The Role of Vitamin K2 in the Human Diet

Vitamin K is an essential micronutrient. The EU nutrient reference value (NRV) is 75µg^[1] and the US Reference Daily Intake (RDI) is 120^[2]. Both intakes are easy to achieve with a varied Western diet. Vitamin K's primary function is that it's needed for efficient blood clotting and vessel integrity, and it therefore has a role in wound healing. In addition, vitamin K is also involved in maintaining bone health.

The primary form of vitamin K is phylloquinone, which is also known as vitamin K1. This is found naturally in plant products and is abundant in a varied diet, and this is why vitamin K deficiency is rare in older children and adults. Another form of vitamin K is menaquinone or vitamin K2. Vitamin K2 is, in fact, a group of several subtypes which all differ structurally with menaquinone-4 (MK-4) and MK-7 being the most commonly found and have the most significant biological activity^[3]. MK-4 is the only form of vitamin K2 that can be synthesized from vitamin K1^[4].

Vitamin K2 has not generally been thought of as essential in its own right over and above vitamin K1 for the reason that there are no deficiency symptoms apparent from not consuming it. However, vitamin K2 can be used as an alternative form of vitamin K to prevent deficiency and is often the supplementary form prescribed by doctors. Despite not being 'essential' in the same way as other nutrients are essential, there are a number of demonstrated health benefits from including it in our diets. Vitamin K2 performs the same functions as vitamin K1 by assisting in blood clotting and vessel integrity, and it has also has been shown to help as an anti-inflammatory agent, with consequential cardiovascular benefits^[5,6], as well as improved bone health^[7,8,9,10]. It may also help reduce the risk of prostate cancer^[11].

The 75µg EU NRV of vitamin K doesn't distinguish between vitamins K1 and K2. This recommendation is based on adequate activation of clotting factors in the blood, and in healthy individuals this amount is sufficient to ensure complete activation of clotting factors^[12,13,14].

Both vitamin K1 and MK-4 have also been shown to promote bone health, but only at very high doses: 1 to 5mg for vitamin K1 and 45mg for MK-4^[15,16,17]. The short half-lives require these high doses. In such high doses, though, vitamins are often classified as drugs, rather than food supplements. For example, MK-4 is used medically in Japan at a dose of 45mg/day to treat osteoporosis^[18].

Some forms of K2, particularly MK-4, are found in animal products and are produced from the fermentation of food by bacteria in our gut with the resulting vitamin K2 being stored or activated in tissues. Vitamin K2 produced by bacterial fermentation as found in natto – a Japanese traditional dish of fermented soybeans – is the MK-7 form. MK-7 is the most biologically effective form due to its stability^[3] and is the subtype of most interest.

Bone Health

The role of vitamin K2 in bone health is particularly interesting. It seems to be involved in the activation of osteocalcin, a protein involved in the transport and integration of calcium into bone. Calcium is a key constituent of bone, and an optimal dietary intake is critical for building and maintaining a healthy skeleton. Vitamin D, which is available from both dietary sources and sunlight, is needed to increase absorption of calcium from the intestines to make it available for bone-building. However, a third nutrient, i.e. vitamin K2, which has until recently been overlooked, is also important in the bone calcification process as it ensures that the calcium in the bloodstream reaches bone and is incorporated into the matrix. Vitamin D plays the primary role here with vitamin K2 acting as a cofactor in the process^[15]. Once activated, osteocalcin binds calcium in the bloodstream for transport into the bone matrix^[19]. In addition, another protein involved in the reaction, known as matrix gamma-carboxyglutamic acid (Gla) protein, is activated by vitamin K2 to ensure that calcium is transported to bones and not areas where it can be harmful^[12].

Of all the menaquinone forms, MK-4 (with a shorter side chain) and MK-7 (with a longer side chain) are the most important for bone health. Although both have demonstrated bone health benefits, MK-7 activates the greatest proportion of osteocalcin and is the preferred form used in vitamin K2 supplements.

Vitamin K2 and Cardiovascular Health

As described above, vitamin K2 is involved in regulating calcium levels and calcium being taken from the blood into bone. Other than the obvious bone benefits, there are other positive effects for removing calcium from blood: if calcium accumulates in blood vessels, areas can become calcified, which reduces vessel elasticity and this increases the risk of cardiovascular disease (CVD).

A study of postmenopausal women found that a high dietary intake of vitamin K2, but not vitamin K1, was associated with reduced calcification of blood vessels^[20] and this is thought to be linked to matrix Gla protein, whose inadequate activation is associated with vascular calcification^[21]. As inflammation is a key process in the etiology of CVD, vitamin K2, which has anti-inflammatory properties, may have a benefit to heart health^[5,6].

Is Vitamin K2 Essential?

Vitamin K1 is widely available in green leafy vegetables, and the daily intake of vitamin K in the general population has been estimated to be 70–250µg^[22], so most people are consuming enough to cover requirements. However, because vitamin K1 and vitamin K2 have distinct functions, a high intake of vitamin K1 cannot fully compensate for an inadequate vitamin K2 intake. To date, we know little about vitamin K2 intakes in the general population although typical Western diets contain minimal amounts of vitamin K2 and only big consumers of fermented cheese and natto will be getting the amounts for positive health benefits. There is therefore an argument for supplementation.

Vitamin K2 in Huel

The majority of vitamin K1 in Huel is from three of the main ingredients, i.e. the sunflower powder, oats and flaxseed, and the rest added as part of our vitamin and mineral blend to a level that meets the US RDI. The K2 in Huel is added as an extra to the RDI which means the vitamin K2 in Huel is available for the health benefits over and above the fundamental blood clotting function of vitamin K, which is met by vitamin K1.

The type of vitamin K2 in Huel is MK-7 and is absolutely pure and the all-trans variant; we use no biologically inactive cis-isomers. We use MK-7 only because it's the most biologically active. Its structure has a long side-chain allowing it to reach beyond the liver, and it has a long half-life of around three days. MK-4 has a shorter side chain and a much shorter half-life.

References

1. Food Drink Europe. Guidance on the Provision of Food Information to Consumers: Regulation (EU) No. 1169/2011. 2013.
2. U.S Food and Drug Administration. Food for Human Consumption: Nutrition labeling of food. 2018; 21(2).
3. Sato T, et al. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. 2012;(12): 11:93.
4. Okano T, et al. Conversion of Phylloquinone (Vitamin K1) into Menaquinone-4 (Vitamin K2) in Mice. J Biol Chem. 2007;283: 11270–9.
5. Geleijnse JM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11): 3100–5.
6. Beulens JW, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203(2): 489–93.
7. Purwosunu Y, et al. Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res. 2006;32(2): 230–4.
8. Knapen MH, et al. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007;18(7): 963–72.
9. Vermeer C & Theuwissen E. Vitamin K, osteoporosis and degenerative diseases of ageing. Menopause Int. 2011;17(1): 19–23.
10. Knapen MH, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013;24(9): 2499–507.
11. Samykutty A, et al. Vitamin K2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells. Evid Based Complement Alt Med. 2013;2013: 287358.
12. Vermeer C. Vitamin K: the effect on health beyond coagulation – an overview. Food Nutr Res. 2012. 56: 10.3402/fnr.v56i0.5329.
13. European Union, Official Journal of the European Union, Commission Directive (EU) No. 432/2012, L 285/9-12. 2008.
14. Nicolaidou P, et al. The Effect of Vitamin K Supplementation on Biochemical Markers of Bone Formation in Children and Adolescents with Cystic Fibrosis. Eur J Pediatr. 2006;165(8): 540–5.
15. Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009; 29: 89–110.
16. Iwamoto J, et al. High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature. Nutr Res. 2009; 29(4): 221–8.
17. Cockayne S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(12): 1256–61.
18. Iwamoto J. Vitamin K2 Therapy for Postmenopausal Osteoporosis. Nutrients. 2014;6(5): 1971–80.
19. Crockett JC, et al. Bone Remodelling at a Glance. J Cell Sci. 2001;124(7): 991–8.
20. Beulens JW, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203(2), 489–93.
21. Schurgers LJ, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb.Vasc Biol. 2005;25(8), 1629–33.
22. Suttie JS (Ed). Vitamin K in Health and Disease (CRC Press, Boca Raton, Florida, USA, 2009).