The Journal of Nutrition Vol. 128 No. 5 May 1998, pp. 785-788

Dietary Intake and Adequacy of Vitamin K¹

Sarah L. Booth^* and J. W. Suttie^{, 2}

^* Vitamin K Laboratory, U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111 and  Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706

	ABSTRACT

Abstract Introduction References

The current daily recommended dietary allowance for vitamin K is 1 µg/kg. Reliable measurements of vitamin K content in foods are now available, and data from 11 studies of vitamin K intake indicate that the mean intake of young adults is ~80 µg phylloquinone/d and that older adults consume ~150 µg/d. The vitamin K concentration in most foods is very low (<10 µg/100 g), and the majority of the vitamin is obtained from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola and olive) that contain high amounts. Limited data indicate that absorption of phylloquinone from a food matrix is poor. Hydrogenated oils also contain appreciable amounts of 2,3-dihydrophylloquinone of unknown physiological importance. Menaquinones absorbed from the diet or the gut appear to provide only a minor portion of the human daily requirement. Measures of the extent to which plasma prothrombin or serum osteocalcin lack essential -carboxyglutamic acid residues formed by vitamin K action, or the urinary excretion of this amino acid, provide more sensitive measures of vitamin K status than measures of plasma phylloquinone or insensitive clotting assays.

	INTRODUCTION

Abstract Introduction References

Vitamin K was not described as an essential nutrient until the mid-1930s, and its role as a substrate for the enzyme catalyzing the posttranslational conversion of specific glutamyl residues in a limited number of proteins to -carboxyglutamyl (Gla)³ residues was not established until the mid-1970s (Suttie 1993). An understanding of the dietary intake of vitamin K in the population and the development of the methods needed to assess nutrient status have also developed slowly. Current medical and nutritional texts commonly state that the average American diet contains between 300 and 500 µg of vitamin K/d, which far exceeds the present adult recommended dietary allowance (RDA) of 1 µg/(kg body wt·d) (National Research Council 1989). Reliable data on the vitamin K content of foods have demonstrated that the vitamin K intake of most individuals is closer to the current RDA but that many individuals fail to meet even this lower level of intake on a daily basis.

Vitamin K content of foods.  Phylloquinone or vitamin K₁ (Fig. 1) is the primary dietary source of vitamin K. The early data on the vitamin K content in foods were obtained by a chick bioassay based on clotting times and were limited to a few foods. The use of high performance liquid chromatography facilitates the routine analysis of phylloquinone in foods and results in values (Table 1) that are generally lower than those derived by chick bioassay. Most notable are animal products, including the liver of certain species, cheeses and whole eggs, all of which were identified previously as important sources of vitamin K. Whereas tea leaves and coffee beans contain appreciable amounts of phylloquinone, the brews are not a dietary source of this vitamin as previously assumed (Booth et al. 1995a, Ferland et al. 1993). Roots, fleshy portions of fruits and fruit juices and other beverages are low in phylloquinone.

View larger version (14K): [in this window] [in a new window]   Fig 1. Structures of important forms of vitamin K. Phylloquinone (I), 2-methyl-3-phytyl-1,4-naphthoquinone is produced by plants. Menaquinones (II) with an unsaturated polyisoprenoid chain at the 3 position are produced in large quantities by human gut bacteria. One menaquinone, MK-4 (III), is not produced in significant quantities by bacteria but is formed in animal tissues from phylloquinone. 2,3-Dihydrophylloquinone (IV) is formed during commercial hydrogenation of oils.

Green leafy vegetables contain the highest content of phylloquinone and contribute 40-50% of total intake (Booth et al. 1996b, Fenton et al. 1997), followed by certain vegetable oils such as soybean, cottonseed, canola and olive. Mixed dishes and meals, because of the phylloquinone-rich oils added during food preparation, contribute ~15% of the total dietary phylloquinone intake. Although certain food items (e.g., tomato-based products and carrots) are relatively low in their phylloquinone content, they are frequently consumed in large enough quantities to be ranked among the top 25 contributors to total dietary intake of phylloquinone.

Menaquinones (MK), collectively referred to as vitamin K₂ (Fig. 1), contribute a relatively small amount to satisfying the human requirement for the vitamin. Absorption in the lower bowel of menaquinones is apparently very limited (reviewed by Suttie 1995). Even less is known about the contribution of dietary menaquinones to overall vitamin K nutrition. Limited amounts of menaquinones have been found in animal products, including chicken egg yolk and butter (Hirauchi et al. 1989a); Shearer et al. (1996) reported that various cheeses contain 5-20 µg/100 g of the menaquinones MK-8 and MK-9. Fermented soybean products contain substantial amounts of MK-6 and MK-8 and may be of nutritional importance for those populations consuming this class of foods (Sakano et al. 1988). In contrast, assumptions that animal livers contain large quantities of menaquinones were not substantiated, with the exception of the cow liver (Hirauchi et al. 1989b, Shearer et al. 1996).

Hydrogenated phylloquinone-rich vegetable oils are used widely by the food industry because of their physical characteristics and oxidative stability. During the commercial hydrogenation of phylloquinone-rich oils, there is some conversion of phylloquinone to 2,3-dihydrophylloquinone (dK) (Davidson et al. 1996). This product (Fig. 1) has been identified in infant formulas (Indyk and Woollard 1997); prepared foods with a high fat content contain 30-60 µg dK/100 g (Booth et al. 1996c). The physiological importance of dK in the food supply depends on its biological activity. The biological activity of various forms of the vitamin is related to both the side-chain length and the configuration, and the biological activity of dK is not currently known. Detectable amounts of dK have been measured in human plasma following dietary intake of partially hydrogenated soybean oil (Booth et al. 1996a), and the abundance of dK in the food supply warrants further investigation into its relative absorption and overall biological activity. The compound could have partial activity or it could be an inhibitor of the action of the vitamin. The influence of the ingestion of foods with a high content of hydrogenated vegetable oils on vitamin K status will therefore not be known until additional information is available.

The availability of more reliable data on the content of phylloquinone in foods has made it possible to obtain reasonable estimates of phylloquinone intake in both large populations and more carefully controlled smaller studies. One consistent finding has been an age-related difference in phylloquinone intakes. In general, mean dietary intakes reported for younger adults (<45 y) range from 60 to 110 µg of phylloquinone/d (Table 2). In contrast, the mean dietary intakes estimated for older adults (>55 y) range from 80 to 210 µg of phylloquinone/d, attributed to their greater vegetable consumption compared to younger age groups (Booth et al. 1996b). It is possible that reported age-related differences in phylloquinone intakes reflect methodological differences. However, two smaller studies (Bach et al. 1996, Booth et al. 1997) directly compared phylloquinone intakes between the two age groups by using the same dietary assessment method and demonstrated significantly higher phylloquinone intakes among older adults. Price et al. (1996) observed no seasonal differences when phylloquinone intake was assessed during spring, summer, autumn and winter. Data on the phylloquinone intakes among children are limited, but children aged <14 y were reported to consume phylloquinone above the current RDA for their respective age groups (Booth et al. 1996b). Children were also reported to consume foods with a 1:2 ratio of dK:phylloquinone, with fast-food french fries, cookies and margarine being the primary dietary sources of dK (Booth et al. 1996c).

The available dietary intake data suggest that a number of adults in the American population, particularly younger adults, do not meet the current RDA for vitamin K. As vitamin K is a fat-soluble vitamin, it has been assumed that phylloquinone obtained from vegetable sources is less bioavailable compared to phylloquinone obtained from oil-based sources, but few data are available. Gijsbers et al. (1996) reported that the bioavailability (the area under an absorption curve) in human subjects of 1 mg phylloquinone in spinach was only 4% that of pure phylloquinone. Adding butter to the spinach increased this to 13%. A similar relatively poor absorption of phylloquinone in spinach was observed by Garber et al. (1998), although the absorption of phylloquinone from raw broccoli was found to be much higher. Much more data will be needed before the contribution of different foods to the maintenance of optimal vitamin K status can be determined.

Dietary vitamin K deficiency.  Efforts to define the human requirement for vitamin K have been hampered by a lack of knowledge of the amount of the vitamin in various foods and by the lack of sensitive methods to assess status (Suttie 1992). The prothrombin time (the classical measure of vitamin K deficiency) is very insensitive, but recent studies have shown that the serum concentration of under--carboxylated prothrombin (PIVKA-II), the percentage of under--carboxylated osteocalcin (% ucOC) and the urinary Gla excretion do respond to alterations in dietary vitamin K. Gender and age were shown to influence both osteocalcin concentration and Gla excretion in 263 healthy subjects (Sokoll and Sadowski 1996). Although there was a weak negative correlation between serum phylloquinone and % ucOC, it was not strong enough to have predictive value as a measure of individual vitamin K status.

Allison et al. (1987) maintained 33 subjects on a defined liquid diet (~5 µg vitamin K/d) for 13 d. Plasma phylloquinone concentration dropped ~70%. Factor VII activity dropped in ~20% of the subjects and a measure of PIVKA-II increased in ~67%. These changes occurred in both the control subjects and those administered various antibiotics with no consistent pattern. Suttie et al. (1988) studied 10 subjects who decreased their vitamin K intake from a median of 82 to <40 µg/d by decreasing their voluntary intake of green vegetables and salad greens. By 3 wks plasma phylloquinone dropped by 50% and there was a significant increase in PIVKA-II and a decrease in urinary Gla. These changes were reversed by the addition of either 50 or 500 µg phylloquinone/d. Ferland et al. (1993) studied 32 subjects in a metabolic unit. After an acclimation period consuming a diet containing 80 µg phylloquinone/d, subjects were switched to a diet containing ~10 µg phylloquinone/d. After 13 d urinary Gla was decreased (in younger subjects only) and PIVKA-II was increased. A gradual repletion with 45 µg phylloquinone brought the urinary Gla of the younger subjects back to near baseline values. The prothrombin time was not altered in these controlled studies.

The acquired vitamin K deficiency produced by the administration of a low dose ("minidose") of the anticoagulant warfarin was also used to assess the relative sensitivity of various measures of vitamin K status. In subjects given 1 mg warfarin/d, Bach et al. (1996) noted elevated PIVKA-II concentrations but no significant decrease in urinary Gla. The most striking change was an increase in % ucOC, which was seen as early as by 3 d. After a 14 d warfarin treatment period, the subjects were given 1 mg phylloquinone for 7 d. At the end of this 7-d period, the % ucOC decreased relative to the baseline period. This study and another by Sokoll et al. (1997), where increasing phylloquinone intake from 100 to 420 µg/d resulted in a significant decline in % ucOC within a 5-d period, suggest that "normal" intakes of vitamin K in the North American population are not sufficient to maximally carboxylate this vitamin K-dependent protein.

The limited controlled studies currently available provided a general understanding of the value of different measures used to assess vitamin K status. Because of its dependence on dietary intake within the last 24 h, serum phylloquinone is not a good indicator of status. Intakes as low as 10 µg/d for a few weeks do not prolong the prothrombin time but do put subjects at risk as assessed by other measures of a vitamin K deficiency. Various PIVKA-II measures do respond to this low intake of vitamin K and Gla excretion, a measure that the total formation of vitamin K-dependent proteins is decreased. It appears that vitamin K intakes equal to the current RDA of 1 µg/(kg·d) are sufficient to prevent these changes. Low vitamin K intakes also increase % ucOC and in this case there is some evidence that the current RDA may not be sufficient to maximally carboxylate this protein.

A number of lines of evidence raised the possibility that vitamin K status may have some influence on bone health (Binkley and Suttie 1995, Vermeer et al. 1995). The demonstration that transgenic mice lacking the vitamin K-dependent matrix Gla protein exhibit a defect related to excessive calcification (Luo et al. 1997) will ensure that this area remains under active investigation. Clarification of the role of osteocalcin and matrix Gla protein in bone metabolism and further studies of a reported dependence of brain sulfatide metabolism on vitamin K status (Sundaram et al. 1996) provide additional input to a reassessment of the current RDA for vitamin K.

Metabolism.  Nondietary factors, such as age, gender and/or menopause, were shown to affect vitamin K metabolism. Older adults (>60 y) have significantly higher plasma phylloquinone concentrations than younger adults (<40 y), independent of dietary intakes (Bach et al. 1996, Booth et al. 1997, Ferland et al. 1993). In one population study the lowest plasma phylloquinone concentrations were measured during the third decade of life for both men and women (Sokoll and Sadowski 1996), after which they increased and remained generally constant. The age differences in phylloquinone concentrations are influenced by plasma triglyceride concentrations, which also increase with age (Sadowski et al. 1989). As phylloquinone is incorporated in chylomicrons following absorption and transported to the liver in the triglyceride-rich lipoproteins (Shearer 1995) there is a strong positive correlation between plasma phylloquinone and triglyceride concentrations (Kohlmeier et al. 1995a, Sadowski et al. 1989, Saupe et al. 1993). When expressed as a ratio of plasma phylloquinone to triglyceride concentrations, older adults have a lower ratio than younger adults, suggestive of an inferior vitamin K status (Sadowski et al. 1989). The relevance of this ratio to vitamin K status is uncertain because older adults were found to be more resistant to functional measures of vitamin K dietary deficiency than younger adults (Ferland et al. 1993).

There have also been recent reports that fasting plasma phylloquinone concentrations are strongly influenced by the polymorphism of apolipoprotein E (apoE) (Kohlmeier et al. 1995a, Saupe et al. 1993). Plasma phylloquinone concentrations were shown to decrease according to apoE genotype: apoE2 > apoE3 > apoE4 (Saupe et al. 1993). This distribution is in accordance with the relationship between the apoE genotype and the rate of hepatic clearance of chylomicron remnants from the circulation, with apoE2 having the slowest rate. Indirect support of this relationship between apoE genotype and plasma phylloquinone concentrations comes from a study of 30 patients on an oral anticoagulant therapy (Kohlmeier et al. 1995b). Patients with an apoE4 genotype had a trend toward greater sensitivity to the oral anticoagulant therapy than those of either apoE2 or apoE3 genotypes; this trend was interpreted as a response to lower circulating plasma phylloquinone concentrations.

Recent investigations have pointed to a unique role for MK-4 within the broad context of vitamin K metabolism. This short-chain menaquinone (Fig. 1) is not produced in significant amounts by bacteria. An apparent conversion of dietary phylloquinone to MK-4 was observed in rats and pigeons in the early 1960s, and it was concluded that the phytyl chain of phylloquinone was removed by gut bacteria and the released menadione was absorbed and converted to MK-4. More recently, other investigators (Guillaumont et al. 1992, Sakamoto et al. 1996, Thijssen and Drittij-Reijnders 1994, Will et al. 1992) reported that MK-4 is present in tissues of animals fed phylloquinone as a sole source of vitamin K. Studies in rats have shown that liver and plasma have low MK-4 concentrations, but that in extrahepatic tissues such as brain, kidney, pancreas, salivary gland and sternum, the concentrations of MK-4 exceed those of phylloquinone. High concentrations of MK-4 are also found in human extrahepatic tissues (Thijssen and Drittij-Reijnders 1996), and rat extrahepatic tissues contain more MK-4 after phylloquinone administration than after MK-4 administration (Thijssen et al. 1996). It has been demonstrated (Davidson et al. 1998) that phylloquinone is converted to MK-4 in germ-free rats and in aseptically cultured kidney cells. The tissue specific localization of MK-4 and a metabolic pathway for its production from phylloquinone strongly suggest that there is a yet-to-be-discovered unique role for this form of vitamin K that is independent of the currently recognized coenzyme function.

	FOOTNOTES

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