“Vitamin K,” the generic name for a family of compounds with a common chemical structure of 2-methyl-1,4-naphthoquinone, is a fat-soluble vitamin that is naturally present in some foods and is available as a dietary supplement [1]. These compounds include phylloquinone (vitamin K1) and a series of menaquinones (vitamin K2) [2]. Menaquinones have unsaturated isoprenyl side chains and are designated as MK-4 through MK-13, based on the length of their side chain [1,2]. MK-4, MK-7, and MK-9 are the most well-studied menaquinones.
Phylloquinone is present primarily in green leafy vegetables and is the main dietary form of vitamin K [3]. Menaquinones, which are predominantly of bacterial origin, are present in modest amounts in various animal-based and fermented foods [1,4]. Almost all menaquinones, in particular the long-chain menaquinones, are also produced by bacteria in the human gut [5,6]. MK-4 is unique in that it is produced by the body from phylloquinone via a conversion process that does not involve bacterial action [7].
Vitamin K functions as a coenzyme for vitamin K-dependent carboxylase, an enzyme required for the synthesis of proteins involved in hemostasis (blood clotting) and bone metabolism, and other diverse physiological functions [3,5]. Prothrombin (clotting factor II) is a vitamin K-dependent protein in plasma that is directly involved in blood clotting. Warfarin (Coumadin®) and some anticoagulants used primarily in Europe antagonize the activity of vitamin K and, in turn, prothrombin [8]. For this reason, individuals who are taking these anticoagulants need to maintain consistent vitamin K intakes.
Matrix Gla-protein, a vitamin K-dependent protein present in vascular smooth muscle, bone, and cartilage, is the focus of considerable scientific research because it might help reduce abnormal calcification [9]. Osteocalcin is another vitamin K-dependent protein that is present in bone and may be involved in bone mineralization or turnover [5].
Like dietary lipids and other fat-soluble vitamins, ingested vitamin K is incorporated into mixed micelles via the action of bile and pancreatic enzymes, and it is absorbed by enterocytes of the small intestine [10]. From there, vitamin K is incorporated into chylomicrons, secreted into the lymphatic capillaries, transported to the liver, and repackaged into very low-density lipoproteins [2,10]. Vitamin K is present in the liver and other body tissues, including the brain, heart, pancreas, and bone [2,3,11].
In the circulation, vitamin K is carried mainly in lipoproteins [2]. Compared to the other fat-soluble vitamins, very small amounts of vitamin K circulate in the blood. Vitamin K is rapidly metabolized and excreted. Based on phylloquinone measurements, the body retains only about 30% to 40% of an oral physiological dose, while about 20% is excreted in the urine and 40% to 50% in the feces via bile [2,11]. This rapid metabolism accounts for vitamin K’s relatively low blood levels and tissue stores compared to those of the other fat-soluble vitamins [11].
Little is known about the absorption and transport of vitamin K produced by gut bacteria, but research indicates that substantial quantities of long-chain menaquinones are present in the large bowel [7]. Although the amount of vitamin K that the body obtains in this manner is unclear, experts believe that these menaquinones satisfy at least some of the body’s requirement for vitamin K [6,7].
In most cases, vitamin K status is not routinely assessed, except in individuals who take anticoagulants or have bleeding disorders. The only clinically significant indicator of vitamin K status is prothrombin time (the time it takes for blood to clot), and ordinary changes in vitamin K intakes have rarely been shown to alter prothrombin time [5]. In healthy people, fasting concentrations of phylloquinone in plasma have been reported to range from 0.29 to 2.64 nmol/L [12]. However, it is not clear whether this measure can be used to quantitatively assess vitamin K status. People with plasma phylloquinone concentrations slightly below the normal range have no clinical indications of vitamin K deficiency, possibly because plasma phylloquinone concentrations do not measure the contribution of menaquinones from the diet and the large bowel [12]. No data on normal ranges of menaquinones are available [2].
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This section focuses on two conditions in which vitamin K might play a role: osteoporosis and coronary heart disease.
OsteoporosisOsteoporosis, a disorder characterized by porous and fragile bones, is a serious public health problem that affects more than 10 million U.S. adults, 80% of whom are women. Consuming adequate amounts of calcium and vitamin D, especially throughout childhood, adolescence, and early adulthood, is important to maximize bone mass and reduce the risk of osteoporosis [29]. The effect of vitamin K intakes and status on bone health and osteoporosis has been a focus of scientific research.
Vitamin K is a cofactor for the gamma-carboxylation of many proteins, including osteocalcin, one of the main proteins in bone [30]. Some research indicates that high serum levels of undercarboxylated osteocalcin are associated with lower bone mineral density [5,30]. Some, but not all, studies also link higher vitamin K intakes with higher bone mineral density and/or lower hip fracture incidence [31-36].
Although vitamin K is involved in the carboxylation of osteocalcin, it is unclear whether supplementation with any form of vitamin K reduces the risk of osteoporosis. In 2006, Cockayne and colleagues conducted a systematic review and meta-analysis of randomized controlled trials that examined the effects of vitamin K supplementation on bone mineral density and bone fracture [37]. Most of the trials were conducted in Japan and involved postmenopausal women; trial duration ranged from 6 to 36 months. Thirteen trials were included in the systematic review, and 12 showed that supplementation with either phytonadione or MK-4 improved bone mineral density. Seven of the 13 trials also had fracture data that were combined in a meta-analysis. All of these trials used MK-4 at either 15 mg/day (1 trial) or 45 mg/day (6 trials). MK-4 supplementation significantly reduced rates of hip fractures, vertebral fractures, and all nonvertebral fractures.
A subsequent clinical trial found that MK-7 supplementation (180 mcg/day for 3 years) improved bone strength and decreased the loss in vertebral height in the lower thoracic region of the vertebrae in postmenopausal women [38]. Other randomized clinical trials since the 2006 review by Cockayne et al. have found that vitamin K supplementation has no effect on bone mineral density in elderly men or women [39,40]. In one of these studies, 381 postmenopausal women received either 1 mg phylloquinone, 45 mg MK-4, or placebo daily for 12 months [40]. All participants also received daily supplements containing 630 mg calcium and 400 IU vitamin D3. At the end of the study, participants receiving either phylloquinone or MK-4 had significantly lower levels of undercarboxylated osteocalcin compared to those receiving placebo. However, there were no significant differences in bone mineral density of the lumbar spine or proximal femur among any of the treatment groups. The authors noted the importance of considering the effect of vitamin D on bone health when comparing the results of vitamin K supplementation studies, especially if both vitamin K and vitamin D (and/or calcium) are administered to the treatment group but not the placebo group [40]. The administration of vitamin D and/or calcium along with vitamin K could partly explain why some studies have found that vitamin K supplementation improves bone health while others have not.
In Japan and other parts of Asia, a pharmacological dose of MK-4 (45 mg) is used as a treatment for osteoporosis [5]. The European Food Safety Authority has approved a health claim for vitamin K, noting that “a cause and effect relationship has been established between the dietary intake of vitamin K and the maintenance of normal bone” [41]. The FDA has not authorized a health claim for vitamin K in the United States.
Coronary heart diseaseVascular calcification is one of the risk factors for coronary heart disease because it reduces aortic and arterial elasticity [42]. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that may play a role in the prevention of vascular calcification [5,43]. Although the full biological function of MGP is unclear, a hypothesis based on animal data suggests that inadequate vitamin K status leads to undercarboxylated MGP, which could increase vascular calcification and the risk of coronary heart disease. These findings might be particularly relevant for patients with chronic kidney disease because their rates of vascular calcification are much higher than those of the general population [9].
In an observational study conducted in the Netherlands in 564 postmenopausal women, dietary menaquinone (but not phylloquinone) intake was inversely associated with coronary calcification [44]. Menaquinone intake was also inversely associated with severe aortic calcification in a prospective, population-based cohort study involving 4,807 men and women aged 55 years and older from the Netherlands [43]. Participants in this study who had dietary menaquinone intakes in the mid tertile (21.6–32.7 mcg/day) and upper tertile (>32.7 mcg/day) also had a 27% and 57% lower risk of coronary heart disease mortality, respectively, than those in the lower tertile of intake (<21.6 mcg/day). Phylloquinone intake had no effect on any outcome.
Despite these data, few trials have investigated the effects of vitamin K supplementation on arterial calcification or coronary heart disease risk. One randomized, double-blind clinical trial examined the effect of phylloquinone supplementation in 388 healthy men and postmenopausal women aged 60–80 years [45]. Participants received either a multivitamin (containing B-vitamins, vitamin C, and vitamin E) plus 500 IU vitamin D3, 600 mg calcium, and 500 mcg phylloquinone daily (treatment) or a multivitamin plus calcium and vitamin D3 only (control) for 3 years. There was no significant difference in coronary artery calcification between the treatment and control groups. However, among the 295 participants who adhered to the supplementation protocol, those in the treatment group had significantly less coronary artery calcification progression than those in the control group. Furthermore, among those with coronary artery calcification at baseline, phylloquinone treatment reduced calcification progression by 6% compared to the control group. Based on these findings, the authors did not make any clinical recommendations, and they called for larger studies in other populations.
At this time, the role of the different forms of vitamin K on arterial calcification and the risk of coronary heart disease is unclear, but it continues to be an active area of research in the general population and in patients with chronic kidney disease [5,9,46].
Health Risks from Excessive Vitamin KThe FNB did not establish ULs for vitamin K because of its low potential for toxicity [3]. In its report, the FNB stated that “no adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals.”
Interactions with MedicationsVitamin K interacts with a few medications. In addition, certain medications can have an adverse effect on vitamin K levels. Some examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin K status with their healthcare providers.
Warfarin (Coumadin®) and similar anticoagulantsVitamin K can have a serious and potentially dangerous interaction with anticoagulants such as warfarin (Coumadin®), as well as phenprocoumon, acenocoumarol, and tioclomarol, which are commonly used in some European countries [7,8]. These drugs antagonize the activity of vitamin K, leading to the depletion of vitamin K-dependent clotting factors. People taking warfarin and similar anticoagulants need to maintain a consistent intake of vitamin K from food and supplements because sudden changes in vitamin K intakes can increase or decrease the anticoagulant effect [47].
AntibioticsAntibiotics can destroy vitamin K-producing bacteria in the gut, potentially decreasing vitamin K status. This effect might be more pronounced with cephalosporin antibiotics, such as cefoperazone (Cefobid®), because these antibiotics might also inhibit the action of vitamin K in the body [6,48]. Vitamin K supplements are usually not needed unless antibiotic use is prolonged (beyond several weeks) and accompanied by poor vitamin K intake [48].
Bile acid sequestrantsBile acid sequestrants, such as cholestyramine (Questran®) and colestipol (Colestid®), are used to reduce cholesterol levels by preventing reabsorption of bile acids. They can also reduce the absorption of vitamin K and other fat-soluble vitamins, although the clinical significance of this effect is not clear [48,49]. Vitamin K status should be monitored in people taking these medications, especially when the drugs are used for many years [49].
OrlistatOrlistat is a weight-loss drug that is available as both an over-the-counter (Alli®) and prescription (Xenical®) medication. It reduces the body’s absorption of dietary fat and in doing so, it can also reduce the absorption of fat-soluble vitamins, such as vitamin K. Combining orlistat with warfarin therapy might cause a significant increase in prothrombin time [50]. Otherwise, orlistat does not usually have a clinically significant effect on vitamin K status, although clinicians usually recommend that patients taking orlistat take a multivitamin supplement containing vitamin K [51-53].
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