Vitamin K

BACKGROUND

Vitamin K is the family name for a series of essential fat-soluble compounds needed for the chemical modification of a small group of proteins with calcium-binding properties (vitamin K dependent proteins or γ-carboxyglutamic acid-proteins, generally known as Gla proteins). The best-known role for vitamin K is the maintenance of normal blood coagulation. Use of anticoagulant drugs such as warfarin can affect vitamin K requirements. The vitamin K-dependent coagulation proteins that are made in the liver have both coagulant and anticoagulant properties. They include the coagulant factors II (prothrombin), VII, IX and X and the anticoagulant proteins C and S.

Vitamin K is involved in the post-translational modification of glutamate residues to γ-carboxyglutamate residues in the formation of the coagulation protein, prothrombin. The glutamate-containing (undercarboxylated) precursors of the vitamin K-dependent proteins are sometimes referred to as 'proteins induced by vitamin K absence' or 'PIVKA'. The glutamate precursor of prothrombin is called PIVKA- II. The vitamin K-dependent procoagulants are secreted from the liver as inactive forms. After the incorporation of Gla residues and in the presence of calcium ions they bind to the surface membrane phospholipids of platelets and endothelial cells where they form membrane-bound complexes with other cofactors. When coagulation is initiated, the inactive clotting factors are cleaved and activated. Two other proteins containing γcarboxyglutamate residues are osteocalcin or bone Gla protein (with 3 Gla residues) produced by the osteoblasts and matrix Gla protein, or MGP, (with 5 Gla residues).

Low vitamin K intakes are associated with undercarboxylated osteocalcin increases and have also been associated with increased rates of hip fracture in two cohort studies (Booth et al 2000, Feskanich et al 1999).

The only important molecular form of vitamin K in plants is phylloquinone (vitamin K 1 ) but bacteria can synthesise a family of compounds called menaquinones (vitamin K 2 ). The major dietary sources of vitamin K are green leafy vegetables such as kale, spinach, salad greens, cabbage, broccoli and brussel sprouts and certain plant oils such as soybean and canola oils (and to a lesser extent cottonseed and olive oils) and margarines and salad dressings made from them. Relatively large amounts of menaquinones can be found in some cheeses (Schurgers et al 1999).

There is little information about the bioavailability of phylloquinone from various foods. One study showed that its availability from a supplement was 25 times greater than that from spinach (Gijsbers et al 1996), although three times as much was absorbed when butter was added to the spinach. Another study showed that the availability from spinach, broccoli or romaine consumed as part of a meal was 80–84% lower than that from a supplement (Garber et al 1999). Overall, absorption from plant sources including plant oils (Booth et al 1999) seems to be no more than 20% of that from a supplement. Animal experiments have shown that high vitamin E intakes can antagonise the action of vitamin K (Rao & Mason 1975, Wooley 1945). Some effects have been seen in anticoagulated patients (Corrigan & Ulfers 1981), but no adverse effects have been shown in healthy humans.

Vitamin K deficiency causes a bleeding tendency through a lack of activity of the procoagulant proteins. A clinically significant deficiency is associated with an increase in prothrombin time (PT). Cases of dietary induced deficiency are rare, but may be associated with lipid malabsorption (Savage & Lindenbaum 1983). Experimentally induced deficiency occurred in 10 healthy subjects fed a diet containing less than 10 µg vitamin K/day (Udall 1965). Frick et al (1967) administered a parenteral nutrient solution to a small number of neomycin-treated adults for 4 weeks and observed prolonged prothrombin times (PTs) that responded to parenteral administration of phylloquinone. Frick et al (1967) concluded that requirements were between 0.30 and 1.05 µg/kg body weight. In more recent studies by Allison et al (1987) and Ferland et al (1993), healthy individuals eating diets containing 5–10 µg/day for two weeks showed no change in PT.

The biologic functions of vitamin K-dependent proteins produced in other tissues, notably osteocalcin and MGP are unclear. Evidence of a possible association of suboptimal vitamin K deficiency with increased risk of adverse outcomes for bone health and bone fracture is under investigation by a number of groups but the outcomes have not been clear cut to date (Binkley & Suttie 1995, Binkley et al 2002, Braam et al 2003, Schaafsma et al 2000, Shearer 1997, Vermeer et al 1995).

Various indicators for vitamin K requirements have been used, including PT, Factor VII, plasma and serum phylloquinone, urinary γ-carboxyglutamyl residues, undercarboxylated prothrombin and under γ-carboxylated osteocalcin. Of these, only prothrombin has been associated with adverse clinical effects. Other indicators respond to dietary intake, but the physiological significance is unclear.