The importance of vitamin K for health

It has long been known that vitamin K, which is involved as a coenzyme in the production of coagulation factors, is essential to the regulation of blood coagulation. But vitamin K also fulfils an important role in the activation of certain enzymes which, together with vitamin D, regulate metabolism and can combat the hardening of soft tissues such as blood vessels and help slow bone demineralization. In recent years interest in this vitamin has grown considerably following the discovery of other potentially health-promoting properties. Attention centers on research into the function of vitamin-K-dependent enzymes (Gla proteins), which are found in bones and teeth as well as in blood vessel linings, the brain and other soft tissues, where they appear to regulate cell division and cell differentiation, among other things. Studies indicate that a sufficient intake of vitamin K could help prevent the occurrence of atherosclerosis, osteoporosis, insulin resistance and inflammation of the joints, and above all could protect against the age-related loss of cognitive abilities.

The role of vitamin K in

Coagulation

Blood coagulation depends on the cascade-like activation of a series of coagulation factors (specific proteins) which stop bleeding by forming blood clots. As a cofactor for an enzyme that catalyzes the carboxylation (introduction of a carboxyl group, -COOH) of certain glutamic acid residues in the coagulation factors to gamma-carboxyglutamate (Gla), vitamin K, is of crucial importance in the activation of the in total seven coagulation factors (1). Vitamin-K-dependent gamma-carboxylation enables these coagulation factors to bind calcium ions (Ca2+) and trigger the coagulation process. Coagulation factors II (prothrombin), VII, IX and X form the center of the coagulation cascade, while protein Z appears to augment the effect of thrombin, the crucial enzyme in plasmacoagulation, by increasing its binding to phospholipids in cell membranes. Protein C, protein S and protein Z have a coagulation-inhibiting function. They are responsible for regulating (coa- gulation time) and equilibrating the coagulation cascade. Because of its dynamics and diversity of functions in the body, protein S is a particular focus of basic research into vitamin-K-dependent proteins (2).

The body stores only relatively small amounts of vitamin K, so its reserves are quickly exhausted if there is no regular intake from the diet (3). A vitamin K recycling process (vitamin K cycle) makes it possible for a small amount of vitamin K to participate several times in the gamma-carboxylation of proteins and hence reduces the need for dietary vitamin K. Coagulation disorders are the first signs of a lack of vitamin K. A marked vitamin K deficiency leads to longer coagulation times and increases the risk of heavy bleeding, blood loss, bruising, poor wound-healing and anemia. In many European countries the recommended daily vitamin K intake for adults is 60 micrograms (for women) to 70 micrograms (for men), whilst in the USA the recommended intake is 120 micrograms of vitamin K per day (for men) and 90 micrograms per day (for women) (4). The main risk group for bleeding on the brain due to vitamin K deficiency is newborns and breastfed infants, who generally only receive small amounts of vitamin K1 via breast milk, whilst their gut flora is not sufficiently developed to produce vitamin K2. For these reason, in many countries infants are given vitamin K prophylactically (5).

Since the vitamin-K-dependent coagulation factors are synthesized in the liver, severe liver disease may be associated with very low blood levels of vitamin-K-dependent coagulation factors and an increased risk of uncontrollable bleeding (hemorrhage). Some people who are at increased risk of blood clots which could block the flow of blood in the coronary arteries, the brain or the lung – potentially causing a heart attack, stroke or pulmonary embolism – take oral anticoagulants (e. g., warfarin). These have an antagonistic effect on vitamin K activity, and can reduce potential blood clotting by blocking the recycling of vitamin K. This can lead to vitamin K deficiencies in the body. Large intakes of vitamin K, on the other hand, can counteract the coagulation-inhibiting effect of vitamin K antagonists, meaning that the vitamin K status of patients taking such medication must be strictly monitored.

Maintenance of bone health

Vitamin K, as well as vitamin D, is essential to healthy bone metabolism. Three vitamin-K-dependent proteins have been isolated from bone: osteocalcin, matrix Gla protein (MGP) and protein S. Osteocalcin is synthesi- zed by bone-forming cells (osteoblasts) and is involved in bone mineralization. After collagen it is the most important protein to be incorporated into the bone matrix. Whereas vitamin D stimulates the production of osteocalcin and increases the availability of calcium, the osteocalcin is activated through the vitamin-K-de- pendent carboxylation of three of its glutamic acid residues. The active form of osteocalcin can bind calcium (hydroxylated calcium phosphate) and store it in the bones (6). Insufficient carboxylation of osteocalcin (e.g., as a result of a vitamin K deficiency) could lead to loss of bone density. Matrix Gla protein (MGP) has been found in bones, cartilage and soft tissue including blood vessels. Experimental studies indicate that MGP prevents hardening of soft tissue and cartilage, whilst it can enhance the normal growth and development of bones. The vitamin-K-dependent anticoagulant protein S is also synthesized by osteoblasts, although its role in bone metabolism has yet to be established (7). Children with an inherited protein S deficiency suffer from complications associated with increased coagulation and reduced bone density.

A number of experimental, epidemiological and clinical studies have provided evidence that a lack of vitamin K in the elderly can be associated with reduced bone mineral density (osteopenia) and an increased risk of fractures. This was observed primarily in postmenopausal women, who are no longer protected against osteoporosis (fragile bones) or its precursor osteopenia by high estrogen levels (8). Reviews indicate that the risk of fractures in older women could be reduced by dietary supplementation with vitamin K (9). Meta-ana- lyses of clinical intervention studies with vitamin K confirm the benefits of targeted administration of vitamin K on skeletal stability and a lower fracture rate for postmenopausal women – albeit through mechanisms that appear to act independently of bone mineral density and bone metabolism (10).

Prevention of cardiovascular disease

Vitamin K also appears to be able to help prevent atherosclerosis: Matrix Gla protein (MGP) is activated by vitamin-K-dependent carboxylation and may possibly reduce calcium deposits in the lining of the blood ves- sels (11, 12). A high level of inactive, undercarboxylated MGP in serum is regarded as a possible marker for (incipient) atherosclerosis. Apart from experimental approaches, clinical studies also indicate that vitamin K may be a protective factor for atherosclerosis and that low vitamin K1 levels may be associated with inc- reased risk of vascular calcification (13–15). This seems to be especially the case when older people have to take vitamin K antagonists to reduce blood coagulation (16). One clinical case-control study provided evi- dence that the administration of 500 micrograms of vitamin K1 daily could slow the progression of early calcification of the coronary arteries in older men and women (17). In patients with chronic renal disease, too, vitamin K1 could possibly combat vascular calcification (18).

Long-term low-level vitamin K deficiency is under debate as a risk factor for atherosclerosis and cancer (19). One prospective cohort study showed that increased consumption of vitamin K could be linked with a reduc- tion in mortality risk from cardiovascular events and cancer (20).

Maintenance of a healthy nervous system and brain

Large concentrations of vitamin K are present in brain tissue and appear to be important for brain function. In combating calcification (hardening) of soft tissue, vitamin K could help prevent neurodegenerative diseases of old age. In the brain, vitamin K is involved in the synthesis of sphingolipids (fatty components of the cell membrane), which are especially abundant in brain cell membranes (21). Sphingolipids participate in essential cellular processes like division, differentiation and senescence as well as in interactions between the cells. Changes to sphingolipid metabolism have been linked to cognitive decline and the onset of neurode- generative diseases. Via vitamin-K-dependent carboxylation the vitamin is also involved in the activation of protein Gas6 and protein S. Gas6 is involved in far-reaching cellular processes, including division, growth and (biologically controlled) cell death (apoptosis). This seems to apply to the cells of the nervous system, inc- luding neurons (for signal transmission) and glial cells (physical support for the nervous system) (22). Gas6 is not only an important regulator for neural cell growth but also in particular for myelinization of glial cells, in which the nerve fibers (axons) are surrounded with an electrically insulating, lipid -rich layer (myelin sheath) and supplied with energy-rich metabolic products. Protein Gas6 could therefore contribute to the stability and functionality of these cells within the nervous system. Experimental data indicate that protein S could pro- mote maintenance of a healthy nervous system through its antithrombotic functions and through neuropro- tective mechanisms controlled via cell-signal transmission.

Diabetes prevention

Preliminary research results indicate that vitamin K might positively influence the blood sugar (blood glucose) balance and could therefore help prevent diabetes. Essentially, two mechanisms are being discussed which could act on glucose metabolism via vitamin K: this could be the activation of osteocalcin (by means of vi- tamin-K-dependent carboxylation), which could improve the sensitivity of cells or of insulin receptors to in- sulin (insulin sensitivity) and the function of the insulin-producing beta-cells; or it could be directly anti-in- flammatory activity of vitamin K (23). Moreover, organs such as the liver and pancreas, which are important for glucose and insulin metabolism, may contain vitamin-K-dependent proteins (prothrombin and protein S) (24). A prospective cohort study was able to show that a diet rich in vitamin K could be associated with a reduced risk of developing type 2 diabetes (25). A randomized controlled study indicated that daily admi- nistration of 500 micrograms of vitamin K1 was able to moderate insulin resistance in older men (26).

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