Vitamin K is a great source for our body’s overall nutrition. Vitamin K can be found in green leafy vegetables, olive oil, canola oil, soybean oil, and cottonseed oil. It can also be found in egg yolks, butter, and certain types of cheeses.
Vitamin K is a generic term for a group of substances which contain the 2-methyl-1, 4-naphthoquinone ring structure and which possess hemostatic activity. Substances with vitamin K activity were originally identified in green leafy vegetables, hemp seeds, liver and fish meal. These substances were found to have antihemorrhagic activity and their collective name was derived from koagulation, the German word for clotting. In addition to its essential role in hemostasis, vitamin K is involved in bone metabolism, among other processes.
Vitamin K1 or phylloquinone is the principal dietary source of vitamin K and its predominant circulating form. Green leafy vegetables are rich in vitamin K1 and contribute 40%-50% of total dietary intake of the vitamin. The next largest contributors to dietary vitamin K intake are the vegetable oils olive oil, canola oil, soybean oil and cottonseed oil. These vegetable oils also contain vitamin K1. Vitamin K1 is a fat-soluble substance. Vitamin K2, which is also fat soluble, is the collective term for a number of substances known as menaquinones. Vitamin K2 is found in chicken egg yolk, butter, cow liver, certain cheeses and fermented soybean products such as natto. This form of vitamin K is also produced by certain bacteria, including some of the bacteria that comprise the microflora of the intestine. The dietary contribution of vitamin K2 is much less than that of vitamin K1. The amount of vitamin K contributed to the body by the intestinal microflora remains unclear. Vitamin K3 or menadione is a fat-soluble synthetic compound which is used in animal feed and dog and cat food. It is metabolized to vitamin K2.
Vitamin K is involved as a cofactor in the posttranslational gamma-carboxylation of glutamic acid residues of certain proteins in the body. These proteins include the vitamin K-dependent coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor), X (Stuart factor), protein C, protein S, protein Zv and a growth-arrest-specific factor (Gas6). In contrast to the other vitamin K-dependent proteins in the blood coagulation cascade, protein C and protein X serve anticoagulant roles. The two vitamin K-dependent proteins found in bone are osteocalcin, also known as bone G1a (gamma-carboxyglutamate) protein or BGP, and the matrix G1a protein or MGP. Gamma-carboxylation is catalyzed by the vitamin K-dependent gamma-carboxylases. The reduced form of vitamin K, vitamin K hydroquinone, is the actual cofactor for the gamma-carboxylases. Proteins containing gamma-carboxyglutamate are called G1a proteins.
Vitamin K deficiency can occur under certain conditions. These include, inadequate dietary intake, malabsorption syndromes (cystic fibrosis, Crohn's disease, ulcerative colitis, Whipple's disease, celiac sprue, short bowel syndrome) and loss of storage sites due to hepatocellular disease. Vitamin K deficiency frequently occurs in those with chronic liver disease, such as primary biliary cirrhosis. Coumarin anticoagulants, such as warfarin, induce a state analogous to vitamin K deficiency by inhibiting the reduction and recycling of vitamin K, and certain cephalosporin antibiotics (see Interactions) may also induce a vitamin K deficiency state by inhibiting the reduction and recycling of the vitamin. Recently, it has been found that space flight may impair vitamin K metabolism and also induce a state of vitamin K deficiency. Symptoms of vitamin K deficiency include easy bruisability, epistaxis, gastrointestinal bleeding, menorrhagia and hematuria. Chronic vitamin K deficiency may also result in osteoporosis and increased risk of fractures. There is some evidence that chronic warfarin use may also cause osteoporosis.
Vitamin K1, in addition to being known as phylloquinone, is also known as phytonadione and 2-methyl-3-phytyl-1, 4-naphthoquinone. The lipophilic side chain is located at position 3 of the naphthoquinone ring. Its molecular formula is C31H46O2 and its molecular weight is 450.71 daltons. The structural formula is:
Vitamin K2 is the collective term for a group of vitamin K compounds called menaquinones. The menaquinone homolgues are characterized by the number of isoprene residues comprising the side chain. The side chain is located at position 3 of the naphthoquinone ring. The group chemical name of the menaquinones is 2-methyl-3-all-trans-polyprenyl-1, 4-naphthoquinones. Menaquinones with side chains of up to 15 isoprene units have been described. Menaquinones of from two to 13 isoprene units have been found in human and animal tissues. Menaquinones are designated by the name menaquinone followed by a number. The number refers to the number of isoprene residues in the structure. Thus, menaquinone-4, abbreviated MK-4, possesses four isoprene residues in the side chain. Menaquinone-7 possesses seven isoprene units in the side chain. The menaquinones may also be designated by the number of carbons in the side chain. An isoprene residue contains five carbons. Thus, menaquinone-4 is also called vitamin K2 (20) and menaquinone-7 is also called vitamin K2 (35). Menaquinone-4 is also known as menatetrenone. The fermented soybean product natto is rich in menaquinone-7. Menaquinone-4 is the predominant form of vitamin K in the rat brain.
Vitamin K3 or menadione is a synthetic naphthoquinone derivative. It is also known as 2-methyl-1, 4-naphthoquinone. Its molecular formula is C11H8O2 and its molecular weight is 172.18 daltons. Vitamin K3 does not possess a lipophilic side chain.
The nutritional supplement forms of vitamin K are vitamin K1 and vitamin K2.
Actions & Pharmacology
Vitamin K has hemostatic activity and may have anti-osteoporotic, antioxidant and anticarcinogenic activities.
Mechanism of Action
The hemostatic activity of vitamin K is well known. Vitamin K is used to treat anticoagulant-induced prothrombin deficiency caused by warfarin, hypoprothrombinemia secondary to antibiotic therapy and hypoprothrombinemia secondary to vitamin C deficiency from various causes, including malabsorption syndromes. The pharmacological action of vitamin K in the treatment of hypoprothrombinemia is related to the normal physiological function of the vitamin. Vitamin K is an essential cofactor for the gamma-carboxylase enzymes which catalyze the posttranslational gamma-carboxylation of glutamic acid residues in inactive hepatic precursors of coagulation factors II, VII, IX and X. Gamma-carboxylation converts these inactive precursors into active coagulation factors which are secreted by hepatocytes into the blood. Supplement vitamin K has no hemostatic activity in those who are not vitamin K-deficient.
The mechanism of the possible anti-osteoporotic activity of vitamin K is not completely understood. Two vitamin K-dependent proteins are found in bone: osteocalcin or bone G1a protein (BGP) and the matrix G1a protein or MGP. Osteocalcin appears to be the most abundant non-collagenous protein in the bone. Most of the osteocalcin synthesized by the osteoblasts during bone matrix formation is incorporated into bone. This is due to the high specificity of the gamma-carboxyglutamyl residues for the calcium ions of hydroxyapatite. A small amount of osteocalcin is released into the circulation. Osteocalcin appears to act as a regulator of bone mineralization. High levels of circulating undercarboxylated (under-gamma-carboxylated) osteocalcin have been associated with low bone mineral density and increased risk of hip fractures. The serum level of undercarboxylated osteocalcin may be a more sensitive marker of vitamin K status than blood coagulation tests. High levels of undercarboxylated osteocalcin are frequently found in the context of normal blood coagulation tests.
In vivo and in vitro studies have shown that vitamin K may directly act on bone metabolism. In vitro studies have demonstrated that vitamin K2 inhibits bone resorption by, in part, inhibiting the production of bone resorbing substances such as prostaglandin E2 and interleukin-6. Vitamin K2 has been reported to enhance human osteoblast-induced mineralization in vitro and to inhibit bone loss in steroid-treated rats and ovariecomized rats.
The reduced form of vitamin K, vitamin K-hydroquinone, is the active cofactor for the gamma-carboxylase enzymes. Vitamin K hydroquinone is produced in the vitamin K cycle. In the vitamin K cycle, vitamin K-hydroquinone is continuously regenerated. Vitamin K-hydroquinone is a potent reactive oxygen species scavenger. Vitamin K-hydroquinone has been found to inhibit lipid peroxidation.
Certain naphthoquinones, in particular the synthetic vitamin K menadione, have been found to have antitumor activity in vitro and in vivo. Vitamin K2 has been found to induce the in vitro differentiation of myeloid leukemic cell lines. The mechanism of the possible anticarcinogenic activity of vitamin K is not well understood. Menadione is an oxidative stress inducer and its possible anticarcinogenic activity may, in part, be explained by induction of apoptotic cell death. One study suggested that the induction of apoptosis by menadione is mediated by the Fas/Fas ligand system. Another study reported that menadione induces cell cycle arrest and cell death by inhibiting Cda 25 phosphatase.
Vitamin K, mainly in the form of vitamin K1, is principally absorbed from the jejunum and ileum. The efficiency of absorption is variable and ranges from 10% to 80%. Vitamin K is delivered to the enterocytes in micelles formed from bile salts and other substances. Vitamin K is secreted by enterocytes into the lymphatics in the form of chylomicrons. It enters the circulation via the thoracic duct and is carried in the circulation to various tissues including hepatic, bone and spleen, in the form of chylomicron remnants. In the liver, some vitamin K is stored, some is oxidized to inactive end products and some secreted with VLDL (very low-density lipoprotein). Approximately 50% of vitamin K is carried in the plasma in the form of VLDL, about 25% in LDL (low-density lipoprotein) and about 25% in HDL (high-density lipoprotein). Vitamin K undergoes some oxidative metabolism. Excretion of vitamin K and its metabolites is mainly via the feces. Some urinary excretion of vitamin K also occurs.
Indications & Usage
Vitamin K is indicated in those with vitamin K deficiency, in some cases of hemorrhagic disease of the newborn, in some malabsorption syndromes and in some on long-term total parenteral nutrition. There is emerging evidence that adequate vitamin K intake may help protect against osteoporosis generally. There is the suggestion in early research that vitamin K may also have some anti-atherosclerotic effects. Claims that vitamin K is an anti-cancer agent derive from very preliminary work utilizing, primarily, vitamin K3 or menadione. There is little or no reliable data yet available to support further claims that vitamin K inhibits platelet aggregation, that it has favorable effects on insulin and glucose, that it is helpful in Alzheimer's disease and that it favorably modulates immunity and has anti-inflammatory effects.
There is no typical dosage for vitamin K. Some multivitamin preparations contain vitamin K as vitamin K1 (phylloquinone or phytonadione) or vitamin K2 (menaquinones) at doses of 25 to 100 micrograms. The amount of vitamin K in these products is stated as the percentage of the daily value (DV) for vitamin K. The DV is the highest RDA for the vitamin, or 80 micrograms. Vitamin K1 is also available in 10 milligram doses. In Japan, vitamin K, usually in the form of vitamin K2, is used for the management of osteoporosis. The fermented soybean product natto is rich in menaquinone-7 or vitamin K2 (35). The bacteria that is used in the preparation of natto, Bacillus natto, is also used in Japan as a dietary supplement source of vitamin K2.
The Food and Nutrition Board of the U.S. National Academy of Sciences has indicated the following Dietary Reference Intakes (DRIs) for vitamin K:
|Category||Age (Years)||AI (adequate intake) (micrograms/day)|
|Infants||0 through 6 months||2.0|
|7 through 12 months||2.5|
|Children||1 through 3 years||30|
|4 through 8 years||55|
|9 through 13 years||60|
|Males||14 through 18 years||75|
|19 through 30 years||120|
|31 through 50 years||120|
|51 through 70 years||120|
|Older than 70 years||120|
|Females||14 through 18 years||75|
|19 through 30 years||90|
|31 through 50 years||90|
|51 through 70 years||90|
|Older than 70 years||90|
|Pregnant||18 years or younger||75|
|19 through 50 years||90|
|Lactating||18 years or younger||75|
|19 through 50 years||90|
The DV (Daily Value) for vitamin K, which is used for determining percentage of nutrient daily values on nutritional supplement and food labels, is 80 micrograms. This is based on the U.S. RDA for vitamin K.
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Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr. 2000;71:1201-1208.Bügel S. Vitamin K and bone health in adult humans. Vitam Horm. 2008;78:393-416.Caillot-Augusseau A, Vico L, Herr M, et al. Space flight is associated with rapid decreases of under carboxylated osteocalcin and increases of markers of bone resorption without changes in their circadian variation: observations in two cosmonauts. Clin Chem. 2000;46:1136-1143.Caricchio R, Kovalenko D, Kaufmann WK, et al. Apoptosis provoked by the oxidative stress inducer menadione (vitamin K3) is mediated by the Fas/Fas ligand system. Clin Immunol. 1999;93:65-74.Chlebowski RT, Akman SA, Block JB. Vitamin K in the treatment of cancer. Cancer Treatment Rev. 1985;12:49-63.Craciun AM, Wolf J, Knapen MH, et al. Improved bone metabolism in female elite athletes after vitamin K supplementation. Int J Sports Med. 1998;19:479-484.Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-125.Feskanich D, Weber P, Willett WC, et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999;69:74-79.Hirao M, Hashimoto J, Ando W, et al. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab. 2008;26(3):260-264.Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press, 2001.Jamal SA, Browner WS, Bauer D, Cummings SR. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1998;128:829-832.Jie K-SG, Bots ML, Vermeer C, et al. Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calcif Tissue Int. 1996;59:352-356.Kawashima H, Nakajima Y, Matubara Y, et al. Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits. Jpn J Pharmacol. 1997;75:135-143.Lipsky JJ. Nutritional sources of vitamin K. Mayo Clin Proc. 1994;69:462-466.Macdonald HM, McGuigan FE, Lanham-New SA, et al. Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. Am J Clin Nutr. 2008;87(5):1513-1520.Nimptsch K, Rohrmann S, Linseisen J. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2008;87(4):985-992.Oldenburg J, Marinova M, Müller-Reible C, et al. The vitamin K cycle. Vitam Horm. 2008;78:35-62.Olson RE. Osteoporosis and vitamin K intake (editorial). Am J Clin Nutr. 2000;71:1031-1032.Olson RE. Vitamin K. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore, MD: Williams and Wilkins; 1999:363-380.Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract. 2007;22(5):517-544.Philip WJ, Martin JC, Richardson JM, et al. Decreased axial and peripheral bone density in patients taking long-term warfarin. QJM. 1995;88:635-640.Rashid M, Durie P, Andrew M, et al. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr. 1999;70:378-382.Sakagami H, Satoh K, Hakeda Y, et al. Apoptosis-inducing activity of vitamin C and vitamin K. Cell Mol Biol (Noisy-le-Grand, France). 2000;46:129-143.Sakamoto N, Wakabayashi I, Sakamoto K. Low vitamin K intake effects on glucose tolerance in rats. Int J Vitam Nutr Res. 1999;69:27-31.Sano M, Fujita H, Morita I, et al. Vitamin K2 (menatetrenone) induces iNOS in bovine vascular smooth muscle cells: no relationship between nitric oxide production and gamma-carboxylation. J Nutr Sci Vitaminol. (Tokyo). 1999;45:711-723.Shearer MJ. Vitamin K. Lancet. 1995;345:229-234.Takami A, Nakao S, Ontachi Y, et al. Successful therapy of myelodysplastic syndrome with menatetrenone, a vitamin K2 analog. Int J Hematol. 1999;69:24-26.Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr Rev. 1999;57:231-240.Vermeer C, Jie KS, Knapen MH. Role of vitamin K in bone metabolism. Annu Rev Nutr. 1995;15:1-22.Vervoort LM, Ronden FE, Thijssen HH. The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation. Biochem Pharmacol. 1997;54:871-876.Wu FY, Sun TP. Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase. 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Research & Summary
Though primary vitamin K deficiency is uncommon, deficiencies secondary to disease or drug therapy arise more often. The most significant instance of acquired vitamin K deficiency manifests as hemorrhagic disease of the newborn (HDN). Causes of HDN are varied and include exclusive breast feeding (vitamin K is in short supply in breast milk) and liver dysfunction. Vitamin K prophylaxis, via oral and intramuscular administration at birth, has been widely used for decades with apparent efficacy. Intramuscular administration is considerably more effective but has been less used in recent years following publication of an epidemiological study suggesting an association between this treatment and a reported doubling of cancer risk in later life. Whether this association is genuinely causal has yet to be confirmed. No such association is seen with oral administration.
A number of drug therapies, including vitamin A and E in pharmacologic doses, some broad-spectrum antibiotics, the 4-hydroxycoumarins and salicylates, antagonize the action of vitamin K and, in some instances, result in deficiencies requiring additional vitamin K intake under a physician's supervision. TPN is frequently another indication for supplemental vitamin K, as are some malabsorption syndromes and gastrointestinal disorders. Those with parenchymal liver disease often have vitamin K deficiency. Recently vitamin K deficiency was found to be significant in many with cystic fibrosis.
Over the past decade, some very important vitamin K roles in bone metabolism have begun to be elucidated. Vitamin K has been demonstrated to promote the gamma-carboxylation of glutamyl residues on many bone proteins. This carboxylation is associated with increased bone mineral density, while undercarboxylation results in diminished bone mineral density and increased risk of bone fracture.
In a prospective analysis, the diets of 72,327 women 38-63 years of age were assessed and the incidence of hip fractures monitored over a ten-year period. A significant association was found between low dietary vitamin K intake and increased risk of hip fracture. This study looked at several specific dietary components and found a significant protective effect from lettuce, a source rich in vitamin K. Women who consumed lettuce (iceberg and romaine) one or more times daily had a significant 45% lower risk of hip fracture than did women who ate lettuce once a week or less.
In another study, gammacarboxyglutamate (Gla) proteins, the formation of which, as noted above, are promoted by vitamin K activity, were observed to play regulatory roles in calcification processes in both bone tissue and atherosclerotic vessel wall. This research suggested that reduced vitamin K status increases vessel wall calcification and reduces bone calcification and that increased vitamin K status might do the opposite.
A recent review of vitamin K research foresees the use of vitamin K in dietary supplements and in functional foods ""for healthy individuals to prevent bone and vascular disease, as well as for patients on oral anticoagulant treatment to offer them protection against coumarin-induced side effects,'' which may include, among other things, accelerated bone loss. Long-term use of oral anticoagulants is a risk factor for developing osteoporosis and arterial calcification. A recent animal study demonstrated that high vitamin K intake is capable not only of preventing this calcification to some degree but also of inducing regression of pre-formed arterial calcifications. Trials are planned to further investigate this early finding. Another recent study associated high dietary vitamin K intake with reduced coronary calcification and concluded that adequate intake ""could therefore be important to prevent cardiovascular disease.'' The vitamin K2 menaquinone was the ester thus associated; the vitamin K1 ester phylloquinone did not have this positive association.
In a recent prospective cohort study, vitamin K dietary intake was inversely and weakly associated with incidence of prostate cancer. The association noted was between menaquinones and not phylloquinones.
Contraindications, Precautions & Adverse Reactions
Vitamin K is contraindicated in those hypersensitive to any component of a vitamin K-containing product.
Those taking warfarin should avoid supplementation with vitamin K unless specifically prescribed by their physicians.
Pregnant women and nursing mothers should avoid supplemental intakes of vitamin K greater than RDA amounts (65 micrograms daily) unless higher amounts are prescribed by their physicians.
Use of vitamin K for the treatment of vitamin K deficiency must be done under medical supervision.
The supplemental forms of vitamin K, vitamin K1 and vitamin K2 are well tolerated. In one study, doses of 90 milligrams daily of vitamin K2 were given for 24 weeks. Few adverse effects were noted. Reversible elevations of some liver tests were noted in a few subjects in the study. Menadione (vitamin K3), which is not used as a nutritional supplemental form of vitamin K for humans, has been reported to cause adverse reactions, including hemolytic anemia.
Broad-Spectrum Antibiotics: Broad-spectrum antibiotics may sterilize the bowel and decrease the vitamin K contribution to the body by the intestinal microflora.
Cephalosporins: Cephalosporins containing side chains of N-methylthiotetrazole (cefmenoxime, cefoperazone, cefotetan, cefamandole, latamoxef) or methylthiadiazole (cefazolin) can cause vitamin K deficiency and hypoprothrombinemia. These cephalosporins are inhibitors of hepatic vitamin K epoxide reductase.
Cholestyramine: Concomitant intake of cholestyramine and vitamin K may reduce the absorption of vitamin K.
Colestipol: Concomitant intake of colestipol and vitamin K may reduce the absorption of vitamin K.
Mineral Oil: Concomitant intake of mineral oil and vitamin K may reduce the absorption of vitamin K.
Orlistat: Orlistat may decrease the absorption of vitamin K.
Salicylates: Salicylates in large doses may inhibit vitamin K epoxide reductase resulting in vitamin K deficiency.
Warfarin: Vitamin K can antagonize the effect of warfarin.
Medium Chain Triglycerides: Concomitant intake of medium-chain triglycerides and vitamin K may enhance the absorption of vitamin K.
Squalene: Concomitant intake of squalene and vitamin K may decrease the absorption of vitamin K.
Vitamin A: Intake of high doses of vitamin A may decrease the absorption of vitamin K.
Vitamin E: Intake of very large doses of vitamin E may result in vitamin K deficiency. A vitamin E metabolite, vitamin E quinone, can inhibit vitamin K-dependent gamma-glutamyl carboxylase activity.
Olestra: The fat substitute olestra inhibits the absorption of vitamin K as well as the other fat-soluble vitamins A, D and E. These vitamins are added to olestra. Olestra contains 8 micrograms of vitamin K per gram.