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TABLE 1 Dietary Reference Intakes for Vitamin K by Life Stage Group DRI values (mg /day) AIa ULb males females Life stage group 0 through 6 mo 2.0 2.0 7 through 12 mo 2.5 2.5 1 through 3 y 30 30 4 through 8 y 55 55 9 through 13 y 60 60 14 through 18 y 75 75 19 through 30 y 120 90 31 through 50 y 120 90 51 through 70 y 120 90 > 70 y 120 90 Pregnancy £ 18 y 75 19 through 50 y 90 Lactation £ 18 y 75 19 through 50 y 90 aAI = Adequate Intake. bUL = Tolerable Upper Intake Level. Data were insufficient to set a UL. In the absence of a UL, extra caution may be warranted in consuming levels above the recommended intake.

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PART III: VITAMIN K 255 VITAMIN K V itamin K functions as a coenzyme for biological reactions involved in blood coagulation and bone metabolism. Phylloquinone, the plant form of vitamin K, is the major form in the diet. Menaquinone forms are produced by bacteria in the lower bowel. Since data were insufficient to set an Estimated Average Requirement (EAR) and thus calculate a Recommended Dietary Allowance (RDA) for vitamin K, an Adequate Intake (AI) was instead developed. The AIs for vitamin K are based on median intakes of the nutrient. Data were insufficient to set a Tolerable Up- per Intake Level (UL). DRI values are listed by life stage group in Table 1. Rich dietary sources of vitamin K include leafy green vegetables, soy and canola oils, and margarine. Vegetables particularly rich in vitamin K include collard greens, spinach, and salad greens. Clinically significant vitamin K defi- ciency is extremely rare in the general population, with cases being limited to individuals with malabsorption syndromes or to those treated with drugs known to interfere with vitamin K metabolism. No adverse effects have been reported with high intakes of vitamin K from food or supplements. VITAMIN K AND THE BODY Function Vitamin K functions as a coenzyme for biological reactions involved in blood coagulation and bone metabolism. It also plays an essential role in the conver- sion of certain residues in proteins into biologically active forms. These pro- teins include plasma prothrombin (coagulation factor II) and the plasma procoagulants, factors VII, IX, and X. Two structurally related vitamin K– dependent proteins have received recent attention as being proteins with pos- sible roles in the prevention of chronic disease. They are osteocalcin, found in bone, and matrix Gla protein, originally found in bone, but now known to be more widely distributed, Absorption, Metabolism, Storage, and Excretion Phylloquinone is the major form of vitamin K in the diet. It is absorbed in the small intestine in a process that is enhanced by the presence of dietary fat and dependent on the normal flow of bile and pancreatic juice. The absorbed phyl-

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 256 loquinone is then secreted into the lymph and enters the circulation as a com- ponent of chylomicrons. The circulating vitamin K is taken up by the liver and other tissues. The liver, which contains the highest concentration of vitamin K in the body, rapidly accumulates ingested phylloquinone. Skeletal muscle contains little phylloquinone, but significant concentrations are found in the heart and some other tissues. Turnover in the liver is rapid and hepatic reserves are rap- idly depleted when dietary intake of vitamin K is restricted. Vitamin K is ex- creted primarily in the bile, but also, to a lesser extent, in the urine. Menaquinone forms of vitamin K are produced by bacteria in the lower bowel, where the forms appear in large amounts. However, their contribution to the maintenance of vitamin K status has been difficult to assess. Although the content is extremely variable, the human liver contains about 10 times as much vitamin K as a mixture of menaquinones than as phylloquinone. DETERMINING DRIS Determining Requirements Since data were insufficient to set an EAR and thus calculate an RDA for vitamin K, an AI was instead developed. The AIs for vitamin K are based on the median intakes of the nutrient indicated by the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994). It has been suggested that vitamin K may have roles in osteoporosis and vascular health. However, this is difficult to establish on the basis of the studies performed thus far. Clinical intervention studies investigating the relationship between vitamin K and osteoporosis are currently being conducted in North America and Europe. 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 verified in studies that employ rigorous experimental designs. Special Considerations Newborns: Vitamin K is poorly transported across the placenta, which puts newborn infants at risk for vitamin K deficiency. Poor vitamin 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 few weeks of life, a condition known as hemorrhagic disease of the newborn (HDNB). Because HDNB can be effectively prevented by administering vitamin K, infants born in the United States and Canada routinely receive 0.5–1 mg of phylloquinone

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PART III: VITAMIN K 257 intramuscularly or 2.0 mg orally within 6 hours of birth. This practice is sup- ported by both U.S. and Canadian pediatric societies. Criteria for Determining Vitamin K Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Average vitamin K intake from human milk 7 through 12 mo Extrapolation from 0 through 6 mo AI 1 through > 70 y Median intake of vitamin K from NHANES III Pregnancy £ 18 y Adolescent female median intake 19 through 50 y Adult female median intake Lactation £ 18 y Adolescent female median intake 19 through 50 y Adult female median intake The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all healthy people. Data were insufficient to set a UL for vitamin K. DIETARY SOURCES Foods Only a relatively small number of food items substantially contribute to the dietary phylloquinone intake of most people. A few green vegetables (collards, spinach, and salad greens) contain in excess of 300 mg of phylloquinone/100 g, while broccoli, brussels sprouts, cabbage, and bib lettuce contain between 100 and 200 mg of phylloquinone/100 g. Other green vegetables contain smaller amounts. Plant oils and margarine are the second major source of phylloquinone in the diet. The phylloquinone content of plant oils varies, with soybean and canola oils containing greater than 100 mg of phylloquinone/100 g. Cottonseed oil and olive oil contain about 50 mg/100 g, and corn oil contains less than 5 mg/100 g. According to the Food and Drug Administration’s (FDA’s) Total Diet Study (1991– 1997), spinach, collard greens, broccoli, and iceberg lettuce are the major con- tributors of vitamin K in the diets of U.S. adults and children.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 258 The hydrogenation of plant oils to form solid shortenings results in some conversion of phylloquinone to 2′,3′-dihydrophylloquinone. This form of vi- tamin K is more prevalent in margarines, infant formulas, and processed foods, and it can represent a substantial portion of total vitamin K in some diets. Some cheeses may also supply a substantial amount of vitamin K (40–80 µg/ 100 g) in the form of menaquinone. However, as earlier mentioned, the contri- bution of menaquinones to the maintenance of vitamin K status has been dif- ficult to assess. Dietary Supplements According to data from NHANES III, median intakes of vitamin K from food and supplements were 93–119 µg/day for men and 82–90 mg/day for women (for those who reported consuming supplements). Bioavailability Studies on the bioavailability of vitamin K (in the form of phylloquinone) have been limited. Until more data are available, the bioavailability of phylloquinone obtained from vegetables should not be considered to be more than 20 percent as available as phylloquinone obtained from supplements. It is known, how- ever, that the absorption of vitamin K from vegetables is enhanced by the pres- ence of dietary fat. Dietary Interactions The main interaction of concern regarding vitamin K involves anticoagulant medications, such as warfarin. Chronic use of these drugs results in an acquired cellular vitamin K deficiency and a decrease in the synthesis of vitamin K– dependent clotting factors. Alterations in vitamin K intake can influence the efficacy of these drugs. Individuals on chronic warfarin therapy may require dietary counseling on how to maintain steady vitamin K intake levels. Because habitual vitamin K intake may modulate warfarin dosage in patients using this anticoagulant, these individuals should maintain their normal dietary and supplementation patterns once an effective dose of warfarin has been established. Short-term, day-to-day variations in vitamin K intake from food sources do not appear to interfere with anticoagulant status and therefore do not need to be carefully monitored. How- ever, changes in supplemental vitamin K intake should be avoided, since the bioavailability of synthetic (supplemental) phylloquinone is considerably greater than the bioavailability of phylloquinone from food sources. There is evidence that vitamin K may also interact with other nutrients and dietary substances (see Table 2).

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PART III: VITAMIN K 259 TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT VITAMIN K Vitamin E Elevated intakes of vitamin E Increased intakes of vitamin E have not been reported may antagonize the action of to antagonize vitamin K status in healthy humans. vitamin K. However, in one study, patients receiving anticoagulation therapy who were supplemented with approximately 400 IU/day of a-tocopherol experienced nonstatistically significant decreases in prothrombin time over a 4-week period. The metabolic basis for the potential antagonism of vitamin K by vitamin E has not been completely determined. INADEQUATE INTAKE AND DEFICIENCY Studies conducted over a number of years have indicated that the simple re- striction of vitamin K intake to levels almost impossible to achieve in any nu- tritionally adequate, self-selected diet does not impair normal hemostatic con- trol 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. In general, clinically significant vitamin K deficiency is extremely rare in the general population, with cases being limited to individuals with various lipid malabsorption syndromes or to those treated with drugs known to interfere with vitamin K metabolism. However, a clinically significant vita- min K deficiency has usually been defined as a vitamin K–responsive hypo- prothrombinemia and is associated with an increase in prothrombin time and, in severe cases, bleeding. There have also been case reports of bleeding occurring in patients taking antibiotics, and the use of these drugs has often been associated with an acquired vitamin K deficiency resulting from a suppression of menaquinone- synthesizing organisms. But the reports are complicated by the possibility of general malnutrition in this given patient population and by the antiplatelet action of many of the same drugs. EXCESS INTAKE No adverse effects have been reported with high intakes of vitamin K from food or supplements in healthy individuals who are not intentionally blocking vita-

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 260 min K activity with anticoagulation medications. A search of the literature re- vealed no evidence of toxicity associated with the intake of either the phyllo- quinone or the menaquinone forms of vitamin K. Menadione, a synthetic form of the vitamin, has been associated with liver damage and is no longer thera- peutically used.

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PART III: VITAMIN K 261 KEY POINTS FOR VITAMIN K Vitamin K functions as a coenzyme for biological reactions 3 involved in blood coagulation and bone metabolism. Since data were insufficient to set an EAR and thus calculate 3 an RDA for vitamin K, an AI was instead developed. The AIs for vitamin K are based on the median intakes 3 indicated by NHANES III. Infants born in the United States and Canada routinely receive 3 0.5–1 mg of phylloquinone intramuscularly or 2.0 mg orally within 6 hours of birth. This practice is supported by both U.S. and Canadian pediatric societies. Data were insufficient to set a UL. 3 Although epidemiological evidence indicates that vitamin K 3 may play a role in osteoporosis prevention, more research in this area is needed. Only a relatively small number of food items contribute 3 substantially to the dietary phylloquinone intake of most people. A few green vegetables (collards, spinach, and salad greens) contain in excess of 300 mg of phylloquinone/100 g, while broccoli, brussels sprouts, cabbage, and bib lettuce contain between 100 and 200 mg of phylloquinone/100 g. The main interaction of concern regarding vitamin K involves 3 anticoagulant medications, such as warfarin. Patients on chronic warfarin therapy may require dietary counseling on how to maintain steady vitamin K intake levels. In general, clinically significant vitamin K deficiency is 3 extremely rare in the general population, with cases being limited to individuals with malabsorption syndromes or those treated with drugs known to interfere with vitamin K metabolism. However, the classic sign of vitamin K deficiency is a vitamin K–responsive increase in prothrombin time and, in severe cases, bleeding. No adverse effects have been reported with high intakes of 3 vitamin K from food or supplements in healthy individuals who are not intentionally blocking vitamin K activity with anticoagulation medications.