That vitamin K is essential for blood clotting is well known. In recent years, interest in this fat-soluble vitamin has increased dramatically due to the discovery of other properties important to health. An important function of vitamin K is to activate (vitamin K-dependent) enzymes (Gla proteins), which regulate calcium metabolism (along with vitamin D) and prevent calcification of soft tissues and decalcification of bones. There is increasing scientific evidence that vitamin K prevents arteriosclerosis, osteoporosis, insulin resistance (syndrome) and joint inflammation and contributes to protection against cancer and (cognitive) aging. The current RDA of 75 mcg of vitamin K per day is based on the amount needed for blood clotting, but leaves out other functions of vitamin K. Research shows that the actual vitamin K requirement is much higher and that the majority of the Dutch population has a non-optimal vitamin K intake. Intake of vitamin K is usually sufficient for hemostasis, however.
Vitamin K includes a group of related, fat-soluble naphthoquinones. Western foods contain mainly vitamin K1 (phytomenadione, phylloquinone, phytonadione), which is found in plants (especially green tea, algae and green vegetables such as spinach, lettuce, parsley and brassicas). Vitamin K2 (menaquinone) is produced by certain bacteria and is found in limited amounts in meat, dairy and eggs. The colon produces vitamin K2, but its absorption is limited (fat-soluble vitamins are absorbed mainly in the ileum). There are different forms of menaquinone, MK-4 to MK-14, with the number indicating the number of isoprenyl side chains. MK-4 is present in meat and is also formed to a limited extent in the body from vitamin K1; MK-5 to MK-9 are found in small amounts in fermented products such as cheese and yogurt; the Japanese food natto (soybeans fermented with Bacillus subtilis) is an exceptionally rich source of MK-7; MK-10 to MK-14 are rare. Vitamin K3 (menadione) is a synthetic (pro)vitamin K. Vitamin K1 and K2 both cause activation of clotting factors in the liver; vitamin K2 in particular is active in extra hepatic tissues, as vitamin K1 is largely absorbed in the liver and less circulated than vitamin K2.
Operation
For more than fifty years, vitamin K was thought to be needed exclusively for the activation (carboxylation) of blood clotting factors in the liver. Several extra-hepatic vitamin K-dependent Gla proteins have since been discovered. In the bones (and teeth) these are osteocalcin (Bone Gla Protein or BGP), protein S and MPG (matrix Gla protein); in the kidneys KGP (kidney Gla protein); in the vessel wall and other soft tissues MPG (matrix Gla protein). The Gla protein Gas6 (growth arrest specific gene 6 protein), among others, is produced by endothelial cells and regulates cell division, cell differentiation and cell migration and protects cells from apoptosis (programmed cell death).
Vitamin K is the cofactor of the enzyme γ-glutamylcarboxylase that carboxylates glutamic acid (Glu) residues in (vitamin K-dependent) enzymes to γ-carboxyglutamic acid (Gla) residues, thereby activating them. Undercarboxylated (Glu) proteins are inactive and useless. In vitamin K insufficiency, undercarboxylated vitamin K-dependent proteins are detectable in the blood. These are called PIVKAs (proteins induced by vitamin K absence). PIVKA-prothrombin (PIVKA-II) is marker for severe vitamin K deficiency (vitamin K is used primarily for γ-carboxylation of coagulation factors); undercarboxylated osteocalcin (ucOC or PIVKA-osteocalcin) is a more sensitive marker for vitamin K insufficiency. In addition to activating Gla proteins, vitamin K has several other functions.
Blood coagulation: vitamin K (K1, K2) is essential for the production of several coagulation factors (Gla proteins) in the liver, including factor II (prothrombin), factor VII (proconvertin), factor IX (thromboplastin component), factor X (Stuart factor) and proteins C, S and Z. A (severe) vitamin K deficiency leads to prolonged clotting time and increases the risk of excessive bleeding, (occult) blood loss, (subcutaneous) hematomas, poorly healing wounds and anemia.
Bone formation, bone mineralization and bone strength: Osteocalcin is a small, calcium-binding protein produced mainly by osteoblasts and is a biochemical marker of bone mineralization; it is the most important protein (after collagen) incorporated into the bone matrix during bone formation. Vitamin D stimulates osteocalcin synthesis and increases calcium availability; vitamin K (especially K2) causes γ-carboxylation of osteocalcin. Only osteocalcin carboxylated by vitamin K is active and can bind to hydroxyapatite and cause calcium deposition in bone tissue. Vitamin K2 improves bone quality not only by activating osteocalcin. In vitro and in vivo studies have shown that vitamin K2 increases osteoblast formation and activity. This is done via stimulation of SXR (steroid and xenobiotic receptor) expression, inhibition of NF-κB and stimulation of osteoblast-specific genes. The formation and activity of osteoclasts is reduced by inhibition of osteoclastogenesis and induction of their apoptosis involving the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and various pro-inflammatory cytokines.
Inhibition of arteriosclerosis: carboxylated Matrix Gla Protein (cMGP) plays a central role in the prevention of arterial calcification by affecting BMP-2 (bone morphogenic protein type 2) and blocking calcium deposition in the vascular matrix. MGP production by (human) vascular smooth muscle cells is stimulated by extracellular calcium (impending calcium deposition); activation of MGP is a vitamin K-dependent process. A high serum level of inactive, undercarboxylated MGP (ucMGP) and a high ratio of ucMGP/cMGP may be a good marker of (incipient) arteriosclerosis. UcMGP levels appear to decrease with progression of arteriosclerosis, perhaps due to binding of ucMGP to calcium in the vessel wall or loss of smooth muscle cells (due to apoptosis or transformation into osteoblast-like cells). In addition to activating MGP, vitamin K2 helps keep blood vessels healthy by lowering cholesterol levels and inhibiting plaque formation (via Gas6).
Blood glucose regulation: Vitamin K is beneficial for glucose homeostasis (insulin sensitivity, insulin secretion), in part by activating osteocalcin. The exact mechanism of action is still unclear; carboxylated osteocalcin possibly improves insulin sensitivity and beta cell function by enhancing adiponectin expression. It is also possible that vitamin K directly affects insulin sensitivity and glycemic status through an anti-inflammatory effect. In addition, vitamin K-dependent proteins (prothrombin and protein S) are present in organs important for glucose and insulin metabolism, such as liver and pancreas.
Inhibition of joint inflammation: vitamin K is an important regulator of bone and cartilage mineralization; in young people, for example, vitamin K regulates the calcification of growth plates (discs of cartilage at the ends of bones that provide additional length growth). There is evidence that vitamin K insufficiency promotes osteoarthritis through undercarboxylation of MGP and Gas6 and increase in inflammatory activity (vitamin K inhibits the expression of several pro-inflammatory cytokines). In vitro and animal studies provide evidence for a beneficial effect of vitamin K2 (MK-4) in rheumatoid arthritis with inhibition of synovial hyperproliferation and dose-dependent inhibition of rheumatoid arthritis progression.
Anticancer activity: Since 1947, research has been conducted on the anticancer activity of vitamin K. Vitamin K (K1, K2) inhibits division in vitro and induces apoptosis in various tumor cell lines (including liver, lung, stomach, prostate, breast, leukemia, multiple myeloma, neuroblastoma, osteosarcoma, bladder), including by acting as a transcription factor of proto-oncogenes such as c-myc, c-fos, and c-jun. Also, in vitro studies with hepatocellular carcinoma cells suggest that vitamin K2 has a tumor-suppressive effect through activation of SXR (steroid and xenobiotic receptors) and the cell cycle regulation protein p21.
Role in brain function and synthesis sphingolipids: vitamin K (K1, MK-4) is present in a high concentration in brain tissue and is probably important for brain function. Vitamin K inhibits calcium deposition in soft tissues, activates Gas6 and plays a role in the synthesis of sphingolipids, a group of complex (membrane) lipids including cerebrosides, sphingomyelin, sulfatides, ceramides and gangliosides. In experimental animals, vitamin K deficiency led to behavioral changes and decrease in myelin sulfatides in particular. Aberrant sphingolipid metabolism is thought to play a role in the pathogenesis of age-related diseases, including neurodegenerative diseases, cardiovascular disease, diabetes and cancer. The question is whether vitamin K insufficiency contributes to the onset and progression of Alzheimer’s disease and multiple sclerosis. In experimental animals, low vitamin K intake from birth led to marked cognitive decline in old age. In an observational study, people with early dementia had a significantly lower intake of vitamin K (average 63 mcg/day) than healthy peers (139 mcg/day). In an animal model of multiple sclerosis, preventive supplementation with vitamin K2 resulted in a milder disease course.
Anti-inflammatory and antioxidant activity: in vitro and in vivo studies have shown that vitamin K has anti-inflammatory activity, partly through inhibition of NF-κB signaling. In addition, vitamin K has powerful antioxidant properties.
Indications
Vitamin K deficiency: Vitamin K deficiency can result from inadequate dietary intake of vitamin K, alcoholism, (chronic) liver disease, cystic fibrosis, chronic gastrointestinal diseases (including chronic diarrhea, celiac disease, Crohn’s disease, ulcerative colitis, regional enteritis, short bowel syndrome), intestinal resection (especially last part of the ileum), bariatric surgery (procedures such as gastric reduction in morbid obesity) and medication use (including antibiotics, see interactions). Vitamin K accumulates particularly in adipose tissue; people with increased fat (overweight, obese) may be more likely to have functional vitamin K deficiency.
Prevention osteoporosis and bone fractures: Several observational studies have found a clear (inverse) relationship between vitamin K intake and the risk of bone fractures. Older women with hip fracture have significantly lower serum levels of vitamin K, compared with women without hip fracture. In one study, elderly people in the highest quartile of vitamin K intake were 65% less likely to have a hip fracture than those in the lowest quartile of intake. The higher incidence of femur fractures in the western part of Japan, compared with other parts, correlates strongly with vitamin K intake. In Japanese research, consumption of natto, rich in MK-7, was significantly associated with a decreased risk of hip fracture in postmenopausal women. A prospective cohort study showed that serum ucOC (undercarboxylated osteocalcin) levels can predict the risk of hip fracture in older women, independent of femoral neck bone mineral density. This conclusion is also drawn in a 2003 World Health Organization report. The relationship between undercarboxylated osteocalcin and bone mineral density is somewhat less clear-cut. In several clinical studies, supplementation with vitamin K2 has been shown to improve bone quality in osteoporosis from a variety of causes, including estrogen deficiency (postmenopause), Parkinson’s disease, biliary cirrhosis, liver cirrhosis, stroke, anorexia nervosa, organ transplantation and medication use (see interactions). These studies usually used 45 mcg of vitamin K2 (as MK-4) per day. In Japan, vitamin K2 (45 mcg/day) has been regularly prescribed for osteoporosis for more than a decade. In a Canadian study of 440 women with osteopenia, vitamin K1 (5,000 mcg/day for at least 2 years) significantly reduced the risk of bone fractures, compared with placebo. The effect of vitamin K1 is greater if additional vitamin D and calcium are also taken. In 221 healthy Japanese women (50-70 years), a significant inverse association was found between dietary vitamin K intake and serum levels of ucOC. Also, ucOC level was negatively correlated with lower back bone mineral density. The average vitamin K intake (especially K1, because these women hardly ate any natto) was 260 mcg/day. Nevertheless, ucOC levels were elevated in 66% of women, meaning that the amount of vitamin K needed for healthy bones is well above the current (Dutch) RDA of 75 mcg per day. Researchers estimate that at least 450 mcg of vitamin K (K1/K2) per day is needed to maintain bone health and that an even higher dose is needed to improve bone quality. Elderly people need more vitamin K to lower ucOC because of accelerated bone turnover. People with type 2 diabetes are more likely to have bone fractures despite normal or increased bone mineral density (hyperinsulinemia promotes bone mineral density). Vitamin K2 possibly lowers the risk of bone fractures in diabetics; in an animal model of type 2 diabetes, vitamin K2 supplementation led to increases in serum levels of osteocalcin, enhancement of (enzymatic) collagen crosslinking, decrease in (non-enzymatic) collagen crosslinking (such as formation of AGEs (advanced glycation end products)) and increases in bone strength.
Bone production children and adolescents: many healthy Dutch children between 6 and 18 years have higher serum levels of undercarboxylated osteocalcin and a higher ucOC/cOC ratio than adults, especially during the growth spurt. This indicates that their vitamin K status is substandard and even more deficient than in adults. In a Dutch placebo-controlled study with 55 healthy prepubertal children, supplementation with vitamin K2 (45 mcg MK-7 daily for 8 weeks) led to significant improvement in ucOC/cOC ratio and vitamin K status. In healthy girls aged 11 or 12 years, better vitamin K status is associated with higher bone mineral density. In an observational study of over 300 healthy peripubertal children (mean 11.2 years), improved vitamin K status over a two-year period led to significantly greater increases in bone mass and total bone mineral content. Until about age 25, until reaching peak bone mass (the maximum amount of bone), bone production exceeds bone breakdown. After that, bone mass gradually decreases. High peak bone mass reduces the risk of osteoporosis and fractures later in life; optimal vitamin K status during growth can contribute significantly.
Arterial calcification (arteriosclerosis): Arterial calcification is a risk factor for cardiovascular complications, not only in people with pre-existing cardiovascular disease, diabetes and/or chronic kidney disease, but also in asymptomatic individuals. Increasing vitamin K intake contributes to lowering cardiovascular risk partly through activation of MGP. Measurement revealed a substantial portion of MGP inactive in a group of healthy Dutch adults, suggesting that many healthy adults have subclinical vitamin K deficiency. Several observational human studies have found a significant inverse association between vitamin K2 intake (particularly MK-7, MK-8 and MK-9) and the degree of arterial calcification and the risk of coronary artery disease, myocardial infarction and sudden cardiac death. The average intake of vitamin K2 in a Dutch study was 31 mcg/day; the risk of coronary heart disease decreased by about 9% for every 10 mcg increase in vitamin K2 intake. The use of vitamin K antagonists (blood thinners such as warfarin) is associated with increased calcification of the heart valve and coronary arteries. In an intervention study involving 388 healthy elderly people, vitamin K1 (500 mcg/day for 3 years) inhibited the progression of coronary artery calcification. Vitamin K2 is more effective than K1 and combats arteriosclerosis and cardiovascular disease at a lower dose. Animal research suggests that vitamin K2 may not only inhibit arteriosclerosis, but may even reverse the process. People with chronic kidney disease have a greatly increased risk of (death from) cardiovascular disease, particularly due to increased arterial calcification (plaque and media calcification). In studies involving 107 patients with chronic kidney disease, serum levels of dephosphorylated, undercarboxylated MGP (dp-ucMGP) were found to increase with progression of kidney disease and significantly positively correlated with the severity of aortic calcification. In a pilot study, vitamin K2 dose-dependently reduced the level of dp-ucMGP in renal patients.
Chronic heart failure: The progression of heart failure is characterized by several cellular and molecular processes, including hypertrophy of cardiomyocytes, enlargement of the ventricle and changes in the extracellular matrix including fibrosis. This ventricular remodeling is partly due to abnormal regulation of the extracellular matrix; insufficient activity of the vitamin K-dependent Matrix Gla Protein (due to vitamin K insufficiency) may play a role. Researchers found that plasma levels of inactive dp-ucMGP were significantly positively associated with chronic heart failure severity and risk of mortality. The exact function of MGP in the heart has not yet been determined, but is probably not related to the prevention of calcification. MGP possibly modulates the activity of growth factors involved in tissue remodeling, such as BMP (bone morphogenic protein), TGFβ (transforming growth factor β) and VEGF (vascular endothelial growth factor). Improvement in vitamin K status may lead to a better prognosis of heart failure.
Insulin resistance and diabetes mellitus: several human studies indicate a positive influence of vitamin K on glucose homeostasis. In healthy young adults who underwent glucose tolerance testing, blood glucose levels rose more sharply in the subjects with low vitamin K intake. In another experiment, 12 healthy young adults underwent oral glucose tolerance testing twice, the first prior and the second after vitamin K2 supplementation (90 mcg MK-4 daily for one week). Compared with the first test, the acute insulin response in the second test was significantly lower in subjects with initially low vitamin K status. In over 2000 Japanese men (over 65 years), serum level of undercarboxylated osteocalcin was inversely associated with fasting plasma glucose level, level of hemoglobin A1c and degree of insulin resistance (HOMA-IR). Higher intake of vitamin K1 was associated with improved insulin sensitivity and glycemic status in both men and women in a large prospective cohort study (Framingham Offspring Cohort). A Dutch prospective cohort study of over 38,000 adults followed for over 10 years found an inverse correlation between vitamin K intake (K1 and K2) and the risk of type 2 diabetes. In a clinical trial, 355 nondiabetic elderly (60-80 years) took 500 mcg of vitamin K1 or a placebo daily for 36 months; in the men, vitamin K supplementation resulted in significant decreases in fasting insulin levels and decreases in insulin resistance.
Osteoarthritis and rheumatoid arthritis: A prospective observational cohort study, the Framingham Offspring Study, with 673 elderly people found an inverse relationship between vitamin K1 plasma levels and the risk of osteoarthritis, osteophyte formation and joint gap narrowing (hand, knee). Intervention studies will have to show whether improving vitamin K status affects the disease process. The role of vitamin K2 in rheumatoid arthritis has not yet been studied in humans.
Cancer: In the prospective EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition-Heidelberg) cohort study, it was observed that men with a high vitamin K2 intake (from dairy) had a lower risk of prostate cancer, particularly advanced prostate cancer, than men with a low intake. The researchers believe that vitamin K2 primarily inhibits tumor promotion and progression rather than tumor initiation. A total of 24,340 men and women (35-65 years) from the EPIC-Heidelberg cohort were followed for 10 to 14 years; 1,755 of them developed cancer, and of this group, 458 died. The study data suggest that higher intake of vitamin K2 from food (especially cheese) is associated with decreases in the risk of morbidity and mortality from cancer; intake of vitamin K1 from food is not associated with lower cancer risk. In several case-control studies, a favorable clinical effect has been achieved with vitamin K2 (20-90 mcg/day) in acute myeloid leukemia and myelodysplastic syndrome. In a placebo-controlled clinical trial involving 43 women with (viral) liver cirrhosis, vitamin K2 (at a dose of 45 mcg daily) reduced the risk of hepatocellular carcinoma by 80%. There is also evidence that vitamin K2 (MK-4) reduces the risk of recurrence of hepatocellular carcinoma.
Contraindications
A supplement that provides a dose greater than 100 mcg of vitamin K per day should be used by people taking blood thinners (vitamin K antagonists) only under medical supervision. Vitamin K is contraindicated in cases of hypersensitivity or allergy to this vitamin (rare).
Side effects
Vitamin K1 and vitamin K2 have no toxic effects. An upper intake limit could not be established based on toxicological studies. In experimental animals, a single oral dose of 25,000 mg/kg (25,000,000 mcg/kg) was not lethal; similarly, no adverse effects were observed after daily administration of 2,000 mg (2,000,000 micrograms) of vitamin K per kilogram of body weight for 30 days. Excessive intake of vitamin K during pregnancy (especially the synthetic K3) increases the risk of jaundice in the newborn and should be avoided. Intake of vitamin K while breastfeeding is safe.
Interactions
Several drugs decrease vitamin K status: antibiotics decrease endogenous vitamin K2 synthesis through their negative impact on intestinal flora; bile acid binders (cholestyramine, cholestipol) inhibit the absorption of fat-soluble nutrients including vitamin K; corticosteroids increase urinary excretion of vitamin K; anticonvulsants (including phenytoin, phenobarbital) increase the breakdown of vitamin K in the liver; salicylates (aspirin) decrease vitamin K status.
Supplementation with vitamin K reduces the efficacy of vitamin K antagonists. Use of these medications requires medical supervision at doses of vitamin K above 100 mcg per day.
Vitamin A and vitamin E (especially in high doses) can lower vitamin K status.
Dosage
The (Dutch) AHD for vitamin K (K1/K2) is 75 mcg per day (1-1.5 mcg/kg/day) for adults (35 mcg/day for children, 75 mcg/day for adolescents); in the United States, the AI (Adequate Intake) for adult men and women is 120 and 90 mcg per day, respectively. Babies are given extra vitamin K1 (1,000 mcg) shortly after birth, and parents are advised to give their child, if breastfed, 150 mcg of vitamin K1 daily from the first week to 3 months to prevent bleeding from vitamin K deficiency.
Based on the RDA, most adults in the Netherlands get enough vitamin K; the median intake is about 100 mcg/day, of which 10% is vitamin K2; people who eat a lot of green vegetables can get 250 mcg per day. However, adequate vitamin K intake, which provides for maximum carboxylation of (extra-hepatic) vitamin K-dependent proteins, is estimated to be 400-1000 mcg of vitamin K (K1/K2) per day for healthy adults. This implies that the majority of Dutch adults have an insufficient vitamin K intake.
Vitamin K intake is more favorable in countries such as China and Japan (about 240 mcg/day), where vitamin K2 (MK-7) makes a much greater contribution to total vitamin K intake. Vitamin K2, compared with K1, is better absorbed, leads to higher and more stable vitamin K plasma levels, has a significantly longer half-life (3 days versus 2 hours) and is better absorbed in extra-hepatic tissues. With regard to lowering ucOC, for example, a dose of 45 mcg of MK-7 corresponds to about 120 mcg of vitamin K1. Vitamin K supplementation uses doses ranging from 45 mcg (vitamin K2) to 10,000 mcg (vitamin K1) per day. The British Expert Group on Vitamins and Minerals (EVM) suggests a general therapeutic dose of 1,000 mcg of vitamin K1 per day (or 20 mcg/kg/day).
Synergism
Vitamin D enhances the effects of vitamin K against osteoporosis, arteriosclerosis and cancer, among other things.
Vitamin C enhances the anticancer activity of vitamin K, among other things.
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SOURCE: Natura Foundation
