healthy subjects (Sokoll and Sadowski, 1996) but respond to dietary alterations. In two independent studies using immunological assays (Booth et al., 1999b; Ferland et al., 1993), intakes of 10 μg/day of phylloquinone were associated with abnormal PIVKA-II concentrations (greater than 2 ng/mL) in the great majority of subjects, whereas an intake of 100 μg/day was associated with normal (less than 2 ng/ mL) PIVKA-II concentrations in 15 of 16 subjects (Booth et al., 1999b). In older studies that used indirect colorimetric assays, abnormal PIVKA-II concentrations were observed with diets containing 40 to 60 μg/day of phylloquinone but were normal when intakes were approximately 80 μg/day (Jones et al., 1991; Suttie et al., 1988). Although it is clear from these data that PIVKA-II concentrations can be influenced by vitamin K intake, results from these studies cannot be used to set dietary vitamin K recommendations. This is because there have been no studies to compare the immunoassay and colorimetric studies for determining whether the data given above can be used collectively. Therefore, at the present there are inadequate dose-response data from a single procedure. Intervention studies using graded intakes of vitamin K and protocols of longer duration need to be conducted before this indicator can be used to establish dietary recommendations for vitamin K. Under-γ-carboxylated Osteocalcin Small amounts of the bone protein, osteocalcin, circulate in plasma, and like PIVKA-II, under-γ-carboxylated osteocalcin (ucOC) has been considered an indicator of suboptimal vitamin K status. Assays for measuring the degree of carboxylation of osteocalcin have been indirect and have relied on the lower affinity of ucOC for hydroxy-apatite (Knapen et al., 1989) or barium sulfate (Sokoll et al., 1995). Only recently has direct assessment of ucOC been possible with the
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc development of a monoclonal antibody specific for the undercarboxylated form of osteocalcin (Vergnaud et al., 1997). As discussed below, a number of reports have correlated decreased bone mineral density (BMD) or increased fracture rate with a five-to eight-fold increase in ucOC. Concurrently, it has been observed that vitamin K intakes similar to those reported for the general population did not ensure complete carboxylation of osteocalcin (Bach et al., 1996; Sokoll and Sadowski, 1996) and that ucOC could be decreased by increasing vitamin K intake (Binkley et al., 1999; Booth et al., 1999b; Douglas et al., 1995; Knapen et al., 1989, 1993). These reports have led to the suggestion that vitamin K requirements for bone function are probably much higher than those needed to maintain normal hemostasis and that the recommendation for vitamin K should be much higher than current recommendations (Weber, 1997). However, a number of issues must be considered before a minimal ucOC concentration can be used as an indicator to estimate an average requirement for vitamin K. Because osteocalcin is used clinically as a marker of bone turnover, there are a number of commercial kits currently marketed. Although they may all be internally reproducible, they react with different epitopes and have different reactivity with osteocalcin degradation fragments. Therefore, they do not give the same “normal” values (Delmas et al., 1990a, 1990b; Gundberg et al., 1998). Because of this, most investigators interested in the influence of vitamin K status on bone have expressed measurements of ucOC as percent ucOC. In apparently healthy subjects, ucOC has ranged from 3 to 45 percent, depending on the assay. The basis for these higher values has not been established but in many cases may reflect the fact that the assay is recognizing some osteocalcin fragments that do not contain potential Gla sites as ucOC. This interpretation of the data is supported by the high ucOC values that have been seen in some studies after vitamin K supplementation (Booth et al., 1999a; Douglas et al., 1995; Knapen et al., 1993). Other investigators have reported nearly complete elimination of ucOC by vitamin K supplementation. Bach and coworkers (1996) reduced ucOC from 8 to 3 percent and from 2 to 1 percent in small groups (n = 9) of younger and older subjects, respectively, with 1 mg phylloquinone for 5 days. Binkley and coworkers (1999) supplemented a larger (n = 107) group of both younger and older subjects by supplementation with 1 mg phylloquinone for 2 weeks and reduced ucOC from 8 to 3 percent and from 7 to 3 percent, respectively. The wide variations in percent ucOC reported for vitamin K-
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc sufficient subjects have made it essentially impossible to compare studies. The emphasis that investigators have placed on ucOC, an indicator of a nonfunctional protein, has also influenced thinking in this field. If percent ucOC in the apparently healthy population is as low as indicated in the more recent studies, about 90 to 95 percent of osteocalcin is in its biologically active form. Whether it is reasonable to assume that an increase in this value to 100 percent would be expected to have any physiological significance is a question that must be considered. Although there is little doubt that vitamin K intake affects the degree of osteocalcin λ-carboxylation, the technical problems associated with the current assays and the uncertainty surrounding the physiological significance of diet-induced changes prevent the use of ucOC for estimating an average requirement for vitamin K. Relationship of Vitamin K Intake to Chronic Disease Vitamin K and Osteoporosis The possibility that vitamin K may have a role in osteoporosis was first suggested with reports of lower circulating phylloquinone concentrations in osteoporotic patients having suffered a spinal crush fracture or fracture of the femur (Hart et al., 1985; Hodges et al., 1991, 1993). More recently, lower circulating phylloquinone and menaquinone concentrations have been observed in subjects with reduced BMD (Kanai et al., 1997; Tamatani et al., 1998) though other studies have not confirmed this finding (Rosen et al., 1993). As the circulating vitamin K concentration can be altered through diet within a few days, the clinical significance of these relationships remains to be established. The role of vitamin K in bone metabolism has also been investigated by studying the vitamin K bone protein osteocalcin and its undercarboxylated form, ucOC. The extent to which osteocalcin is undercarboxylated has been assessed with respect to age, bone status, and risk of hip fracture (Binkley and Suttie, 1995; Vermeer et al., 1996). Although ucOC was reported to increase with age in some studies (Knapen et al., 1998; Liu and Peacock, 1998; Plantalech et al., 1991), other reports have not confirmed this finding (Sokoll and Sadowski, 1996). Negative correlations have also been reported between ucOC and BMD, but the strength of the associations has varied depending on the population studied (Knapen et al., 1998; Liu and Peacock, 1998; Vergnaud et al., 1997). Although the observed relationship between ucOC and BMD is of interest, it
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc requires further investigation as significant inverse relationships have also been observed between BMD and total osteocalcin (Liu and Peacock, 1998; Ravn et al., 1996) and between BMD and the active (carboxylated) form of osteocalcin (Knapen et al., 1998). Undercarboxylated osteocalcin has also been associated with increased risk of hip fracture. In a series of reports involving institutionalized elderly women studied for periods of up to 3 years, women with elevated ucOC at the start of the study had a three- to six-fold higher risk of suffering a hip fracture during the follow-up period (Szulc et al., 1993, 1996). It is of interest that in these studies the concentration of carboxylated osteocalcin, presumably the biologically active form, also was highest in the hip fracture group. Similar results subsequently were observed in a 22-month follow-up study involving a group of 359 independently living women (104 women having suffered a hip fracture and 255 controls) (Vergnaud et al., 1997). When the risk of hip fracture was related to levels of ucOC, increased baseline ucOC levels were associated with increased hip fracture risk with an odds ratio of 2. Although it is not possible to calculate carboxylated osteocalcin by quartiles from the data presented, this biologically active form of osteocalcin was not reduced in the hip fracture group. These studies are of interest with respect to a potential role of vitamin K in bone health, but they should be interpreted with caution given that in most cases they did not control for confounding factors such as overall quality of the diet or for nutrients known to influence bone metabolism (i.e., vitamin D and calcium). The increased concentration of circulating carboxylated osteocalcin in the fracture-prone population would also suggest that if vitamin K status has a role in bone health, it is not mediated through the action of osteocalcin. Vitamin K intake has been associated with bone health in an epidemiological study. Utilizing the Nurse’s Health Study cohort, researchers found that vitamin K intakes were inversely related to the risk of hip fractures in a 10-year follow-up period (Feskanich et al., 1999). Vitamin K intakes of 71,327 women aged 38 to 63 years were assessed through the use of a food frequency questionnaire. Women in quintiles two through five of vitamin K intake had a lower age-adjusted relative risk of hip fracture (relative risk, 0.70; 95 percent confidence interval, 0.53–0.93) than women in the lowest quintile (vitamin K intake less than 109 μg/day). Risk did not decrease between quintiles two and five, a finding that should be explored further. Intervention studies using different K vitamers in physiological and pharmacological dosages have also been performed. In a study
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc involving a group of secluded nuns, 2-week supplementation with 1 mg of phylloquinone was associated with significant decreases in urinary hydroxyproline and calcium excretion in subjects characterized as being “fast losers” of calcium (calcium/creatinine greater than 0.6) (Knapen et al., 1989). These results were subsequently confirmed in a larger group of free-living women, but the effect was again limited to postmenopausal, “fast loser” subjects (Knapen et al., 1993). The fact that in these two studies the positive effect of phylloquinone supplementation was restricted to subgroups of the populations limits the generalizability of the results. More recently, administration of pharmacological doses (45 mg/ day) of menoquinone (MK-4) to osteoporotic patients for 6 months was associated with an increase in metacarpal bone density, increased total osteocalcin, and reduced urinary calcium excretion. Interestingly, MK-4 treatment was associated with increased para-thyroid hormone and had no effect on BMD of the lumbar spine (Orimo et al., 1992). Although this study is probably the most rigorous one conducted thus far with respect to study design and clinical outcomes, it has little relevance to vitamin K nutrition as the action of MK-4 in bone may be quite different from that of phylloquinone. Studies have indeed shown that the action of MK-4 may be independent of its usual role in the γ-carboxylation of the Gla proteins (Hara et al., 1995). Although many of the studies discussed so far point to a role for vitamin K in bone, results from studies involving patients undergoing anticoagulant therapy with warfarin, a vitamin K antagonist, tend not to support this possibility. Because patients treated with warfarin are in a constant state of relative vitamin K deficiency by virtue of the drug’s action, these patients would likely be at risk of bone disorders. In a recent meta-analysis (nine studies), long-term exposure to oral anticoagulants, including warfarin, was assessed in relation to bone density (Caraballo et al., 1999). Oral anticoagulant exposure was found to be associated with lower bone density in the ultradistal radius; however, there was no significant effect on the distal radius, lumbar spine, femoral neck, or femoral trochanter. Finally, it should be mentioned that mice lacking the gene that codes for osteocalcin were recently studied (Ducy et al., 1996). The phenotype was not that of decreased mineralization; but rather these animals were found to present greater bone mass and stronger bones than the wild-type animals. Whether vitamin K intake is a significant etiological component of osteoporosis is difficult to establish on the basis of the studies performed thus far. However, clinical intervention studies presently
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc K in some diets. The bioavailability and the relative biological activity of dihydrophylloquinone have not been determined with any certainty. The long-chain menaquinones, which are produced in substantial amounts by intestinal microorganisms, can also serve as active forms of vitamin K, but they are not widely distributed in commonly consumed foods. Green vegetables and plant oils, the major dietary sources of vitamin K, do not contain menaquinones, and only small amounts are found in animal products. Relatively large amounts (40–80 μg/100 g) can, however, be obtained from some cheeses (Schurgers et al., 1999). Dietary Intake The availability of reliable data on the vitamin K content of foods has now made it possible to obtain reasonable estimates of the dietary phylloquinone intake of the North American population. The results of a number of studies on phylloquinone intake that used dietary records, with or without recall or a food frequency questionnaire, have been summarized by Booth and Suttie (1998) and are presented in Table 5-2. These data are somewhat variable but indicate a mean phylloquinone intake of about 150 μg/day for older (above 55 years) and 80 μg/day for younger men and women. Gender differences were not apparent in these studies. Data from nationally representative U.S. surveys are available to estimate vitamin K intakes (Appendix Tables C-10, C-11, E-1). Data from the Third National Health and Nutrition Examination Survey (NHANES III) shows that median intakes of dietary vitamin K ranged from 79 to 88 μg/day for women and 89 to 117 μg/day for men (Appendix Table C-10). Because of the relatively small number of foods that provide significant amounts of phylloquinone in the diet, the daily variation in intake is high, and Booth and coworkers (1995) have estimated that a 5-day record of intake is needed to get a true measure of dietary intake. Data on phylloquinone intake have recently been calculated (Booth et al., 1999c) from 14-day food diaries collected by the Market Research Corporation of America. These data reflect the intake of nearly 4,000 men and women aged 13 years or older with a demographic profile similar to that of the U.S. census. These data clearly demonstrate the large daily variation in phylloquinone intake and indicate an average intake of 70 to 80 μg/day for the U.S. adult population. The same data provide an estimate of the dihydrophylloquinone intake of this population (19 μg/day for men and 15 μg/day for women) that is about 20 to 25 percent as much as the intake of phylloquinone.
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc The adult phylloquinone intake in The Netherlands has been reported to be two to three times higher than that of the U.S. population (Schurgers et al., 1999). Whether this represents a real difference in the consumption of phylloquinone-rich foods or differences in methods used to estimate foods consumed is not known at the present time. This study has also provided an estimate of the average intake of long-chain menaquinones of 21 μg/day. Comprehensive data on menaquinone intake are not available for the U.S. population. Intake from Supplements The median intakes of vitamin K from food and supplements for the four adult age groups was 93 to 119 μg/day for American men who took supplements (Appendix Table C-11). The median vitamin K intake from food and supplements for women who reported consuming supplements was 82 to 90 μg/day. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. Hazard Identification No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals. Therefore, a quantitative risk assessment cannot be performed and a UL cannot be derived for vitamin K. A search of the literature revealed no evidence of toxicity associated with the intake of either the phylloquinone or menaquinone forms of vitamin K. A synthetic form of vitamin K, menadione, has been associated with liver damage (Badr et al., 1987; Chiou et al., 1998) and therefore is no longer used therapeutically. One study showed a significant association between intramuscu-
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc larly (IM) administered vitamin K and childhood cancer, particularly leukemia (Golding et al., 1992). This study compared 195 children diagnosed with cancer between 1971 and 1991 and born in one of two major hospitals (between 1965 and 1987) with 558 controls. Golding and coworkers (1992) reported a significant association between IM vitamin K and cancer incidence (p = 0.002; observed risk, 1.97; 95 percent confidence interval, 1.3–3.0). No significantly increased risk was reported for children who had been given oral vitamin K. These findings on IM vitamin K doses have limited relevance to ULs based on oral intake. Furthermore, evidence from other population studies fails to confirm an association between vitamin K and cancer (Ansell et al., 1996; Klebanoff et al., 1993; McKinney et al., 1998; Parker et al., 1998; Passmore et al., 1998). In a nested case-control study that used data from a large, multicenter prospective study (54,795 children), Klebanoff and coworkers (1993) found no association between vitamin K exposure and an increased risk of any childhood cancer or of all childhood cancers combined. Ansell and coworkers (1996) assessed associations between leukemia and prenatal and neonatal exposures and failed to show an increased risk of childhood leukemia in neonates receiving IM-administered vitamin K. The findings of Ansell and coworkers (1996) were confirmed by three similar case-control studies (McKinney et al., 1998; Parker et al., 1998; Passmore et al., 1998). Data from animal models have shown no toxicity of vitamin K (NRC, 1987). No adverse effects were reported with administration of up to 25 g/kg of phylloquinone either parenterally or orally to laboratory animals (Molitor and Robinson, 1940). Dose-Response Assessment The data on adverse effects from high vitamin K intakes are not sufficient for a quantitative risk assessment, and a UL cannot be derived. Intake Assessment The highest intake of dietary vitamin K reported for the U.S. population was 340 μg/day in women aged 19 through 30 years (Appendix Table C-10). The highest intake of vitamin K from food and supplements was 367 μg/day, also in women aged 19 through 30 years (Appendix Table C-11).
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Risk Characterization No adverse effects have been reported with high intakes of vitamin K. RESEARCH RECOMMENDATIONS FOR VITAMIN K Clinical studies of vitamin K supplementation aimed at elucidating the physiological significance of undercarboxylated osteocalcin; these studies should be designed so as to relate this indicator to overall bone health and integrity. Knowledge of the function of all of the vitamin K-dependent proteins and their role in human physiology. Knowledge of a possible role of vitamin K in promoting human health other than that mediated by the known Gla-containing vitamin K-dependent proteins. Further knowledge of the bioavailability of dietary vitamin K. REFERENCES AAP (American Academy of Pediatrics). 1993. Controversies concerning vitamin K and the newborn. Pediatrics 91:1001–1003. Alexander GD, Suttie JW. 1999. The effects of vitamin E on vitamin K activity. FASEB J 13:A535. Allison PM, Mummah-Schendel LL, Kindberg CG, Harms CS, Bang NU, Suttie JW. 1987. Effects of a vitamin K-deficient diet and antibiotics in normal human volunteers. J Lab Clin Med 110:180–188. Anai T, Hirota Y, Yoshimatsu J, Oga M, Miyakawa I. 1993. Can prenatal vitamin K1 (phylloquinone) supplementation replace prophylaxis at birth? Obstet Gynecol 81:251–254. Ansell P, Bull D, Roman E. 1996. Childhood leukaemia and intramuscular vitamin K: Findings from a case-control study. Br Med J 313:204–205. Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW. 1996. Assessment of vitamin K status in human subjects administered “minidose” warfarin. Am J Clin Nutr 64:894–902. Badr M, Yoshihara H, Kauffman F, Thurman R. 1987. Menadione causes selective toxicity to periportal regions of the liver lobule. Toxicol Lett 35:241–246. Bettger WJ, Olson RE. 1982. Effect of alpha-tocopherol and alpha-tocopherolquinone on vitamin K-dependent carboxylation in the rat. Fed Proc 41:344. Binkley NC, Suttie JW. 1995. Vitamin K nutrition and osteoporosis. J Nutr 125:1812–1821. Binkley NC, Krueger D, Todd H, Foley A, Engelke J, Suttie J. 1999. Serum undercarboxylated osteocalcin concentration is reduced by vitamin K supplementation. FASEB J 13:A238. Blanchard RA, Furie BC, Jorgensen M, Kruger SF, Furie B. 1981. Acquired vitamin K-dependent carboxylation deficiency in liver disease. N Engl J Med 305:242–248.
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Booth SL, Suttie JW. 1998. Dietary intake and adequacy of vitamin K. J Nutr 128:785–788. Booth SL, Sadowski JA, Weihrauch JL, Ferland G. 1993. Vitamin K1 (phylloquinone) content of foods: A provisional table. J Food Comp Anal 6:109–120. Booth SL, Sokoll LJ, O’Brien ME, Tucker K, Dawson-Hughes B, Sadowski JA. 1995. Assessment of dietary phylloquinone intake and vitamin K status in postmenopausal women. Eur J Clin Nutr 49:832–841. Booth SL, Pennington JA, Sadowski JA. 1996a. Dihydro-vitamin K1: Primary food sources and estimated dietary intakes in the American diet. Lipids 31:715–720. Booth SL, Pennington JA, Sadowski JA. 1996b. Food sources and dietary intakes of vitamin K-1 (phylloquinone) in the American diet: Data from the FDA Total Diet Study. J Am Diet Assoc 96:149–154. Booth SL, Charnley JM, Sadowski JA, Saltzman E, Bovill EG, Cushman M. 1997a. Dietary vitamin K1 and stability of oral anticoagulation: Proposal of a diet with constant vitamin K1 content. Thromb Haemost 77:504–509. Booth SL, Tucker KL, McKeown NM, Davidson KW, Dallal GE, Sadowski JA. 1997b. Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. J Nutr 127:587–592. Booth SL, O’Brien-Morse ME, Dallal GE, Davidson KW, Gundberg CM. 1999a. Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: Comparison of younger and older adults. Am J Clin Nutr 70:368–377. Booth SL, O’Brien-Morse ME, Saltzman E, Lichtenstein AH, McKeown NM, Wood RJ, Gundberg CM. 1999b. Influence of dietary vitamin K1 (phylloquinone) on bone resorption. FASEB J 13:A580. Booth SL, Webb DR, Peters JC. 1999c. Assessment of phylloquinone and dihydrophylloquinone dietary intakes among a nationally representative sample of US consumers using 14-day food diaries. J Am Diet Assoc 99:1072–1076. Canfield LM, Hopkinson JM, Lima AF, Martin GS, Sugimoto K, Burr J, Clark L, McGee DL. 1990. Quantitation of vitamin K in human milk. Lipids 25:406–411. Canfield LM, Hopkinson JM, Lima AF, Silva B, Garza C. 1991. Vitamin K in colostrum and mature human milk over the lactation period—A cross-sectional study. Am J Clin Nutr 53:730–735. Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ III. 1999. Changes in bone density after exposure to oral anticoagulants: A meta-analysis. Osteoporos Int 9:441–448. Chiou TJ, Chou YT, Tzeng WF. 1998. Menadione-induced cell degeneration is related to lipid peroxidation in human cancer cells. Proc Natl Sci Counc Repub China B 22:13–21. Corrigan JJ Jr, Ulfers LL. 1981. Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency. Am J Clin Nutr 34:1701–1705. CPS (Canadian Paediatric Society). 1998. Routine administration of vitamin K to newborns. Joint position paper of the Canadian Paediatric Society and the Committee on Child and Adolescent Health of the College of Family Physicians of Canada. Can Fam Physician 44:1083–1090. Davidson KW, Booth SL, Dolnikowski GG, Sadowski JA. 1996. The conversion of phylloquinone to 2',3'-dihydrophylloquinone during hydrogenation of vegetable oils. J Agric Food Chem 44:980–983.
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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Kohlmeier M, Saupe J, Drossel HJ, Shearer MJ. 1995. Variation of phylloquinone (vitamin K1) concentrations in hemodialysis patients. Thromb Haemost 74:1252–1254. Kohlmeier M, Salomon A, Saupe J, Shearer MJ. 1996. Transport of vitamin K to bone in humans. J Nutr 126:1192S–1196S. Koivu TJ, Piironen VI, Henttonen SK, Mattila PH. 1997. Determination of phylloquinone in vegetables, fruits, and berries by high-performance liquid chromatography with electrochemical detection. J Agric Food Chem 45:4644–4649. Lamon-Fava S, Sadowski JA, Davidson KW, O’Brien ME, McNamara JR, Schaefer EJ. 1998. Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. Am J Clin Nutr 67:1226–1231. Lane PA, Hathaway WE. 1985. Vitamin K in infancy. J Pediatr 106:351–359. Levy RJ, Lian JB, Gallop P. 1979. Atherocalcin, a gamma-carboxyglutamic acid containing protein from atherosclerotic plaque. Biochem Biophys Res Commun 91:41–49. Liu G, Peacock M. 1998. Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density, bone quality, and hip fracture. Calcif Tissue Int 62:286–289. Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H. 1999. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 81:396–399. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. 1997. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81. Mandelbrot L, Guillaumont M, Leclercq M, Lefrere JJ, Gozin D, Daffos F, Forestier F. 1988. Placental transfer of vitamin K1 and its implications in fetal hemostasis. Thromb Haemost 60:39–43. McCarthy DJ, Lindamood C 3d, Gundberg CM, Hill DL. 1989. Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. Toxicol Appl Pharmacol 97:300–310. McKinney PA, Juszczak E, Findlay E, Smith K. 1998. Case-control study of childhood leukaemia and cancer in Scotland: Findings for neonatal intramuscular vitamin K. Br Med J 316:173–177. Molitor H, Robinson J. 1940. Oral and parenteral toxicity of vitamin K1, phthiocol, and 2 methyl 1,4 naphthoquinone. Proc Soc Exp Biol Med 43:125–128. Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Marsalisi F. 1988. The use of antenatal vitamin K in the prevention of early neonatal intraventricular hemorrhage. Am J Obstet Gynecol 159:774–779. Motohara K, Matsukane I, Endo F, Kiyota Y, Matsuda I. 1989. Relationship of milk intake and vitamin K supplementation to vitamin K status in newborns. Pediatrics 84:90–93. NRC (National Research Council). 1987. Vitamin Tolerance of Animals. Washington, DC: National Academy Press. Olsen JH, Hertz H, Blinkenberg K, Verder H. 1994. Vitamin K regimens and incidence of childhood cancer in Denmark. Br Med J 308:895–896. Orimo H, Shiraki M, Fujita T, Onomura T, Inoue T, Kushida K. 1992. Clinical evaluation of menatetrenone in the treatment of involutional osteoporosis—A double-blind multicenter comparative study with 1-α-hydroxyvitamin D3. J Bone Miner Res 7:S122.
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Representative terms from entire chapter: