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Tuesday, October 31, 2006

Vitamin K

Vitamin K is a fat-soluble vitamin. The "K" is derived from the German word "koagulation". Coagulation refers to blood clotting, because vitamin K is essential for the functioning of several proteins involved in blood clotting (1). There are two naturally occurring forms of vitamin K. Plants synthesize phylloquinone, also known as vitamin K1. Bacteria synthesize a range of vitamin K forms, using repeating 5-carbon units in the side chain of the molecule. These forms of vitamin K are designated menaquinone-n (MK-n), where n stands for the number of 5-carbon units. MK-n are collectively referred to as vitamin K2 (2). MK-4 is not produced in significant amounts by bacteria, but appears to be synthesized by animals (including humans) from phylloquinone. MK-4 is found in a number of organs other than the liver at higher concentrations than phylloquinone. This fact, along with the existence of a unique pathway for its synthesis, suggests there is some unique function of MK-4 that is yet to be discovered (3).

Function
The only known biological role of vitamin K is that of the required coenzyme for a vitamin K-dependent carboxylase that catalyzes the carboxylation of the amino acid, glutamic acid, resulting in its conversion to gamma-carboxyglutamic acid (Gla) (4). Although vitamin K-dependent gamma-carboxylation occurs only on specific glutamic acid residues in a small number of proteins, it is critical to the calcium-binding function of those proteins (5, 6).

Coagulation (clotting)
The ability to bind calcium ions (Ca2+) is required for the activation of the 7 vitamin K-dependent clotting factors in the coagulation cascade. The term, coagulation cascade, refers to a series of events, each dependent on the other that stops bleeding through clot formation. Vitamin K-dependent gamma-carboxylation of specific glutamic acid residues in those proteins makes it possible for them to bind calcium. Factors II (prothrombin), VII, IX, and X make up the core of the coagulation cascade. Protein Z appears to enhance the action of thrombin (the activated form of prothrombin) by promoting its association with phospholipids in cell membranes. Protein C and protein S are anticoagulant proteins that provide control and balance in the coagulation cascade. Because uncontrolled clotting may be as life threatening as uncontrolled bleeding, control mechanisms are built in to the coagulation cascade. Vitamin K-dependent coagulation factors are synthesized in the liver. Consequently, severe liver disease results in lower blood levels of vitamin K-dependent clotting factors and an increased risk of uncontrolled bleeding (hemorrhage) (7).

Some people are at risk of forming clots, which could block the flow of blood in arteries of the heart, brain, or lungs, resulting in heart attack, stroke, or pulmonary embolism, respectively. Some oral anticoagulants, such as warfarin, inhibit coagulation through antagonism of the action of vitamin K. Although vitamin K is a fat-soluble vitamin, the body stores very little of it, and its stores are rapidly depleted without regular dietary intake. Perhaps, because of its limited ability to store vitamin K, the body recycles it through a process called the vitamin K cycle. The vitamin K cycle allows a small amount of vitamin K to function in the gamma-carboxylation of proteins many times, decreasing the dietary requirement. Warfarin prevents the recycling of vitamin K by inhibiting two important reactions and creating a functional vitamin K deficiency (see diagram). Inadequate gamma-carboxylation of vitamin K-dependent coagulation proteins interferes with the coagulation cascade, and inhibits blood clot formation. Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists, so patients taking these drugs are cautioned against consuming very large or highly variable quantities of vitamin K in their diets (see Drug interactions). Experts now advise a reasonably constant dietary intake of vitamin K that meets current dietary recommendations (60-80 mcg/day) for patients on vitamin K antagonists, like warfarin (8).

Bone mineralization
Three vitamin-K dependent proteins have been isolated in bone. Osteocalcin is a protein synthesized by osteoblasts (bone forming cells). The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol. The mineral-binding capacity of osteocalcin requires vitamin K-dependent gamma-carboxylation of three glutamic acid residues. The function of osteocalcin is unclear, but is thought to be related to bone mineralization. Matrix Gla protein (MGP) has been found in bone, cartilage, and soft tissue, including blood vessels. The results of animal studies suggest MGP prevents the calcification of soft tissue and cartilage, while facilitating normal bone growth and development. The vitamin K-dependent anticoagulant protein S is also synthesized by osteoblasts, but its role in bone metabolism is unclear. Children with inherited protein S deficiency suffer complications related to increased blood clotting as well as to decreased bone density (6, 7, 9).

Cell growth
Gas6 is a vitamin K-dependent protein that was identified in 1993. It has been found throughout the nervous system, as well in the heart, lungs, stomach, kidneys, and cartilage. Although the exact mechanism of its action has not been determined, Gas6 appears to be a cellular growth regulation factor with cell signaling activities. It may also play important roles in the developing and aging nervous system (10, 11).

Deficiency
Overt vitamin K deficiency results in impaired blood clotting, usually demonstrated by laboratory tests that measure clotting time. Symptoms include easy bruising and bleeding that may be manifested as nosebleeds, bleeding gums, blood in the urine, blood in the stool, tarry black stools, or extremely heavy menstrual bleeding. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage) (7).

Adults
Vitamin K deficiency is uncommon in healthy adults for a number of reasons: 1) vitamin K is widespread in foods (see Food sources), 2) the vitamin K cycle conserves vitamin K, and 3) bacteria that normally inhabit the large intestine synthesize menaquinones (vitamin K2), though it is unclear whether a significant amount is absorbed and utilized. Adults at risk of vitamin K deficiency include those taking vitamin K antagonist anticoagulant drugs and individuals with significant liver damage or disease (7).

Infants
Newborn babies that are exclusively breast-fed are at increased risk of vitamin K deficiency for the following reasons: 1) human milk is relatively low in vitamin K compared to formula, 2) the newborn's intestines are not yet colonized with bacteria that synthesize menaquinones, and 3) the vitamin K cycle may not be fully functional in newborns, especially premature infants. Infants whose mothers are on anticonvulsant medication to prevent seizures are also at risk of vitamin K deficiency. Vitamin K deficiency in newborns may result in a bleeding disorder called vitamin K deficiency bleeding (VKDB) of the newborn. Because VKDB is life threatening and easily prevented, the American Academy of Pediatrics and a number of similar international organizations recommend that an injection of phylloquinone (vitamin K1) be administered to all newborns (12).

Controversies around vitamin K administration and the newborn
Vitamin K and childhood leukemia: Controversy arose regarding the routine use of vitamin K injections for newborns in the early 1990s when two retrospective studies were published that suggested the possibility of an association between vitamin K injections in newborns and the development of childhood leukemia and other forms of childhood cancer. However, two large retrospective studies in the U.S. and Sweden that reviewed the medical records of 54,000 and 1.3 million children, respectively, found no evidence of a relationship between childhood cancers and vitamin K injections at birth (13,14). Moreover, a pooled analysis of 6 case-control studies including 2,431 children diagnosed with childhood cancer and 6,338 cancer-free children found no evidence that vitamin K injections for newborns increased the risk of childhood leukemia (15). In a policy statement, the American Academy of Pediatrics recommended that routine vitamin K prophylaxis for newborns be continued because VKDB is life threatening and the risks of cancer are unproven and unlikely (16). Full text of the AAP policy statement on vitamin K and the newborn.
Lower doses of vitamin K1 for premature infants: The results of two studies of vitamin K levels in premature infants suggest that the standard initial dose of vitamin K1 for full term infants (1.0 mg) may be too high for premature infants (17,18). These findings have led some experts to suggest the use of an initial vitamin K1 dose of 0.3 mg/kg for infants with birth weights less than 1,000 g (2 lbs, 3 oz) (19), and an initial dose of 0.5 mg for other premature infants (17).

The Adequate Intake (AI)
In January 2001, the Food and Nutrition Board (FNB) of the Institute of Medicine established the adequate intake (AI) level for vitamin K in the U.S. based on consumption levels of healthy individuals (20).

Adequate Intake (AI) for Vitamin K
Life Stage                              Age                            Males (mcg/day)         Females (mcg/day)
Infants                               0-6 months                               2.0                              2.0
Infants                              7-12 months                              2.5                              2.5
Children                            1-3 years                                  30                               30
Children                            4-8 years                                  55                               55
Children                          9-13 years                                  60                               60
Adolescents                  14-18 years                                  75                               75
Adults                           19 years and older                       120                              90
Pregnancy                     18 years and younger                     -                                75
Pregnancy                     19 years and older                         -                                90
Breastfeeding                18 years and younger                     -                                75
Breastfeeding                19 years and older                         -                                90


Disease Prevention 

Osteoporosis
The discovery of vitamin K-dependent proteins in bone has led to research on the role of vitamin K in maintaining bone health.

Dietary vitamin K and osteoporotic fracture
Epidemiological studies have demonstrated a relationship between vitamin K and age-related bone loss (osteoporosis). The Nurses Health Study followed more than 72,000 women for 10 years. Investigators found that women whose vitamin K intake was in the lowest quintile (1/5) had a 30% higher risk of hip fracture than women with vitamin K intakes in the highest four quintiles (21). A study of over 800 elderly men and women followed in the Framingham Heart Study for 7 years found that men and women with dietary vitamin K intakes in the highest quartile (1/4) had only 35% of the risk of hip fracture experienced by those with dietary vitamin K intakes in the lowest quartile (approximately 250 mcg/day vs. 50 mcg/day of vitamin K). However, the investigators found no association between dietary vitamin K intake and bone mineral density (BMD) in the Framingham subjects (22). Because the primary dietary source of vitamin K is generally green leafy vegetables, high vitamin K intake could just be a marker for a healthy diet that is high in fruits and vegetables (23).

Vitamin K-dependent carboxylation of osteocalcin and osteoporotic fracture
Osteocalcin, a bone-related protein that circulates in the blood, has been shown to be a sensitive marker of bone formation. Vitamin K is required for the gamma-carboxylation of osteocalcin. Undercarboxylation of osteocalcin adversely affects its capacity to bind to bone mineral, and the degree of osteocalcin gamma-carboxylation has been found to be a sensitive indicator of vitamin K nutritional status (3). Circulating levels of undercarboxylated osteocalcin (ucOC) were found to be higher in postmenopausal women than premenopausal women and markedly higher in women over the age of 70. In a study of 195 institutionalized elderly women, the relative risk of hip fracture was six times higher in those who had elevated ucOC levels at the beginning of the study (24). In a much larger sample of 7500 elderly women living independently, circulating ucOC was also predictive of fracture risk (25). Although vitamin K deficiency would seem the most likely cause of elevated blood ucOC, investigators have also documented an inverse relationship between measures of vitamin D nutritional status and ucOC levels, as well as a significant lowering of ucOC by vitamin D supplementation (6). It is also possible that an increased ucOC level is a marker for poor vitamin D or protein nutritional status.

Vitamin K antagonists and osteoporotic fracture
Certain oral anticoagulants, like warfarin, are known to be antagonists of vitamin K. Two recent studies examined the chronic use of warfarin and the risk of fracture in older women. One study reported no association between long-term warfarin treatment and fracture risk (26), while the other found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers (27). A meta-analysis of the results of 11 published studies found that oral anticoagulation therapy was associated with a very modest reduction in bone density at the wrist, and no change in bone density at the hip or spine (28).

Vitamin K supplementation studies and osteoporosis
Vitamin K supplementation of 1,000 mcg/day of phylloquinone (Vitamin K1) for 2 weeks (more than 10 times the AI for vitamin K) resulted in a decrease of ucOC levels in postmenopausal women, as well as increases in several biochemical markers of bone formation. In Japan, intervention trials in hemodialysis patients and osteoporotic women using very high pharmacologic doses (45 mg/day) of menatetrenone (MK-4) have reported significant reductions in the rate of bone loss (29, 30). MK-4 is not found in significant amounts in the diet, but can be synthesized in small amounts by humans from phylloquinone. The dose used in the Japanese studies is about 50 times higher than the AI for vitamin K. Experts are not sure whether the effects of such high doses of MK-4 represent a true vitamin K effect.

In the absence of long-term intervention studies using nutritionally optimal doses of vitamin K, evidence of a relationship between vitamin K nutritional status and bone health in adults is considered weak. Further investigation is required to determine the physiological function of vitamin K-dependent proteins in bone and the mechanisms by which vitamin K affects bone health and osteoporotic fracture risk (6).

Vascular calcification and cardiovascular disease
One of the hallmarks of cardiovascular disease is the formation of atherosclerotic plaques in arterial walls. Calcification of atherosclerotic plaques occurs as the condition progresses, resulting in decreased elasticity of the affected vessels and increased risk of clot formation, the usual cause of a heart attack or stroke. One study of postmenopausal women found low dietary vitamin K intake to be associated with increased risk of aortic calcification, as visualized by chest x-ray (31). Additionally, laboratory tests examining the vitamin K-dependent gamma-carboxylation of osteocalcin indicated that elevated blood levels of undercarboxylated osteocalcin (ucOC) were also associated with increased aortic calcification. The mechanism by which vitamin K may promote mineralization of bone, while inhibiting mineralization (calcification) of vessels is not entirely clear. One hypothesis is based on the function of two different bone proteins, osteocalcin and matrix Gla protein (MGP). MGP has been found to inhibit the calcification of cartilage and bone during early embryonic development. Osteocalcin appears later during bone development and appears to promote bone mineralization. Some investigators have hypothesized that high levels of MGP found in calcified vessels may represent a defense against vessel calcification, but that inadequate vitamin K nutritional status results in inadequate carboxylation, and presumably inactive MGP. Thus, insufficient dietary vitamin K may increase the risk of vascular calcification (32). However, it should be noted that this line of reasoning is based on animal research and only one epidemiological study in humans. Further investigations are necessary to establish the nature of the role of bone proteins in human atherosclerotic plaque calcification.

Sources

Food sources
Phylloquinone (vitamin K1) is the major dietary form of vitamin K. Green leafy vegetables and some vegetable oils (soybean, cottonseed, canola, and olive) are major contributors of dietary vitamin K. Hydrogenation of vegetable oils may decrease the absorption and biological effect of dietary vitamin K. If you wish to check foods you eat frequently for their nutrient content, including vitamin K, search the USDA food composition database or view a list of foods containing a specific nutrient. A number of good sources of vitamin K are listed in the table below along with their vitamin K content in micrograms (mcg).

Food                                         Serving                                          Vitamin K (mcg)
Olive oil                               1 Tablespoon                                                6.6
Soybean oil                          1 Tablespoon                                              26.1
Canola oil                            1 Tablespoon                                                9.7
Mayonnaise                         1 Tablespoon                                              11.9
Broccoli, cooked                 1 cup (chopped)                                          420
Kale, raw                            1 cup (chopped)                                          547
Spinach, raw                       1 cup (chopped)                                          120
Leaf lettuce, raw                  1 cup (shredded)                                         118
Swiss chard, raw                 1 cup (chopped)                                          299
Watercress, raw                  1 cup (chopped)                                            85
Parsley, raw                        1 cup (chopped)                                           324

Intestinal bacteria
Bacteria that normally colonize the large intestine synthesize menaquinones (vitamin K2), which are an active form of vitamin K. Until recently it was thought that up to 50% of the human vitamin K requirement might be met by bacterial synthesis. Recent research indicates that the contribution of bacterial synthesis is much less than previously thought, although the exact contribution remains unclear (34).

Supplements
In the U.S. vitamin K1 is without a prescription in multivitamin and other supplements in doses that generally range from 10-120 mcg per dose (35). A form of vitamin K2, menatetrenone (MK-4) has been used to treat osteoporosis in Japan and is currently under study in the U.S (36).

Safety

Toxicity
Although allergic reaction is possible, there is no known toxicity associated with high doses of phylloquinone (vitamin K1), or menaquinone (vitamin K2) forms of vitamin K (20). The same is not true for menadione (vitamin K3) and its derivatives. Menadione can interfere with the function of glutathione, one of the body's natural antioxidants, resulting in oxidative damage to cell membranes. Menadione given by injection has induced liver toxicity, jaundice, and hemolytic anemia (due to the rupture of red blood cells) in infants, and is no longer used for treatment of vitamin K deficiency (5, 7). No tolerable upper level (UL) of intake has been established for vitamin K (20).

Drug interactions
The anticoagulant effect of vitamin K antagonists (e.g., warfarin) may be inhibited by very high dietary or supplemental vitamin K intake. It is generally recommended that individuals using warfarin try to consume the AI for vitamin K (90-120 mcg), while avoiding large fluctuations in vitamin K intake that might interfere with the adjustment of their anticoagulant dose (8). Large doses of vitamin A and vitamin E have been found to antagonize vitamin K. Excess vitamin A appears to interfere with vitamin K absorption, while a form of vitamin E (tocopherol quinone) may inhibit vitamin K-dependent carboxylase enzymes. Bleeding was reported in a man taking 5 mg of warfarin and 1,200 IU of vitamin E daily (7). When given to pregnant women, warfarin, anticonvulsants, rifampin, and isoniazid can interfere with fetal vitamin K synthesis and place the newborn at increased risk of vitamin K deficiency (12). Prolonged use of broad spectrum antibiotics may decrease vitamin K synthesis by intestinal bacteria. Cephalosporins and salicylates may decrease vitamin K recycling by inhibiting vitamin K epoxide reductase (diagram). Cholestyramine, cholestipol, orlistat, mineral oil, and the fat substitute olestra may decrease vitamin K absorption (35).

Linus Pauling Institute Recommendation
Although the AI for vitamin K was recently increased, it is not clear if it will be enough to opitmize the gamma-carboxylation of vitamin K-dependent proteins in bone (see Osteoporosis). Multivitamins generally contain 10 to 25 mcg of vitamin K while vitamin K or "bone" supplements may contain 100 to 120 mcg of vitamin K. To consume the amount of vitamin K associated with a decreased risk of hip fracture in the Framingham Heart Study (about 250 mcg/day), an individual would need to eat a little more than 1/2 cup of chopped broccoli or a large salad of mixed greens every day. Though the dietary intake of vitamin K required for optimal function of all vitamin K dependent proteins is not yet known, the Linus Pauling Institute recommends taking a multivitamin/mineral supplement and eating at least 1 cup of dark green leafy vegetables daily. Replacing dietary saturated fats like butter and cheese with monounsaturated fats found in olive oil and canola oil will also increase dietary vitamin K intake, and may also decrease the risk of cardiovascular diseases.

Older adults (65 years and older)
Because older adults are at increased risk of osteoporosis and hip fracture, the above recommendation for a multivitamin/mineral supplement and at least 1 cup of dark green leafy vegetables/day is especially relevant.