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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 Âµg/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; âlong chainâ menaquinones (MK-n), pro- duced 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 pro- duced from phylloquinone in germ-free animals and in tissue cul- ture (Davidson et al., 1998). 162
VITAMIN K 163 Function Vitamin K plays an essential role in the posttranslational conver- sion of specific glutamyl residues in a limited number of proteins to Î³-carboxyglutamyl (Gla) residues (Suttie, 1993). These proteins in- clude plasma prothrombin (coagulation factor II) and the plasma procoagulants, factors VII, IX, and X. Because under-Î³-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 de- creased biological activity of any of the other vitamin K-dependent proteins and a disease-related physiological response has been pos- tulated. Physiology of Absorption, Metabolism, and Excretion Phylloquinone, the major form of vitamin K in the diet, is ab- sorbed 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 circula- tion 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 vita- min enters the liver through the endocytosis of chylomicron rem- nants. 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.,
164 DIETARY REFERENCE INTAKES 1974). The excretion products have not been extensively character- ized 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 vita- min 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 phyllo- quinone (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 Î³-carboxylation of vitamin K-dependent pro- teins. 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 asso- ciated 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 bleed- ing 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 malnutri- tion 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
VITAMIN K 165 that probably contained less than 10 Âµg /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 solu- tion to a small number of neomycin-treated adults for 4 weeks and observed prolonged PT that responded to the parenteral adminis- tration of phylloquinone. They concluded that the minimal daily requirement was between 0.3 and 1.05 Âµg 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 Âµg/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 im- possible 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 sensi- tive 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 ânormalâ range (Suttie, 1992). Furthermore, studies conducted thus far clearly indicate that PT does not respond to a change in dietary vitamin K in healthy
166 DIETARY REFERENCE INTAKES 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 Âµg/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 chang- es 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 concen- tration reflects recent intakes and has been shown to respond to changes in dietary intake within 24 hours (Sokoll et al., 1997). How- ever, 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 sub- jects 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).
VITAMIN K 167 Urinary Î³-Carboxyglutamyl Residues After protein catabolism, Î³-carboxyglutamyl (Gla) residues con- tained in the vitamin K-dependent proteins are not further metabo- lized 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 ob- served (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 Âµg/day of phylloquinone. Urinary Gla excretion decreased 22 percent after 3 weeks and returned to base- line values 12 days after supplementation with 50 or 500 Âµg of phylloquinone. In a recent study, increasing phylloquinone intakes from 100 Âµg/day to a range of 377 to 417 Âµg/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 Âµg of phylloquinone for 4 days followed by a low vitamin K diet (approximately 10 Âµg 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 Âµg/day of phylloquinone re- versed the decline to near baseline values. In another study involv- ing 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 esti- mating an average requirement. Undercarboxylated Prothrombin In humans, an insufficiency of vitamin K leads to the secretion into plasma of biologically inactive, under-Î³-carboxylated forms of the vitamin K-dependent clotting factors. These proteins are re- ferred 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
168 DIETARY REFERENCE INTAKES 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 insuffi- ciency, are now commercially available. Typically, these kits will detect changes of a few ng/mL whereas plasma prothrombin con- centration averages 100 Âµg/mL. Concentrations of PIVKA-II vary little with aging in healthy sub- jects (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 Âµg/day of phyllo- quinone were associated with abnormal PIVKA-II concentrations (greater than 2 ng/mL) in the great majority of subjects, whereas an intake of 100 Âµg/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, ab- normal PIVKA-II concentrations were observed with diets contain- ing 40 to 60 Âµg/day of phylloquinone but were normal when intakes were approximately 80 Âµg/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. Interven- tion 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-Î³-carboxylated Osteocalcin Small amounts of the bone protein, osteocalcin, circulate in plas- ma, and like PIVKA-II, under-Î³-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
VITAMIN K 169 development of a monoclonal antibody specific for the undercar- boxylated 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 require- ments for bone function are probably much higher than those needed to maintain normal hemostasis and that the recommenda- tion for vitamin K should be much higher than current recommen- dations (Weber, 1997). However, a number of issues must be considered before a mini- mal 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 com- mercial 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 ânormalâ 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 measure- ments 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 supple- mentation (Booth et al., 1999a; Douglas et al., 1995; Knapen et al., 1993). Other investigators have reported nearly complete elimina- tion 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-
170 DIETARY REFERENCE INTAKES 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 ques- tion that must be considered. Although there is little doubt that vitamin K intake affects the degree of osteocalcin Î»-carboxylation, the technical problems asso- ciated 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 con- centrations 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 investi- gated 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; Planta- lech 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 associa- tions 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
VITAMIN K 171 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 in- creased risk of hip fracture. In a series of reports involving institu- tionalized 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 bio- logically 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 in- creased 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., vita- min 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 Nurseâs 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, 0.53â0.93) than women in the lowest quintile (vitamin K intake less than 109 Âµg/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
172 DIETARY REFERENCE INTAKES 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 charac- terized as being âfast losersâ 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, âfast loserâ 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, in- creased 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 rigor- ous 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 indepen- dent of its usual role in the Î³-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 under- going 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 drugâs 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
VITAMIN K 173 being conducted in North America and in Europe will help eluci- date this question within the next few years. Vitamin K and Atherosclerosis A role for vitamin K in atherosclerosis was hypothesized when proteins containing Gla residues were isolated from hardened atherosclerotic plaque (Gijsbers et al., 1990; Levy et al., 1979). These were later identified as osteocalcin and matrix Gla proteins (Ferland, 1998). In a more recent study involving 113 postmenopausal women, lower vitamin K intakes and higher ucOC levels were associated with the presence of atherosclerotic calcification in the abdominal aorta (Jie et al., 1995). Although these results are interesting, they should be considered with caution as the assessment of vitamin K status was performed 5 years after the diagnosis of atherosclerosis was made. To what extent this time lag affected the findings is un- known. Furthermore, the vitamin K intake reported for this popula- tion is quite high, in fact much higher than what is usually reported for subjects of similar age (Booth and Suttie, 1998). A role of vitamin K in vascular health is supported by the finding of extensive arterial calcification in the matrix Gla protein knock- out mouse (Luo et al., 1997). Whether vitamin K status within the range of normal intake plays a significant role in the development of atherosclerosis requires further investigation and should be veri- fied in studies using rigorous experimental designs. FACTORS AFFECTING THE VITAMIN K REQUIREMENT Bioavailability The predominant form of vitamin K in the North American diet is phylloquinone from green leafy vegetables, and the available data on the vitamin K content of foods have been reviewed (Booth and Suttie, 1998). These data are comprehensive, but little information on the relative bioavailability of phylloquinone from various foods in human subjects is available. Gijsbers and colleagues (1996) have compared the relative bioavailability, measured as area under an absorption curve, of 1,000 Âµg of phylloquinone from a synthetic preparation and from a food matrix. Phylloquinone in the form of cooked spinach was reported to be 4 percent as bioavailable as that from a phylloquinone supplement. Three times as much phyllo- quinone was absorbed when butter was consumed with the spinach. Garber and coworkers (1999) observed that when 500 Âµg of phyllo-
174 DIETARY REFERENCE INTAKES quinone was consumed with a 400 kcal (27 percent energy from fat) meal, the relative absorption was between five and six times lower from spinach than from a phylloquinone tablet. In this study, phylloquinone absorption from fresh spinach, broccoli, or romaine lettuce did not differ and was highly variable between subjects. It is apparent from these limited studies that until more data are avail- able, the bioavailability of phylloquinone from vegetable sources should not be considered to be more than 20 percent as available as phylloquinone consumed as a supplement. Approximately 34 percent of phylloquinone in the American diet is consumed from fats and oils (Booth et al., 1995). It might be expected that phylloquinone dissolved in oil would be more avail- able than from a food matrix, but this may not be true. Vitamin K is not well absorbed by patients exhibiting lipid malabsorption syn- dromes (Savage and Lindenbaum, 1983), and efficient absorption of this fat-soluble vitamin from the digestive tract does require dietary fat. Although direct measures of bioavailabilty have not been reported, a recent study reported no difference in fasting plasma phylloquinone concentrations when 400 Âµg of phylloquinone as broccoli or as phylloquinone-fortified oil was added to a diet con- taining 100 Âµg of phylloquinone (Booth et al., 1999a). Hydrogenated fats contain significant amounts of 2',3'-dihydrophylloquinone formed from phylloquinone during processing. Dietary intake of this form of the vitamin in the United States is estimated to be about 20 percent of phylloquinone (Booth et al., 1999c). Neither the biological activity nor the bioavailability of this form of vitamin K is known. The amount of dietary fat needed for optimal absorp- tion has not been determined. Drug-Nutrient Interactions Oral 4-hydroxycoumarin derivatives such as warfarin are widely prescribed anticoagulants for the prevention of thrombotic dis- orders. These drugs function through the inhibition of a hepatic vitamin K-epoxide reductase. This enzyme reduces the coproduct of the Î»-glutamyl carboxylase reaction, the vitamin K 2,3-epoxide, to the hydronaphthoquinone form of the vitamin, which is the sub- strate for the enzyme. The result is an acquired cellular vitamin K deficiency and a decrease in the synthesis of the vitamin K-depen- dent plasma clotting factors. Alterations in vitamin K intake can, therefore, influence warfarin efficacy, and numerous case reports of these occurrences have been reviewed (Booth et al., 1997a). Short-term, day-to-day variations in vitamin K intake do not appear
VITAMIN K 175 to alter anticoagulant status, and there are few data on the extent to which long-term differences in dietary vitamin K intake modulate the response to warfarin. Lubetsky and coworkers (1999) studied a population of 46 patients with an estimated (by food frequency recall) median intake of 179 Âµg/day of phylloquinone. Patients with intakes greater than 250 Âµg/day were maintained at the targeted international normalized ratio with 5.8 mg/day warfarin, while pa- tients with an intake of less than 250 Âµg/day of phylloquinone were maintained on a lower warfarin intake of 4.4 mg/day. These data suggest that alterations in vitamin K intake might influence warfarin dosage. As an effective warfarin dose varies widely within individuals, patients are closely monitored. Once a dose has been established, patients can avoid any complications resulting from variations in vitamin K intake by continuing to follow their normal dietary patterns. Nutrient-Nutrient Interactions The ability of elevated intakes of vitamin E to antagonize vitamin K action has been clearly established. Woolley (1945) first demonstrated that increased dietary or parenteral Î±-tocopherol or Î±-tocopherol quinone could induce a hemorrhagic syndrome in the rat, and vita- min K administration was demonstrated to reverse this response (Rao and Mason, 1975). Studies of the microsomal vitamin K- dependent carboxylase have demonstrated that the enzyme can be inhibited by Î±-tocopherol and that it is even more sensitive to Î±- tocopherol quinone (Bettger and Olson, 1982; Dowd and Zheng, 1995). Increased intakes of vitamin E have not been reported to antago- nize vitamin K status in healthy humans. However, in one study, oral supplementation of anticoagulated patients (50 percent plasma prothrombin concentrations) with approximately 360 mg/day (400 IU/day) of Î±-tocopherol resulted in nonstatistically significant de- creases in prothrombin concentrations over a 4-week period, and a statistically significant decrease in the ratio of biologically active prothrombin to prothrombin antigen (Corrigan and Ulfers, 1981). More sensitive measures of vitamin K status are now available and should be used to assess the potential impact of vitamin E supple- mentation in anticoagulated patients or subjects with low vitamin K intakes. The metabolic basis for vitamin E antagonism of vitamin K func- tion has not been completely elucidated. Recent data from a study using a rat model have demonstrated an adverse effect of dietary Î±-
176 DIETARY REFERENCE INTAKES tocopherol on phylloquinone absorption (Alexander and Suttie, 1999), and it is likely that both this response and cellular inter- actions are responsible for the antagonism that has been observed in both animals and human subjects. Antagonism of vitamin K action in animal models by retinoids (retinyl acetate, 13-cis retinoic acid, and N-(7-hydroxyphenyl retina- mide) has been reported by a group of investigators (McCarthy et al., 1989). High doses of these compounds have been used in animal studies, and adverse responses in humans have not been reported. The metabolic basis for this interaction has not been determined. FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Vitamin K is poorly transported across the placenta, which puts newborn infants at risk for vitamin K deficiency (Greer, 1995). Con- centrations of vitamin K in cord blood are usually less than 0.1 nmol/L or undetectable (Mandelbrot et al., 1988; Widdershoven et al., 1988), and elevated concentrations of undercarboxylated pro- thrombin (PIVKA-II) have been reported (Greer, 1995). Poor vita- min K status added to the fact that the concentrations of most plasma clotting factors are low at the time of birth increases the risk of bleeding during the first weeks of life, a condition known as hemorrhagic disease of the newborn (HDNB). Because HDNB can be effectively prevented by administration of vitamin K, infants born in the United States and in Canada routinely receive 0.5 to 1 mg of phylloquinone intramuscularly or 2.0 mg orally within 6 hours of birth. Compared to oral prophylaxis, intramuscular (IM) treatment has been shown to be more efficacious in the prevention of HDNB (Greer, 1995). In light of this and because an oral dosage form of vitamin K has not been readily available in North America, new- borns have typically been administered vitamin K via the IM route. Studies published in the early nineties reporting an association be- tween IM prophylaxis and childhood cancer created some concern and questioned the safety of this practice. In two studies, Golding and coworkers (1990, 1992) reported an increased risk (odds ratio, 1.97â2.6) of leukemia and other forms of cancer in children who had received vitamin K intramuscularly at birth. Subsequent studies conducted in the United States and European countries (Ansell et al., 1996; Ekelund et al., 1993; Klebanoff et al., 1993; Olsen et al., 1994; von Kries et al., 1996) have failed to confirm Goldingâs find- ings and quieted the debate. Recently, both the American and the
VITAMIN K 177 Canadian pediatric societies reaffirmed their confidence in the IM prophylaxis, encouraging its general use (AAP, 1993; CPS, 1998). Method Used to Set the Adequate Intake No functional criteria of vitamin K status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of vitamin K are based on an Adequate Intake (AI) that reflects a calculated mean vitamin K intake of infants principally fed human milk and provided vitamin K prophylaxis. Although vitamin K prophylaxis at birth offers good protection with respect to HDNB during the first few weeks of life, infants become increasingly dependent on vitamin K intake in subsequent weeks. Though not a major concern in the United States or Canada, late HDNB occurs between 3 and 8 weeks of life and is usually associated with breast-feeding (Lane and Hathaway, 1985; von Kries et al., 1993). Milk intake appears to be an important factor in the etiology of late HDNB as inverse correlations have been reported between human milk intake and undercarboxylated prothrombin (Motohara et al., 1989; von Kries et al., 1987a). Vitamin K concentrations in mature human milk have ranged from 0.85 to 9.2 Âµg/L with a mean concentration of 2.5 Âµg/L (Table 5-1) (Canfield et al., 1990, 1991; Greer et al., 1991, 1997; Haroon et al., 1982; Hogenbirk et al.,1993; von Kries et al., 1987b). Vitamin K content of colostrum is slightly higher than that of mature milk, but concentrations do not vary significantly through the first 6 months of lactation (Canfield et al., 1991; Greer et al., 1991; von Kries et al., 1987b). Vitamin K content of human milk can be increased by maternal intakes of pharmacological doses of vitamin K (Greer et al., 1991; Haroon et al., 1982). In a study by Greer and coworkers (1997), supplementing mothers with a dose of 5 mg/day of phyllo- quinone for 12 weeks increased the vitamin K concentration of milk by 70-fold (82.1 versus 1.17 Âµg/mL in unsupplemented mothers). In another study, supplementing one mother with 0.1 mg/day of phylloquinone, an amount that can be obtained in the diet, raised milk concentrations from 2.5 to 4.9 ng/L (von Kries et al., 1987b). Ages 0 through 6 Months. The AI for infants 0 through 6 months of age is based on a reported average intake of milk of 0.78 L/day (Chapter 2) and on an average phylloquinone concentration of 2.5 mg/L in human milk. This gives an AI of 2.0 Âµg/day after round- ing. The AI assumes that infants also receive prophylactic vitamin K at birth in amounts suggested by the American and Canadian pedi-
178 DIETARY REFERENCE INTAKES TABLE 5-1 Vitamin K in Human Milk Reference Study Group Maternal Intake (Âµg/d) Stage of L Haroon et al., 1982 60 women Not reported Mature von Kries et al., 1987b 9 women, 17â34 y Not reported 8â36 d Canfield et al., 1990 15 women, 20â35 y Not reported 1 mo Canfield et al., 1991 15 women, 20â35 y Not reported Colostrum 1 mo 3 mo 6 mo Greer et al., 1991 23 women, 31 Â± 3.6 y Not reported 1 wk 302 Â± 361 (SD)b 6 wk 296 Â± 169 (SD) 12 wk 436 Â± 667 (SD) 26 wk Hogenbirk et al., 1993 26 women Not reported 1 wk 6 wk Greer et al., 1997 22 women No vitamin K 3d supplements taken 2 wk 6 wk 12 wk a Vitamin K intake based on reported data or concentration (Âµg/L) Ã 0.78 L/day for 0â6 months postpartum. b SD = standard deviation. atric societies. The AI agrees with intakes of 0.6 to 2.3 Âµg/day re- ported for infants exclusively fed human milk (Canfield et al., 1991; Greer et al., 1991; Pietschnig et al., 1993). The AI is significantly lower than recently reported intakes based on the Food and Drug Administration Total Diet Study of 77 Âµg/ day (Booth et al., 1996b) and 111 Âµg/day (Appendix Table E-1). However, these values exclude intakes from human milk and in- clude only intakes from other food sources. Booth and coworkers (1996b) reported that 87 percent of the estimated intake of 77 Âµg/ day was attributed to infant formulas, which on average contain 50 to 100 mg/L of phylloquinone (Greer, 1995; Haroon et al., 1982). Ages 7 through 12 Months. Using the method described in Chapter 2 to extrapolate from the AI for infants ages 0 through 6 months, the AI for older infants is 2.5 Âµg/day after rounding. Because com- plementary foods become a more important part of the infant diet in the second 6 months of life, vitamin K intake for this age category is expected to be higher than the AI based solely on human milk consumption. However, data concerning the vitamin K content of
VITAMIN K 179 Estimated Vitamin K e (Âµg/d) Stage of Lactation Milk Concentration Intake of Infants (Âµg/d)a Mature 2.5 Âµg/L 1.95 8â36 d 1.2 Âµg/L 0.94 1 mo 3.15 Âµg/L 2.45 Colostrum 30â81 h 3.39 Âµg/L 2.64 1 mo 3.14 Âµg/L 2.45 3 mo 2.31 Âµg/L 1.81 6 mo 2.59 Âµg/L 2.03 1 wk 0.64 Âµg/L 0.50 b 6 wk 0.86 Âµg/L 0.67 12 wk 1.14 Âµg/L 0.88 26 wk 0.87 Âµg/L 0.52 1 wk 1.21 Âµg/L 0.94 6 wk 0.9 Âµg/L 0.7 3d 1.10 Âµg/L 0.86 ken 2 wk 1.17 Âµg/L 0.92 6 wk 1.14 Âµg/L 0.89 12 wk 1.17 Âµg/L 0.92 weaning foods and their contribution to daily vitamin K intake are not presently available. Alternatively, if the adult AI of 80 Âµg/day is extrapolated down by means of the method described in Chapter 2, the AI would be 23 Âµg/day. Because older infant vitamin K intakes of 2.5 Âµg/day have not been associated with adverse clinical out- comes (Greer et al., 1991), the AI is set at the level obtained by extrapolating up from young infants. Vitamin K AI Summary, Ages 0 through 12 Months AI for Infants 0â6 months 2.0 Âµg/day of vitamin K 7â12 months 2.5 Âµg/day of vitamin K Special Considerations Human milk does not contain as much vitamin K as cow milk (5 Âµg/mL) or infant formulas (50â100 Âµg/L) (Greer, 1995; Haroon et al., 1982). Significant amounts of menaquinone-4 have been detect-
180 DIETARY REFERENCE INTAKES ed in cow milk, yet its physiological function in infant nutrition is unknown (Indyk and Woollard, 1997). Vitamin K has been shown to specifically and reversibly bind to a protein complex in cow milk (Fournier et al., 1987). There is no information on the bioavailabil- ity of vitamin K in infant formula. Children and Adolescents Ages 1 through 18 Years Method Used to Set the Adequate Intake No data were found on which to base an Estimated Average Re- quirement (EAR) for vitamin K for children or adolescents. There- fore AIs are set on the basis of the highest median intake for each age group reported by the Third National Health and Nutrition Examination Survey (NHANES III) (Appendix Table C-10) and rounding. The significant increase in the AI from infancy to early childhood is most likely due to the method used to set the AI for older infants and the increased portion of the diet containing vita- min K-rich fruits and vegetables as the diet becomes more diversified. Vitamin K AI Summary, Ages 1 through 18 Years AI for Children 1â3 years 30 Âµg/day of vitamin K 4â8 years 55 Âµg/day of vitamin K AI for Boys 9â13 years 60 Âµg/day of vitamin K 14â18 years 75 Âµg/day of vitamin K AI for Girls 9â13 years 60 Âµg/day of vitamin K 14â18 years 75 Âµg/day of vitamin K Adults Ages 19 Years and Older Method Used to Set the Adequate Intake Clinically significant vitamin K deficiency is extremely rare in the general population, with cases being limited to individuals with mal- absorption syndromes or those treated with drugs known to inter- fere with vitamin K metabolism. The recent development of indica- tors sensitive to vitamin K intake, though useful to describe relative
VITAMIN K 181 diet-induced changes in vitamin K status, were not used for estab- lishing an EAR because of the uncertainty surrounding their true physiological significance and the lack of sufficient dose-response data. Therefore, the AI for adults is based on reported vitamin K dietary intakes in apparently healthy population groups. In a recent paper, Booth and Suttie (1998) reviewed 11 studies in which phylloquinone intakes ranged from 61 to 210 Âµg/day with average intakes of ap- proximately 80 Âµg/day for adults younger than 45 years and ap- proximately 150 Âµg/day for adults older than 55 years (Table 5-2). NHANES III data (Appendix Table C-10) indicate that median vita- min K intakes of adults varied between 82 and 117 Âµg/day. Studies have demonstrated that abnormal PIVKA-II concentra- tions were observed in individuals consuming 40 to 60 Âµg/day of vitamin K but were normal when intakes were approximately 80 Âµg/ TABLE 5-2 Dietary Phylloquinone Intake in Healthy Men and Women Mean Intake Reference Sex Age (y) Subjects Method (Âµg/day) Suttie et al., 1988 Men 20â35 10 Duplicate 77 portion Jones et al., 1991 Men and 18â55 221 Diet record 61 women Booth et al., Women 41â71 362 Diet record 156 1995 Vermeer et al., Women 60â79 80 Food frequency 210 1995 questionnaire Bach et al., 1996 Men 20â28 9 Diet record 83 Bach et al., 1996 Men 55â75 9 Diet record 164 Booth et al., Men and 25â30, 1,490 Diet recall and 71 1996b women 40â45 record Booth et al., Men and 60â65, 1,216 Diet recall and 80 1996b women > 70 record Price et al., 1996 Men and 22â54 65 Diet record 68 women Booth et al., Men and 20â40 17 Diet record 111 1997b women Booth et al., Men and 60â80 17 Diet record 143 1997b women SOURCE: Booth and Suttie (1998).
182 DIETARY REFERENCE INTAKES day (Jones et al., 1991; Suttie et al., 1988). Healthy individuals with phylloquinone intakes approaching 80 Âµg/day have been investigated and have shown no signs of a deficiency, a finding that suggests this level of intake is probably adequate for the majority of the adult population (Bach et al., 1996; Ferland et al., 1993; Suttie et al., 1988). Reported vitamin K intakes are slightly lower for women than men (Booth et al., 1996b; Appendix Table C-10). Reported phylloquinone intakes of older adults have generally been higher than those of younger individuals, a finding explained by their higher intakes of vegetables (Booth et al., 1996b). Older subjects have been found to be more resistant to vitamin K deficien- cy than younger adults (Ferland et al., 1993). The AI is based on median intake data from NHANES III (Appen- dix Table C-10). Because dietary intake assessment methods tend to underestimate the actual daily intake of foods, the highest intake value reported for the four adult age groups was used to set the AI for each gender; numbers are rounded up to the nearest 5 Âµg. Vitamin K AI Summary, Ages 19 Years and Older AI for Men 19â30 years 120 Âµg/day of vitamin K 31â50 years 120 Âµg/day of vitamin K 51â70 years 120 Âµg/day of vitamin K > 70 years 120 Âµg/day of vitamin K AI for Women 19â30 years 90 Âµg/day of vitamin K 31â50 years 90 Âµg/day of vitamin K 51â70 years 90 Âµg/day of vitamin K > 70 years 90 Âµg/day of vitamin K Pregnancy Method Used to Set the Adequate Intake Data pertaining to vitamin K status of pregnant women are limit- ed but suggest that status is not different from that of nonpregnant women, that is, lack of signs of clinical deficiency and comparable circulating vitamin K concentrations (Mandelbrot et al., 1988; von Kries et al., 1992). Furthermore, there are no data on the vitamin K content of fetal tissue for estimating additional needs during preg- nancy. Therefore, median vitamin K intake was used for setting the
VITAMIN K 183 AI. In the Total Diet Study, phylloquinone intakes of pregnant women were lower than those of nonpregnant women (Appendix Table E-1). Similarly, the median vitamin K intake for pregnant women was approximately 80 Âµg/day, whereas the vitamin K intake of premenopausal women was approximately 85 to 90 Âµg/day from NHANES III (Appendix Table C-10). In a recent report by Booth and coworkers (1999c), phylloquinone intakes were estimated from 14-day food diaries for a small group of pregnant women (n = 17) and were found to be similar (72 Â± 56 Âµg/day [SD]) to those of nonpregnant women (73 Â± 46 Âµg/day [SD]). Although supplementation with pharmacological doses of vitamin K during the later stages of pregnancy has been shown to increase plasma concentrations of vitamin K and improve coagulation func- tion of pregnant women in some studies (Anai et al., 1993; Morales et al., 1988), the impact of antenatal supplementation on status of the newborn has been mixed (Dickson et al., 1994; Kazzi et al., 1990; Morales et al., 1988). Until more data are available, there is no evidence to suggest that the AI for pregnant women should be different from that for nonpregnant women. Therefore, the AI is based on median NHANES III intake estimates of nonpregnant women. Vitamin K AI Summary, Pregnancy AI for Pregnancy 14â18 years 75 Âµg/day of vitamin K 19â30 years 90 Âµg/day of vitamin K 31â50 years 90 Âµg/day of vitamin K Lactation Method Used to Set the Adequate Intake Available studies suggest the vitamin K status of lactating women is comparable to that of nonlactating women. Reported vitamin K intake of pregnant women does not differ significantly from those of nonlactating women. In a study by Greer and coworkers (1991) involving 23 lactating mothers, phylloquinone intakes at 6, 12, and 26 weeks were 302 Â± 361 (standard deviation [SD]), 296 Â± 169 (SD), and 436 Â± 667 (SD) Âµg/day, respectively. There was no significant correlation between phylloquinone intake and breast milk concen- tration. Based on NHANES III intake estimates, median phyllo- quinone intakes of 99 lactating women was 74 Âµg/day, which is
184 DIETARY REFERENCE INTAKES lower than the median intake of premenopausal women (approxi- mately 85 to 90 Âµg/day) (Appendix Table C-10). Although the phylloquinone content in maternal milk can be in- creased after treatment of mothers with pharmacological doses of vitamin K (Greer et al., 1997; Haroon et al., 1982; von Kries et al., 1987b), results from Greer and coworkers (1991) suggest that vita- min K content of milk is little affected by intake of lactating women who consume typical diets. Because vitamin K is not significantly secreted in milk, there is no evidence to suggest that the AI for lactating women should be different from that for nonlactating women. Therefore, the AI is the same as for nonpregnant women. Vitamin K AI Summary, Lactation AI for Lactation 14â18 years 75 Âµg/day of vitamin K 19â30 years 90 Âµg/day of vitamin K 31â50 years 90 Âµg/day of vitamin K INTAKE OF VITAMIN K Food Sources Early data obtained by chick bioassay on the vitamin K content of foods were unreliable and a limited number of foods were assayed. Over the last decade, rapid and reliable chromatographic proce- dures for vitamin K have been developed, and data for the phyllo- quinone content of most commonly consumed foods are available (Booth et al., 1995). Only a relatively small number of food items (Table 5-3) contribute substantially to the dietary phylloquinone intake of most people. A few green vegetables (collards, spinach, and salad greens) contain in excess of 300 Âµg of phylloquinone/100 g, while broccoli, brussels sprouts, cabbage, and bib lettuce contain between 100 and 200 Âµg of phylloquinone/100 g. Other green veg- etables contain smaller amounts. Plant oils and margarine are the second major source of phylloquinone in the diet. The phylloqui- none content of plant oils is variable, with soybean and canola oils containing greater than 100 Âµg of phylloquinone/100 g. Cotton- seed oil and olive oil contain about 50 Âµg/100 g, and corn oil con- tains less than 5 Âµg/100 g. Prepared foods contain variable amounts of vitamin K depending on their content of green vegetables and the source and amount of oil used in their preparation. Informa- tion relative to the important food sources of vitamin K for infants
VITAMIN K 185 TABLE 5-3 Phylloquinone Concentration of Common Foodsa Food Item Âµ g/100 g Food Item Âµ g/100 g Vegetables Protein sources Collards 440 Dry soybeans 47 Spinach 380 Dry lentils 22 Salad greens 315 Liver 5 Broccoli 180 Eggs 2 Brussels sprouts 177 Fresh meats <1 Cabbage 145 Fresh fish <1 Bib lettuce 122 Whole milk <1 Asparagus 60 Tuna in oil 24 Okra 40 Iceberg lettuce 35 Prepared foodsb Green beans 33 Salad dressings 100 Green peas 24 Coleslaw 80 Cucumbers 20 Mayonnaise 41 Cauliflower 20 Beef chow mein 31 Carrots 10 Muffins 25 Tomatoes 6 Doughnuts 10 Potatoes 1 Apple pie 11 Potato chips 15 Fats and oils French fries 5 Soybean oil 193 Macaroni/cheese 5 Canola oil 127 Lasagna 5 Cottonseed oil 60 Pizza 4 Olive oil 55 Hamburger/bun 4 Corn oil 3 Hot dog/bun 3 Margarine 42 Baked beans 3 Butter 7 Bread 3 a Median value obtained from Booth et al. (1993, 1995), Koivu et al. (1997), Piironen et al. (1997), and Shearer et al. (1996). Both cooked and raw food values were used. b Phylloquinone content may vary widely depending on the source of oil used in prepa- ration. and children of various age groups and for adults by gender and age group are available from data obtained from the U.S. Food and Drug Administration Total Diet Study (Booth et al., 1996b). Spinach, collards, broccoli, and iceberg lettuce are the major contributors of vitamin K in the diet of U.S. adults and children. Hydrogenation of plant oils to form solid shortenings results in some conversion of phylloquinone to 2â²,3â²-dihydrophylloquinone (Davidson et al., 1996). This form of the vitamin is most prevalent in margarines, infant formulas, and prepared foods (Booth et al., 1996a) and can represent a substantial portion of the total vitamin
186 DIETARY REFERENCE INTAKES K in some diets. The bioavailability and the relative biological activ- ity 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 (40â80 Âµg/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 Âµg/day for older (above 55 years) and 80 Âµg/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 Âµg/day for women and 89 to 117 Âµg/day for men (Appendix Table C-10). Because of the relatively small num- ber of foods that provide significant amounts of phylloquinone in the diet, the daily variation in intake is high, and Booth and co- workers (1995) have estimated that a 5-day record of intake is needed to get a true measure of dietary intake. Data on phyllo- quinone intake have recently been calculated (Booth et al., 1999c) from 14-day food diaries collected by the Market Research Corpora- tion of America. These data reflect the intake of nearly 4,000 men and women aged 13 years or older with a demographic profile sim- ilar to that of the U.S. census. These data clearly demonstrate the large daily variation in phylloquinone intake and indicate an aver- age intake of 70 to 80 Âµg/day for the U.S. adult population. The same data provide an estimate of the dihydrophylloquinone intake of this population (19 Âµg/day for men and 15 Âµg/day for women) that is about 20 to 25 percent as much as the intake of phylloquinone.
VITAMIN K 187 The adult phylloquinone intake in The Netherlands has been re- ported to be two to three times higher than that of the U.S. popula- tion (Schurgers et al., 1999). Whether this represents a real differ- ence 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 Âµg/day. Comprehensive data on menaquinone intake are not available for the U.S. popula- tion. Intake from Supplements The median intakes of vitamin K from food and supplements for the four adult age groups was 93 to 119 Âµg/day for American men who took supplements (Appendix Table C-11). The median vita- min K intake from food and supplements for women who reported consuming supplements was 82 to 90 Âµg/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, in- take 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-
188 DIETARY REFERENCE INTAKES larly (IM) administered vitamin K and childhood cancer, particu- larly leukemia (Golding et al., 1992). This study compared 195 chil- dren diagnosed with cancer between 1971 and 1991 and born in one of two major hospitals (between 1965 and 1987) with 558 con- trols. Golding and coworkers (1992) reported a significant associa- tion between IM vitamin K and cancer incidence (p = 0.002; observed risk, 1.97; 95 percent confidence interval, 1.3â3.0). No significantly increased risk was reported for children who had been given oral vitamin K. These findings on IM vitamin K doses have limited rele- vance to ULs based on oral intake. Furthermore, evidence from other population studies fails to con- firm 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 chil- dren), Klebanoff and coworkers (1993) found no association be- tween 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 child- hood 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. pop- ulation was 340 Âµg/day in women aged 19 through 30 years (Ap- pendix Table C-10). The highest intake of vitamin K from food and supplements was 367 Âµg/day, also in women aged 19 through 30 years (Appendix Table C-11).
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