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Vitamin K

Red Arrow  Facts Red Arrow  Functions
Red Arrow  Requirements & Recommendations Red Arrow  Deficiency Signs and Symptoms
Red Arrow  Toxicity Red Arrow  Dietary Sources
Red Arrow  Populations w/ Special Needs Red Arrow  Drug-Vitamin Interaction
Red Arrow  Research Summary

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Facts

  • Vitamin K is a fat-soluble vitamin.
  • Vitamin K is required for normal coagulation of the blood and is therefore known as an anti-hemorrhagic vitamin. Vitamin K is necessary for the synthesis of four of the thirteen cofactors required for blood coagulation. Also, Vitamin K is necessary for the synthesis of four other proteins involved in hemostasis: proteins C, S, Z, and M.
  • Vitamin K is essential for formation of healthy bone through synthesis of osteocalcin, matrix Gla protein, and protein S which are thought to promote bone formation and maintenance. 6
  • There are a number of compounds possessing vitamin K activity. Two naturally occurring forms of vitamin K exist: vitamin K1 (phylloquinone) and K2 (menaquinone). Vitamin K1 is found in green plants and vitamin K2 is found in animal liver, curd and cheese, and fermented foods.
  • Natural vitamin K (K1 and K2) requires bile and pancreatic juice for absorption in the small intestine.
  • Vitamin K1 and K2 are stable during cooking. Vitamin K1 is not stable under sunlight.
  • There are also synthetic forms of vitamin K, one of which is menadione. Menadione is converted to vitamin K2 in the body. Synthetic vitamin K (e.g. menadione) is water-soluble and destroyed to a great degree during cooking.
  • Vitamin K2 is synthesized by microflora in the small and large intestine. However, the degree of contribution to vitamin K status in the body and absorption are not well understood.


  • Functions

    • Vitamin K is critical for synthesis of four blood clotting factors in the liver: factor II (prothrombin), factor VII (proconuertin), factor IX (Christmas factor), and factor X (Stuart-Power factor).
    • Vitamin K has hemostatic activity and is used to treat anticoagulant-induced prothrombin deficiency. Vitamin K works as a cofactor for the gamma-carboxylase enzymes. It helps convert these inactive precursors into active coagulation factors, which are secreted by hepatocytes into the blood.
    • Vitamin K may have anti-osteoporotic activity, although this mechanism is not fully understood. There are two vitamin K dependent proteins found in bone. Osteocalcin is the one that appears to act as a regulator of bone mineralization and gamma-carboxyglutamate (Gla) protein is the other. High circulating concentrations of uncarboxylated osteocalcin have been associated with low bone mineral density and increased risk for hip fractures.
    • Vitamin K2 has been shown in vitro and in vivo to inhibit bone resorption substances such as prostaglandin E2 and interleukin-6 and to enhance human osteoblast-induced mineralization.
    • Vitamin K may have antioxidant activity. Vitamin K-hydroquinone is a potent reactive oxygen species scavenger and has been found to inhibit lipid peroxidation in vitro.
    • Synthetic vitamin K (menadione) has shown to have anti-tumor activity in vitro and in vivo. Vitamin K2 was shown to induce in vitro differentiation of myeloid leukemic cell lines.


  • Requirements & Recommendations

    Vitamin K: Dietary Reference Intake 1
    mcg/day
    Infants
    0 to 6 months
    7 to 12 months
    2.0
    2.5
    Children
    1 to 3 years
    4 to 8 years
    30
    55
    Males
    9 to 13 years
    14 to 18 years
    19+ years
    Females
    9 to 13 years
    14 to 18 years
    19+ years
    60
    75
    120

    60
    75
    90
    Pregnancy
    <= 18 years
    19 to 30 years
    31 to 50 years
    75
    90
    90
    Lactation
    <= 18 years
    19 to 30 years
    31 to 50 years
    75
    90
    90


    Values are Adequate Intake (AI). Tolerable upper intake levels (UL)are not determinable due to lack of data of adverse effects and concern with regard to lack of ability to handle excess amounts.


  • Deficiency Signs and Symptoms

    • Deficiency of vitamin K causes hypoprothombinemia manifested by defective coagulation of the blood and hemorrhage.
    • Lack of intestinal bacterial flora might explain part of the hypoprothrombinemia observed during the first 3 to 5 days of life in neonates. Low concentrations of plasma clotting protein factors II, VII, IX, and X may reflect hepatic immaturity.
    • Secondary deficiency of vitamin K often results from impaired absorption of the vitamin due to lack of bile salts in patients with obstructive jaundice, external biliary fistulas or other gastrointestinal conditions. Severe liver disease may inhibit prothrombin synthesis and may be unresponsive to vitamin K therapy.
    • In obstructive jaundice, hemorrhage usually begins after the fourth or fifth day. Blood may ooze slowly from wounds, gums, nose, gastrointestinal mucosa or may cause a massive bleed into the gastrointestinal tract. Some infants may have intracranial hemorrhages at birth or within the first days of life. Breast-fed infants who have not received vitamin K at birth are susceptible to deficiency because human milk is a poor source of vitamin K.


  • Toxicity

    Natural forms of vitamin K have caused no symptoms of toxicity, even when supplemented in large amounts. The synthetic product, menadione, has an unsubstituted carbon that can react with tissue sulfhydryl groups, promoting oxidation of membrane phospholipids. Toxic effects such as hemolytic anemia, hyperbilirubinemia, and kernicterus, have been reported in infants supplemented with menadione.


  • Dietary Sources

    Green leafy vegetables supply 40 to 50% of the total dietary intake of vitamin K. Vegetable oils, olive, canola, soybean and cottonseed oil contain vitamin K1. Vitamin K2 is found in egg yolk, butter, cow liver, certain cheeses, and fermented soybean products. A study compared the bioavailability of 495 mcg of phylloquinone (vitamin K1) from 150 g raw spinach to 500 mcg of supplemental vitamin K1 in eleven subjects aged 22 to 30 years. Researchers found that the area under the curve was higher from the consumption of the phylloquinone tablet than the consumption of the raw spinach. However, no difference of absorption of vitamin K from different food sources (fresh spinach, broccoli and romaine lettuce) was found, indicating that the choice of specific food may not affect vitamin K bioavailability. 5

    Food Source
    Vitamin K (mcg)
    per cup of food
    frozen kale
    1,146
    frozen spinach
    1,027
    canned spinach
    987
    frozen turnip greens
    851
    collards
    836
    frozen Brussels sprouts
    299
    frozen broccoli
    183
    raw broccoli
    89
    frozen collards
    1,059
    raw spinach
    145
    Source: USDA Food Nutrient Database


  • Populations w/ Special Needs

    • A normal diet contains from 300 to 500 mcg of vitamin K daily. This meets the recommended concentrations, therefore deficiency is highly unlikely.
    • Newborn infants and persons who have been injured have renal insufficiency, or are being chronically treated with antibiotics are at risk for vitamin K deficiency.
    • Other conditions and populations associated with increased risk of vitamin K deficiency include: biliary fistula, obstructive jaundice, steatorrhea, chronic diarrhea, intestinal bypass, Whipple’s disease, celiac sprue, Crohn’s disease, liver disease, and chronic pancreatitis.


  • Drug-Vitamin Interaction

    2 3 4
    • Therapy with non-absorbable sulfonamides or oral antibiotics may interfere with vitamin K synthesis in the intestines.
    • Patients who receive warfarin (Coumadin) for anticoagulant therapy should not consume large amounts of vitamin K supplements or vitamin K-rich vegetables due to the pro-coagulant activities of vitamin K.
    • Concurrent oral administration of mineral oil may decrease gastrointestinal absorption of vitamin K.
    • Anticonvulsant agents, such as phenytoin (Dilantin), can speed up the normal breakdown of vitamin K into its inactive byproduct and long-term use can lead to vitamin K deficiency (resulting in bleeding disorders or facial bone abnormalities) and bone problems, such as osteoporosis in babies born to mothers taking the drugs. Mothers on these medications may need to take vitamin K supplements during pregnancy to prevent these problems.
    Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.


  • Research Summary

    Topic: Bone Health

    Vitamin K intake and hip fractures in women: a prospective study.
    The Nurses' Health Study investigated dietary intakes of vitamin K (median intake 169 mcg/d) and the incidence of hip fractures in 72,327 women aged 38 to 63 years. Dietary intake was based on food frequency questionnaires during ten years of follow-up. A total of 270 hip fractures from low or moderate impact were reported during the follow-up period. Women in the highest quintiles of vitamin K intake had a significantly lower risk for hip fracture (RR=0.70, 95% CI 0.53, 0.93) compared to those in the lowest quintile (less than 109 mcg/day). No increased benefit was noted for increasing vitamin K intake in quintiles two through five. The results from this large prospective study suggest that vitamin K is important for promoting bone health. 7
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    Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.
    In a randomized clinical intervention trial, vitamin K2 supplements to support bone health were investigated. Participants included 325 post-menopausal women who were randomly assigned to receive 45 mg/d of menatetrenone (vitamin K2) or a placebo for three years. Bone mineral content (BMC) and hip geometry were assessed by dual energy X-ray absorptiometry (DXA); bone strength indices were calculated from DXA-bone mineral density (DXA-BMD), femoral neck width (FNW), and hip axis length (HAL). No differences between DXA-BMD values were found between the placebo and vitamin K2 groups. However, BMC and FNW were increased in the vitamin K2 group relative to the placebo group. Maximal improvements were seen after 12 months and no additional improvements were found during the remainder of the study. These results suggest that vitamin K2 may support bone health and also indicate that some of the contradictory results may have been due to the specific bone health tests used. 13
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    Serum vitamin K level and bone mineral density in post-menopausal women.
    Blood vitamin K concentrations, osteocalcin, and bone mineral density were assessed in 71 post-menopausal women (19 with reduced bone mineral density) and 24 women with climacteric symptoms receiving hormone replacement therapy (HRT; 6 with reduced bone mineral density). For post-menopausal women with reduced bone mineral density, vitamin K levels were lower than vitamin K levels of post-menopausal women with normal bone mineral density. For women with climacteric symptoms, osteocalcin and vitamin K were reduced for those with reduced bone mineral density but not affected by HRT. Researchers concluded that vitamin K was related to post-menopausal bone mineral loss. 8
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    Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women.
    Dietary intake of vitamin K was assessed in 335 men and 553 women (average age 75.2 years) who took part in the Framingham Heart Study. The incidence of hip fractures was also recorded. Individuals with high vitamin K intakes had a significantly lower adjusted relative risk of hip fractures (median intake of 254 mcg/day; RR=0.35; 95% CI: 0.13, 0.94) than those with a low intake of vitamin K (median of 56 mcg/day). However, no association between vitamin K intake and BMD was found. Potential explanations for the lack of association between dietary K intake and BMD include the older age of the cohort, who may not have had current dietary patterns that were consistent with those throughout adulthood, small sample size, and the possibility that any putative role of vitamin K in the risk of hip fracture was independent of BMD. 9
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    Vitamin K intake and bone mineral density in women and men.
    The objective of this study was to examine cross-sectional associations between dietary vitamin K intake and bone mineral density (BMD) at the hip and spine in a group of 1,112 men and 1,479 women (median age 59 years) who participated in the offspring cohort of the Framingham Heart Study. Dietary and supplemental intakes of vitamin K were assessed with the use of a food-frequency questionnaire. Women in the lowest quartile of vitamin K intake (median 70.2 mcg/day) had significantly lower bone mineral density (P=0.005) at the femoral neck (0.854 g/cm3) and spine (1.140 g/cm3) versus women in the highest quartile (median 309 mcg/day; 0.888 g/cm3 and 1.190 g/cm3, respectively). No associations between vitamin K and bone mineral density were found in men. These results suggest that low dietary vitamin K intake was associated with low BMD in women, but not men.

    Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.
    In a randomized, double-blind, placebo-controlled trial, the impact of vitamin K, vitamin D, and calcium supplements on markers of bone health was investigated. This trial included 244 healthy, non-osteoporotic women at least 60 years of age. Participants were randomized to receive a daily placebo, 200 mcg/day vitamin K1, 10 mcg/day vitamin D3 with 1000 mg/day calcium, or vitamin K2, vitamin D3, and calcium. Participants consumed the placebo or supplements and were monitored for two years. Significant bone loss was only found in the mid distal radius and changes were not different between the groups. Bone mineral density (BMD) and bone mineral content (BMC) at the site of the ultradistal radius significantly increased during the trial for women who took combined vitamin K and vitamin D plus calcium. Serum vitamin K2 increased by 157% (p<0.001) during the two year trial. In addition, the percentage of undercarboxylated osteocalcin decreased by 51% (p<0.001), serum 25-hydroxyvitamin D increased by 17% (p<0.001), and parathyroid hormone decreased by 11% (p=0.049). These results indicate that vitamins D and K along with calcium may work together to protect bone health. 14
    Red Arrow Read Abstract
    Topic: Athletes

    Improved bone metabolism in female elite athletes after vitamin K supplementation.
    Bone metabolism was compared in eight female long-distance runners. Four women had amenorrhoea and the other four women were taking oral contraceptives. All participants were given 10 mg/day of supplemental vitamin K for a one month period. In all participants, vitamin K supplements were associated with increased calcium-binding capacity of osteocalcin. In the low estrogen group, there was a 15 to 20% increase in bone formation markers and a 20 to 25% decrease in bone resorption markers after one month of vitamin K supplementation. The researchers concluded that long distance runners prone to calcium deficiency should be evaluated for calcium and vitamin D supplementation, and vitamin K status should be assessed. 10
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    Topic: Atherosclerosis

    Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study.
    Vitamin K status was assessed for 113 postmenopausal women with abdominal aortic calcification. Women with atherosclerotic calcification had 7% lower bone mass (P=0.06). It was also found that markers for vitamin K status measured by serum immunoreactive osteocalcin with low affinity for hydroxyapatite were inversely associated with bone mass. For women with atherosclerosis, vitamin K was inversely associated with bone mass (n=34, r=-0.47, P=0.013). The data suggest that vitamin K deficiency may play a role in both aortic calcification and bone loss. 11
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