Can you give me a quick overview on vitamin K? I keep hearing about this vitamin on the news and am wondering if I am getting enough in my diet. (with featured abstracts)

Vitamin K has been finding its way back into the nutrition spotlight, and for good reason. In the past, we've traditionally focused on this fat-soluble vitamin as a blood-clotting agent. When we are injured, we cannot stop the bleeding unless our blood can coagulate and form a clot to help seal off the wound. The proteins we need to accomplish this task cannot be recruited into action without vitamin K. (The very name of this vitamin originally came from the German word koagulation.)

Beyond Blood Clotting

More recently, researchers have determined that this role played by vitamin K in coagulation is only one of its key functions. Just as important is the role it plays in bone health since it is necessary for our bones to properly mineralize. In fact, there is good evidence to show that vitamin K can be helpful in both prevention and treatment of osteoporosis (loss of bone mineral density). Vitamin K may also play an important role in heart health since it prevents excess depositing of calcium in our arteries, a condition called arterial calcification that can lead to hardening of the arteries. (While there is not yet an abundance of research showing vitamin K to help prevent or treat hardening of the arteries, this area of research is still a very active one.) Cystic fibrosis, atherosclerosis, and several types of cancer are also conditions that are actively being investigated for possible links with vitamin K deficiency.

The K1 versus K2 Controversy

Along with the wealth of new research on vitamin K described above has come a controversy over the health benefits provided by different forms of vitamin K. Traditionally, research in this area focused the phylloquinones (K1) and their benefits for healthy blood clotting. Along with this focus has come a recommendation for more green leafy vegetables in the diet since these foods are top sources of K1. Olive oil is also a key source for dietary K1. The vast majority of vitamin K in our diet comes from the K1 in vegetables and vegetable oils.

K1 is not the only form of vitamin K found in food, however, and it is not the form of vitamin K best able to support healthy bone. For optimal support in this area of our health, we need K2.

As K2 is better at bone support than K1, a controversy has arisen over dietary approaches to adequate vitamin K intake and also over the issue of diet versus supplements for optimal vitamin K support. It is definitely possible for us to obtain K2 from food: our best dietary sources of this form of the nutrient are meats, eggs, and fermented foods including cheese, curd, and fermented soy products. (Since Bacillus natto are bacteria that can convert K1 into K2 and these bacteria are often involved in the production of fermented soy products, you will sometimes find the word "natto" being used to refer to these foods.)

From a practical standpoint, we may or may not eat enough of these foods to get optimal K2 intake. In studies on women in Japan, the intake of fermented soy foods appears to be very important in providing them with ample K2 intake in their diet. If you are a person who does not eat any of the foods described above, you can still obtain K2, but in this case, you are depending on the bacteria in your digestive tract or metabolic events in your cells to take the K1 content of your food and convert it into K2. Under healthy circumstances, the bacteria in your digestive tract and the enzymes in your cells may be able to keep an optimal balance between the K1 and K2 forms of this vitamin.

But under other circumstances, an optimal balance may not be possible. One of these circumstances under active research investigation is aging, and especially aging as it occurs in postmenopausal women. Other circumstances include liver problems and problems with fat absorption. If any of these circumstances apply to you, you should consult with your healthcare provider to work out an optimal approach to vitamin K.

The MK-4 versus MK-7 Controversy

Gut bacteria, cell metabolism, and foods can provide us with several different forms of K2. The best studied of these forms are MK-4 (menaquinone 4) and MK-7 (menaquinone 7). Meats and eggs are our most common food sources of MK-4. Fermented soy foods are our most common source of MK-7. Remember that both MK-4 and MK-7 are forms of K2 and both are helpful when it comes to bone support. We suspect that within this vitamin K2 area, the right amount of MK-4 and MK-7 is an amount that can vary from moment to moment and from individual to individual. From a research perspective, we also believe that the jury is still out on these specific forms of K2 and their best mix in the diet.

Vitamin K3

Although our bodies may regularly use vitamin K3 (menadione) as a transport form for vitamin K or for excretion of this vitamin out of the body, vitamin K3 is not found preformed in food in significant amounts. It is also not allowed as a form of vitamin K in dietary supplements. You don't need to worry about this form of vitamin K from a dietary standpoint.

Types of Vitamin K--A Quick Summary

Below is a table that summarizes the information described above:

Categories	Vitamin K1	Vitamin K2	Vitamin K3
Scientific name	phylloquinones	menaquinones (including MK-4 and MK-7)	menadione
Sources	plant foods, especially green leafy vegetables	gut bacteria or cellular metabolism (MK-4 and MK-7), meats and eggs (MK-4), fermented foods including cheese and fermented soybean (MK-7)	primarily man-made but may be an intermediate form created in the body for vitamin K transport and excretion

Food Sources of Vitamin K and Practical Dietary Steps

Along with the green leafy vegetables mentioned earlier (especially kale, chard, mustard greens, turnip greens, and spinach), your best food sources of vitamin K include: parsley, broccoli, leaf lettuce, romaine lettuce, endive, cabbage, cauliflower, watercress, eggs, meats, cheeses, curd, and fermented soybean products.

If you do not consume plentiful amounts of the plant foods listed above, you may be at risk not only for vitamin K1 deficiency, but for K2 deficiency as well since your body will not have enough K1 to convert into K2. Even if you do include meat, eggs, or cheese in your diet, you may still not be getting enough vitamin K2 in your diet (since life stage and health considerations-like aging and postmenopausal status-confer special needs), but that issue involves your personal health situation and needs to be discussed with your healthcare provider.

To boost your overall vitamin K nourishment, we recommend that you focus as much as possible on the green leafy vegetables that are such outstanding sources of K1. Overdoing it with animal foods is not a good way to try and balance your overall vitamin K status or offset a vitamin K2 deficiency because it will put you at too great a risk for other dietary imbalances. Fermented soy products are your best way to try to improve your K2 intake if you want to focus on this form of vitamin K.

Can I Get Too Much Vitamin K?

Most people are not going to get too much vitamin K from their diet under any circumstance and in any form. An exception involves individuals who are taking warfarin (a prescription drug more commonly referred to by its brand name, Coumadin®). This medication is given to help block the activity of vitamin K and slow down the process of clot formation. Coumadin® is often prescribed for individuals who are at risk of forming blood clots too quickly or too easily. If you are taking this medication, or have a history of problems related to blood clotting, you should follow your doctor's instructions about diet and vitamin K-containing foods since you are likely to need restriction of vitamin K-rich foods in your diet.

References

Shearer MJ and Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008 Oct;100(4):530-47

Danziger J. Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification

Danziger 2008 Clin. J. Am. Soc. Nephrol. 3:1504-1510.

Cockaybe S, Adamson J, Lanham-New S et al. Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis. 2006 Arch Intern Med 166:1256-1261.

Adams J, Pepping J. Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm 2005 Aug 1;62(15):1574-81.

Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm 2008;78:131-56.

Booth SL. Vitamin K status in the elderly. Curr Opin Clin Nutr Metab Care 2007 Jan;10(1):20-3.

Booth SL, Al Rajabi A. Determinants of vitamin K status in humans. Vitam Horm 2008;78:1-22.

Bugel S. Vitamin K and bone health. Proc Nutr Soc 2003 Nov;62(4):839-43.

Bugel S. Vitamin K and bone health in adult humans. Vitam Horm 2008;78:393-416.

Conway SP. Vitamin K in cystic fibrosis. J R Soc Med 2004;97 Suppl 44:48-51.

Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007 Jul;98(1):120-5.

Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008 Feb;19(1):39-42.

Hey E. Vitamin K--what, why, and when. Arch Dis Child Fetal Neonatal Ed 2003 Mar;88(2):F80-3.

Kaneki M. . Clin Calcium 2008 Feb;18(2):224-32.

Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev 2003 Aug;8(3):303-18.

Lanham-New SA. Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment. Proc Nutr Soc 2008 May;67(2):163-76.

Merli GJ, Fink J. Vitamin K and thrombosis. Vitam Horm 2008;78:265-79.

Mizuta T, Ozaki I. Hepatocellular carcinoma and vitamin K. Vitam Horm 2008;78:435-42.

Neafsey P. Of blood, bones, and broccoli: warfarin-vitamin K interactions. Home Healthc Nurse 2004 Mar;22(3):178-82; quiz 183-4.

Oldenburg J, Marinova M, Muller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm 2008;78:35-62.

Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract 2007 Oct;22(5):517-44.

Ryan-Harshman M, Aldoori W. Bone health. New role for vitamin K? Can Fam Physician 2004 Jul;50:993-7.

Homma K, Wakana N, Suzuki Y, Nukui M, Daimatsu T, Tanaka E, Tanaka K, Koga Y, Nakajima Y, Nakazawa H. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol (Tokyo) 2006 Oct;52(5):297-301.

Kamao M, Suhara Y, Tsugawa N, Uwano M, Yamaguchi N, Uenishi K, Ishida H, Sasaki S, Okano T. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo) 2007 Dec;53(6):464-70.

Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2007 Apr 15;109(8):3279-83.

Tsugawa N, Shiraki M, Suhara Y et al. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for {gamma}-carboxylation of osteocalcin. Am. J. Clinical Nutrition, Feb 2006; 83: 380 - 386.

A version of this article without a detailed list of references with abstracts is also available.

Abstracts

Adams J, Pepping J. Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm 2005 Aug 1;62(15):1574-81. Abstract: PURPOSE: The role of vitamin K in the prevention and treatment of osteoporosis and arterial calcification is examined. SUMMARY: Vitamin K is essential for the activation of vitamin K-dependent proteins, which are involved not only in blood coagulation but in bone metabolism and the inhibition of arterial calcification. In humans, vitamin K is primarily a cofactor in the enzymatic reaction that converts glutamate residues into gamma-carboxyglutamate residues in vitamin K-dependent proteins. Numerous studies have demonstrated the importance of vitamin K in bone health. The results of recent studies have suggested that concurrent use of menaquinone and vitamin D may substantially reduce bone loss. Menaquinone was also found to have a synergistic effect when administered with hormone therapy. Several epidemiologic and intervention studies have found that vitamin K deficiency causes reductions in bone mineral density and increases the risk of fractures. Arterial calcification is an active, cell-controlled process that shares many similarities with bone metabolism. Concurrent arterial calcification and osteoporosis have been called the "calcification paradox" and occur frequently in postmenopausal women. The results of two dose-response studies have indicated that the amount of vitamin K needed for optimal gamma-carboxylation of osteocalcin is significantly higher than what is provided through diet alone and that current dosage recommendations should be increased to optimize bone mineralization. Few adverse effects have been reported from oral vitamin K. CONCLUSION: Phytonadione and menaquinone may be effective for the prevention and treatment of osteoporosis and arterial calcification.

Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm 2008;78:131-56. Abstract: Vitamin K-dependent (VKD) protein carboxylation uses vitamin K epoxidation to convert Glus to carboxylated Glus (Glas), rendering VKD proteins active in physiologies that include hemostasis, apoptosis, bone mineralization, calcium homeostasis, growth control, and signal transduction. Clusters of Glus are modified by a processive carboxylase, generating a calcium-binding module that allows binding to either hydroxyapatite in the extracellular matrices or cell surfaces where anionic phospholipids become exposed, for example, during apoptosis or cell activation. Naturally occurring carboxylase mutations have been informative for function and are associated with bleeding complications and, surprisingly, a pseudoxanthoma elasticum (PXE)-like phenotype. A major advance in defining carboxylase function is the identification of the base that initiates carboxylation, which raises interesting possibilities for how vitamin K epoxidation is regulated by Glu substrate and carboxylase membrane topology. Vitamin K oxidoreductase (VKOR), the target of warfarin, generates the reduced vitamin K cofactor used by the carboxylase. Oxidation of active site thiols during vitamin K reduction inactivates VKOR, and activity is regenerated by an unknown reductase. The amounts of reduced vitamin K limit the capacity for carboxylation in cells, and overexpression of VKOR, but not carboxylase, improves carboxylation. However, the effect of VKOR overexpression is small, possibly because the reductase that regenerates VKOR activity is saturated. The review discusses these advances, as well as the potential impact of secretory components on carboxylation, which occurs during VKD protein secretion. Also discussed is the role of the carboxylase in mammals and lower organisms, including the bacterial pathogen Leptospira interrogans that has acquired a VKD carboxylase by horizontal transfer.

Booth SL. Vitamin K status in the elderly. Curr Opin Clin Nutr Metab Care 2007 Jan;10(1):20-3. Abstract: PURPOSE OF REVIEW: Poor vitamin K nutrition has recently been linked to several chronic diseases associated with abnormal calcification, which affect many elderly. To understand the impact of vitamin K nutrition on healthy aging it is necessary to assess both the determinants and the adequacy of vitamin K nutritional status of the elderly. RECENT FINDINGS: Overall, elderly persons consume more vitamin K than young adults. However, a subgroup of the elderly population does not meet the current recommended dietary intakes for this nutrient. The first meta-analysis evaluating the data on the role of vitamin K and bone health concluded that increased intakes of vitamin K are warranted to reduce bone loss and fracture risk among the elderly. Recent studies suggest that nondietary determinants of vitamin K status need to be factored into any discussion on the adequacy of nutritional status of the elderly. One promising area of research is the interrelationship between estrogen and vitamin K. SUMMARY: Evidence is emerging to support recommendations to increase intakes of vitamin K among the elderly to reduce bone loss and fracture risk. Much more research is required, however, to identify nondietary determinants of vitamin K status, and their impact on the elderly.

Booth SL, Al Rajabi A. Determinants of vitamin K status in humans. Vitam Horm 2008;78:1-22. Abstract: To understand the role of vitamin K in human health, it is important to identify determinants of vitamin K status throughout the life cycle. Our current understanding of vitamin K physiology and metabolism only partially explains why there is wide interindividual variation in vitamin K status, as measured by various biochemical measures. Dietary intake of vitamin K is one of the primary determinants of vitamin K status, and intakes vary widely among age groups and population subgroups. How dietary sources of vitamin K are absorbed and transported varies with the form and food source of vitamin K. Likewise, the role of plasma lipids as a determinant of vitamin K status varies with the form of vitamin K ingested. There is also some evidence that other fat-soluble vitamins antagonize vitamin K under certain physiological conditions. Infants are at the greatest risk of vitamin K deficiency because of a poor maternal-fetal transfer across the placenta and low vitamin K concentrations in breast milk. During adulthood, there may be subtle age-related changes in vitamin K status but these are inconsistent and may be primarily related to dietary intake and lifestyle differences among different age groups. However, there is some suggestion that absence of estrogen among postmenopausal women may be a determinant of vitamin K, status. Genetics may explain some of the observed interindividual variability in vitamin K, but to date, there are few studies that have systematically explored the associations between individual genetic polymorphisms and biochemical measures of vitamin K status.

Bugel S. Vitamin K and bone health. Proc Nutr Soc 2003 Nov;62(4):839-43. Abstract: Vitamin K, originally recognised as a factor required for normal blood coagulation, is now receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). Gla residues attract Ca2+ and incorporate these ions into the hydroxyapatite crystals. There are at least three Gla proteins associated with bone tissue, of which osteocalcin is the most abundant and best known. Osteocalcin is the major non-collagenous protein incorporated in bone matrix during bone formation. However, approximately 30% of the newly-produced osteocalcin stays in the circulation where it may be used as an indicator of bone formation. Vitamin K deficiency results in an increase in undercarboxylated osteocalcin, a protein with low biological activity. Several studies have demonstrated that low dietary vitamin K intake is associated with low bone mineral density or increased fractures. Additionally, vitamin K supplementation has been shown to reduce undercarboxylated osteocalcin and improve the bone turnover profile. Some studies have indicated that high levels of undercarboxylated osteocalcin (as a result of low vitamin K intake?) are associated with low bone mineral density and increased hip fracture. The current dietary recommendation for vitamin K is 1 microg/kg body weight per d, based on saturation of the coagulation system. The daily dietary vitamin K intake is estimated to be in the range 124-375 microg/d in a European population. Thus, a deficiency based on the hepatic coagulation system would be unusual, but recent data suggest that the requirement in relation to bone health might be higher.

Bugel S. Vitamin K and bone health in adult humans. Vitam Horm 2008;78:393-416. Abstract: Vitamin K is receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). The gamma-carboxylation of the Gla proteins is essential for the proteins to attract Ca2+ and to incorporate these into hydroxyapatite crystals. The best known of the three known bone-related Gla proteins is osteocalcin (OC). Even though the exact role of OC is not known, a number of studies have shown that vitamin K insufficiency or high levels of undercarboxylated osteocalcin (ucOC) is associated with an increase in the concentration of circulating ucOC. Furthermore, several studies have demonstrated that vitamin K insufficiency is associated with low bone mineral density (BMD) and increased fractures. Vitamin K supplementation, on the other hand, has been shown to improve the bone turnover profile and decrease the level of circulating ucOC. Dietary recommendations are based on saturation of the coagulation system, and in most countries the dietary intake is sufficient to obtain the amount recommended. In relation to bone, requirements might be higher. The aim of this chapter is to give an overview of the importance of vitamin K in relation to bone health in adult humans and thereby in the prevention of osteoporosis. Furthermore, I will shortly discuss the interaction with vitamin D and the paradox in relation to warfarin treatment.

Conway SP. Vitamin K in cystic fibrosis. J R Soc Med 2004;97 Suppl 44:48-51. No abstract available.

Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007 Jul;98(1):120-5. Abstract: Vitamin K, discovered in the 1930s, functions as cofactor for the posttranslational carboxylation of glutamate residues. Gammacarboxy glutamic acid (Gla)-residues were first identified in prothrombin and coagulation factors in the 1970s; subsequently, extra-hepatic Gla proteins were described, including osteocalcin and matrix Gla protein (MGP). Impairment of the function of osteocalcin and MGP due to incomplete carboxylation results in an increased risk for developing osteoporosis and vascular calcification, respectively, and is an unexpected side effect of treatment with oral anticoagulants. It is conceivable that other side effects, possible involving growth-arrest-specific gene 6 (Gas6) protein will be identified in forthcoming years. In healthy individuals, substantial fractions of osteocalcin and MGP circulate as incompletely carboxylated species, indicating that the majority of these individuals is subclinically vitamin K-deficient. Potential new application areas for vitamin K are therefore its use in dietary supplements and 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 and to reduce diet-induced fluctuations in their INR values.

Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008 Feb;19(1):39-42. Abstract: PURPOSE OF REVIEW: It has been hypothesized that insufficient intake of vitamin K may increase soft-tissue calcification owing to impaired gamma-carboxylation of the vitamin K-dependent protein matrix gamma-carboxyglutamic acid. The evidence to support this putative role of vitamin K intake in atherosclerosis is reviewed. RECENT FINDINGS: In animal models, multiple forms of vitamin K have been shown to reverse the arterial calcification created by vitamin K antagonists. The human data, however, are less consistent. Phylloquinone, the primary dietary form, has not been associated consistently with the risk of cardiovascular diseases. High menaquinone intake may be associated with lower risk of coronary heart disease mortality, but this needs to be confirmed. SUMMARY: The role of vitamin K in calcification remains controversial. Although biologically plausible, results from the human studies have not consistently supported this hypothesis.

Hey E. Vitamin K--what, why, and when. Arch Dis Child Fetal Neonatal Ed 2003 Mar;88(2):F80-3. Abstract: Policies for giving babies vitamin K prophylactically at birth have been dictated, over the last 60 years, more by what manufacturers decided on commercial grounds to put on the market, than by any informed understanding of what babies actually need, or how it can most easily be given. By a pure fluke a 1 mg IM dose, designed to prevent early vitamin deficiency bleeding ("haemorrhagic disease of the newborn") has been found to protect against late deficiency bleeding-a condition unrecognised at the time this policy took hold. Alternative strategies for oral prophylaxis are now opening up (see pp 109 and 113), but these are also, at the moment, dictated more by what the manufacturers choose to provide than by what would make for ease of delivery either in poor countries, or in the developed world.

Homma K, Wakana N, Suzuki Y, Nukui M, Daimatsu T, Tanaka E, Tanaka K, Koga Y, Nakajima Y, Nakazawa H. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol (Tokyo) 2006 Oct;52(5):297-301. Abstract: The purpose of this study is to find a method of cooking natto that prevents the appearance of high-plasma vitamin K concentrations after the consumption of natto, so that patients taking warfarin can benefit from eating natto. Five cooking methods were examined to determine which could most effectively decrease the count of the living Bacillus subtilis in natto. Volunteers ate natto or treated natto, and their plasma vitamin K level was measured at 5, 8, 24 and 48 h thereafter. One gram of natto contained 9.7+/-0.1 Log cfu/mL of Bacillus subtilis. Boiling significantly reduced the Bacillus subtilis count to 5.1+/-0.3 Log cfu/mL, and concomitantly reduced the content of menaquinone-7 (MK-7), which is a form of vitamin K synthesized by Bacillus subtilis, from 660.40+/-65.32 ng/mL to 78.50+/- 11.12 ng/mL. Untreated natto increased the MK-7 concentration in blood from 1.86+/-1.51 ng/mL to 14.54+/-4.12 ng/mL at 5 h after intake, and the MK-7 concentration remained elevated at 8, 24 and 48 h (7.29+/-2.20, 6.97+/-2.60, and 5.37+/-1.94 ng/mL, respectively). In contrast, boiled natto increased plasma MK-7 only mildly (from 1.61+/-1.11 to 4.02+/-0.82 ng/ mL at 5 h) and the concentration remained relatively stable up to 48 h (3.46+/-0.83, 4.22+/-1.51 and 2.77+/-0.75 ng/mL at 8, 24 and 48 h, respectively). In conclusion, boiled natto did not cause a marked increase in the plasma concentration of vitamin K in subjects who consumed it. Thus, patients on warfarin may be able to eat boiled natto without ill effects.

Kamao M, Suhara Y, Tsugawa N, Uwano M, Yamaguchi N, Uenishi K, Ishida H, Sasaki S, Okano T. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo) 2007 Dec;53(6):464-70. Abstract: Several reports indicate an important role for vitamin K in bone health as well as blood coagulation. However, the current Adequate Intakes (AI) might not be sufficient for the maintenance of bone health. To obtain a closer estimate of dietary intake of phylloquinone (PK) and menaquinones (MKs), PK, MK-4 and MK-7 contents in food samples (58 food items) were determined by an improved high-performance liquid chromatography method. Next, we assessed dietary vitamin K intake in young women living in eastern Japan using vitamin K contents measured here and the Standard Tables of Food Composition in Japan. PK was widely distributed in green vegetables and algae, and high amounts were found in spinach and broccoli (raw, 498 and 307 microg/100 g wet weight, respectively). Although MK-4 was widely distributed in animal products, overall MK-4 content was lower than PK. MK-7 was observed characteristically in fermented soybean products such as natto (939 microg/100 g). The mean total vitamin K intake of all subjects (using data from this study and Japanese food composition tables) was about 230 microg/d and 94% of participants met the AI of vitamin K for women aged 18-29 y in Japan, 60 microg/d. The contributions of PK, MK-4 and MK-7 to total vitamin K intake were 67.7, 7.3 and 24.9%, respectively. PK from vegetables and algae and MK-7 from pulses (including fermented soybean foods) were the major contributors to the total vitamin K intake of young women living in eastern Japan.

Kaneki M. . Clin Calcium 2008 Feb;18(2):224-32. Abstract: Vitamin K is a nutrient originally identified as an essential factor for blood coagulation. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone, exists widely in the otherwise healthy adult population. Both vitamin K1 and K2 have been shown to exert protective effects against osteoporosis. The new biological functions of vitamin K in bone are considered to be attributable, at least in part, to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by both vitamins K1 and K2. A recent evidence of significant correlation between polymorphism of gamma-glutamyl carboxylase gene and bone mineral density supports the role of gamma-carboxylation-dependent actions of vitamin K. In contrast, vitamin K2-specific,gamma-carboxylation-unrelated functions have recently attracted scientific attention. Recent findings of vitamin K2-specific transactivation of steroid and xenobiotic receptor (SXR/PXR) may lead to new research avenue. The impact of genotype of apoE, a major vitamin K transporter, on ostepporosis as well as Alzheimer disease and atherosclerosis, raises a question whether vitamin K is involved in the pathogenesis of these diseases. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in bone health deserve further investigations.

Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev 2003 Aug;8(3):303-18. Abstract: Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential. Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects. Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos. Tyrosine kinases associated with cyclins have also been shown to be affected by vitamin K, which can lead to cell cycle arrest and cell death.

Lanham-New SA. Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment. Proc Nutr Soc 2008 May;67(2):163-76. Abstract: Throughout the life cycle the skeleton requires optimum development and maintenance of its integrity to prevent fracture. Bones break because the loads placed on them exceed the ability of the bone to absorb the energy involved. It is now estimated that one in three women and one in twelve men aged >55 years will suffer from osteoporosis in their lifetime and at a cost in the UK of > 1.7 pounds x 10(9) per year. The pathogenesis of osteoporosis is multifactorial. Both the development of peak bone mass and the rate of bone loss are determined by key endogenous and exogenous factors. Ca supplements appear to be effective in reducing bone loss in women late post menopause (>5 years post menopause), particularly in those with low habitual Ca intake (<400 mg/d). In women early post menopause (<5 years post menopause) who are not vitamin D deficient, Ca supplementation has little effect on bone mineral density. However, supplementation with vitamin D and Ca has been shown to reduce fracture rates in the institutionalised elderly, but there remains controversy as to whether supplementation is effective in reducing fracture in free-living populations. Re-defining vitamin D requirements in the UK is needed since there is evidence of extensive hypovitaminosis D in the UK. Low vitamin D status is associated with an increased risk of falling and a variety of other health outcomes and is an area that requires urgent attention. The role of other micronutrients on bone remains to be fully defined, although there are promising data in the literature for a clear link between vitamin K nutrition and skeletal integrity, including fracture reduction.

Merli GJ, Fink J. Vitamin K and thrombosis. Vitam Horm 2008;78:265-79. Abstract: Vitamin K was discovered in the 1930s during cholesterol metabolism experiments in chickens. It is a fat-soluble vitamin which occurs naturally in plants as phylloquinone (vitamin K1) and is produced by gram-negative bacteria in the human gastrointestinal tract as menaquinone (vitamin K2). This vitamin was found to be essential for normal functioning of hemostasis. In addition, a number of clinical conditions in which vitamin K deficiency was found to be the underlying pathophysiologic problem were discovered. These conditions include hemorrhagic disease of the newborn, obstructive jaundice, and malabsorption syndromes. The importance of this vitamin has become more apparent with the discovery of the anticoagulant warfarin which is a vitamin K antagonist. There are millions of patients on this therapy for a variety of thrombogenic conditions such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, and prosthetic cardiac valves. The wide use of this narrow therapeutic index drug has resulted in significant risk for major bleeding. Vitamin K serves as one of the major reversing agent for patients over-anticoagulated with warfarin. In the past few years, research has focused on new areas of vitamin K metabolism, which include bone and endovascular metabolism; cell growth, regulation, migration, and proliferation; cell survival, apoptosis, phagocytosis, and adhesion. These new areas of research highlight the significance of vitamin K but raise new clinical questions for patients who must be maintained on long-term warfarin therapy.

Mizuta T, Ozaki I. Hepatocellular carcinoma and vitamin K. Vitam Horm 2008;78:435-42. Abstract: On the basis of reports of the antitumor effects of vitamin K on various cancers, we clinically investigated the suppressive effects of vitamin K2 on tumor recurrence after curative treatment for hepatocellular carcinoma (HCC). Our results showed that vitamin K2 administration significantly suppressed HCC recurrence. Our laboratory findings revealed that the inhibitory effect of vitamin K2 against HCC cell growth was generated by suppressing cyclin D1 expression through inhibition of NF-kappaB activation.

Neafsey P. Of blood, bones, and broccoli: warfarin-vitamin K interactions. Home Healthc Nurse 2004 Mar;22(3):178-82; quiz 183-4. No abstract available.

Oldenburg J, Marinova M, Muller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm 2008;78:35-62. Abstract: Vitamin K is a collective term for lipid-like naphthoquinone derivatives synthesized only in eubacteria and plants and functioning as electron carriers in energy transduction pathways and as free radical scavengers maintaining intracellular redox homeostasis. Paradoxically, vitamin K is a required micronutrient in animals for protein posttranslational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation. Vitamin K shuttles reducing equivalents as electrons between two enzymes: VKORC1, which is itself reduced by an unknown ER lumenal reductant in order to reduce vitamin K epoxide (K>O) to the quinone form (KH2); and gamma-glutamyl carboxylase, which catalyzes posttranslational gamma-carboxylation and oxidizes KH2 to K>O. This article reviews vitamin K synthesis and the vitamin K cycle, outlines physiological roles of various vitamin K-dependent, gamma-carboxylated proteins, and summarizes the current understanding of clinical phenotypes caused by genetic mutations affecting both enzymes of the vitamin K cycle.

Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract 2007 Oct;22(5):517-44. Abstract: BACKGROUND: Vitamin K's effects extend beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis. Vitamin K is required for the gamma-carboxylation of osteocalcin. Likewise, this gamma-carboxylation also occurs in the liver for several coagulation proteins. This mechanism is interrupted by coumarin-based anticoagulants in both the liver and bone. METHODS: A thorough review of the literature on vitamin K, osteocalcin and their role in bone metabolism and osteoporosis, as well as the potential bone effects of anticoagulant therapy was conducted. CONCLUSIONS: Epidemiological studies and clinical trials consistently indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk. Typical dietary intakes of vitamin K are below the levels associated with better BMD and reduced fracture risk; thus issues of increasing dietary intakes, supplementation, and/or fortification arise. To effectively address these issues, large-scale, intervention trials of vitamin K are needed. The effects of coumarin-based anticoagulants on bone health are more ambiguous, with retrospective studies suggesting that long-term therapy adversely affects vertebral BMD and fracture risk. Anticoagulants that do not affect vitamin K metabolism are now available and make clinical trials feasible to answer the question of whether coumarins adversely affect bone. The research suggests that at a minimum, clinicians should carefully assess anticoagulated patients for osteoporosis risk, monitor BMD, and refer them to dietitians for dietary and supplement advice on bone health. Further research is needed to make more efficacious decisions about vitamin K intake, anticoagulant therapy, and bone health.

Ryan-Harshman M, Aldoori W. Bone health. New role for vitamin K? Can Fam Physician 2004 Jul;50:993-7. Abstract: OBJECTIVE: To assess growing evidence that vitamin K (phylloquinone) plays an important role in bone health and, subsequently, in prevention of osteoporotic fractures. QUALITY OF EVIDENCE: We searched MEDLINE from January 1972 to December 2002 using the key words vitamin K and bone health. We reviewed 30 articles that seemed relevant or had a human focus. All evidence can be categorized as level II. MAIN MESSAGE: Evidence suggests that dietary phylloquinone intake of <100 microg daily might not be optimal for bone health. Low intake of vitamin K could contribute to osteoporosis and subsequent fracture due to the undercarboxylation of osteocalcin. CONCLUSION: Family physicians need to be aware of the importance of encouraging adequate vitamin K intake, particularly among institutionalized elderly people, to prevent increased bone resorption. Further study is needed to determine the exact role of vitamin K in bone metabolism, and methods of assessing vitamin K requirements need to be standardized.

Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2007 Apr 15;109(8):3279-83. Abstract: Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1) and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K(1) and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.

Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008 Oct;100(4):530-47. Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.

Send this page to a friend...