Vitamin K

Vitamin K

 
 

Beyond its primary role in coagulation, vitamin K has other important roles, in particular bone metabolism. Currently, dietary recommendations for vitamin K do not consider its secondary roles in the body and as such subclinical deficiencies such as bone loss exist in otherwise healthy individuals. This level of vitamin K deficiency can remain undetected because individuals will not necessarily present with excessive bleeding, the most acknowledged symptom of vitamin K deficiency.

Background

Vitamin K is a fat-soluble vitamin with two natural homologs, K1 and K2. K1 (also known as phytomenadione, phylloquinone or phytonadione) is synthesized by plants and plays a direct role in photosynthesis. Green leafy vegetables are one of the richest K1 supplies for humans. K2 (also known as menaquinones) is a form found in animals. Both types are useful for humans as they can easily and readily convert K1 into K2. These natural homologs are nontoxic, though synthetic forms (K3) have shown toxicity.

Function

Vitamin K is a co-factor for the enzyme, γ-glutamate carboxylase (GGCX). Together they are required for the post-translational modifications of proteins (carboxylation). The carboxylation of proteins is achieved by converting glutamic acid residues within the protein structure into γ-carboxyglutamic acid (Gla) residues (Figure 1). These Gla residues express a strong binding affinity with calcium. This modification allows proteins to carry out their desired function.
Figure 1.

 Carboxylation of proteins

Primary Role

The primary role of vitamin K is to complete the carboxylation process of certain proteins within the intrinsic and extrinsic clotting cascade pathways (prothrombin, factors VII, IX and X) (Figure 2). This means coagulation is dependent on vitamin K.

Figure 2. Clotting cascade pathways (stars indicate the proteins that rely on vitamin K)

 Clotting

Secondary Roles

Bone Health

Vitamin K is involved in bone health as it is required for the carboxylation of osteocalcin (Figure 2), the most abundant non-collagenous protein found in bone. Vitamin K and GGCX modify osteocalcin, creating three Gla residues, all with a strong binding affinity to calcium. Carboxylated osteocalcin in the bone can readily bind to calcium and then place the mineral in a hydroxyapatite structure so it can be deposited into bone in a formation that is rigid. This means strong bone formation and maintenance is reliant on vitamin K.

Figure 3. Osteocalcin

 Osteocalcin

Inhibition of Arterial Calcification

Vitamin K is required for the carboxylation of the Matrix Gla Protein (MGP), a protein once carboxylated can bind and aid the proper distribution of calcium in the body. Carboxylated MGP is important for ensuring that calcium minerals do not form in blood vessels, which would reduce blood flow and increases the risk of cardiovascular disease. MGP is found in bone, heart, kidney and lung. This cardiovascular health relies on vitamin K.

Cell Growth Regulation

Vitamin K is involved in cell growth regulation as it is needed for the carboxylation of the Growth-arrest specific 6 protein (Gas 6), a ligand for tyrosine kinase receptors (AXL, TYRO3 & MER). These signals are implicated in cell growth, survival, adhesion and migration, but all require the carboxylation of Gas 6 to be transmitted. This means the regulation of cell growth is influenced by vitamin K.

Vitamin K deficiency

The primary, clinical vitamin K deficiency symptom is excessive bleeding (haemorrhaging). The secondary, subclinical vitamin K deficiency sign is bone loss. This usually occurs before the primary deficiency symptom and typically goes undetected, in early years.

Dietary Requirements

A recent study demonstrated that to prevent the primary deficiency symptom in adolescents, the dietary requirement for vitamin K would be 50μg/day – 60μg/day [1]. However to prevent the subclinical signs of vitamin K deficiency, the study showed adolescents require 150μg/day – 190μg/day [1].

The table below shows the current dietary requirements of vitamin K for adolescents and adults set out by the World Health Organization (WHO) [2], the Australian National Health & Medical Research Council (NHMRC) [3] and the United States Food and Nutrition Board (FNB) [4].

  WHO NHMRC FNB
Adolescence (9-18 years) 35 – 55μg/d 45 – 55μg/d 60 – 75μg/d
Adults (18+ years) 55 – 65μg/d 60 – 70μg/d 90 – 120μg/d

 

Only the FNB recommendations will significantly prevent the clinical vitamin K deficiency symptom. However none of the recommendations come close to preventing the subclinical signs of vitamin K deficiency, indicating that these are not adequate intake levels. Even compared to adults, none of the adequate intake levels would prevent the sign of vitamin K subclinical deficiency, bone loss.

Pharmacokinetics

A reason for this disparity lies within the pharmacokinetics of vitamin K. All ingested vitamin K is first transported to the liver to carry out its primary function, the carboxylation of coagulation proteins. Once this has been achieved and if and only if there is excess vitamin K, the remaining vitamin K is then transported to non-hepatic tissues, like the bone to carry out its secondary roles. This is why the levels to prevent bone loss are higher than they are to prevent excessive bleeding. It indicates that while people may not present with excessive bleeding, they may still be deficient in vitamin K with underlying problems such as bone loss.

Concerns

Children

During childhood, the body produces a 10-fold higher amount of osteocalcin than any other time after the peak bone mass is reached. This is no surprise as bone mineralization and formation is at its peak during childhood. However, the amount of osteocalcin that is produced is wasted if it is not carboxylated. A recent study showed healthy children have higher uncarboxylated levels of osteocalcin than adults and that many displayed vitamin K deficiencies for bone metabolism [5]. Insufficient vitamin K intake during childhood can reduce bone formation. When children were able to improve their vitamin K status, it had a positive effect on total bone mineral content [6, 7].

Adults

A low vitamin K status and high non-carboxylated level of osteocalcin is linked to an increased risk of bone fractures and a reduction in bone mineral density (BMD) [8, 9]. Vitamin K when added and used in supplementation has shown to improve hydroxyapatite binding capacity and reduce the decline in BMD in postmenopausal women [10, 11].

References

  1. Tsugawa, N., K. Uenishi, H. Ishida, T. Minekami, A. Doi, S. Koike, T. Takase, M. Kamao, Y. Mimura, and T. Okano, (2012) ‘A novel method based on curvature analysis for estimating the dietary vitamin K requirement in adolescents.’ Clin Nutr. 31(2): p. 255-60.
  2. World Health Organization (WHO) Vitamin and mineral requirements in human nutrition. (1998).WHO
  3. National Health & Medical Research Council (NHMRC) Nutrient reference values for Australia & New Zealand. (2005).NHMRC
  4. Food Nutrition Board (FNB) Institute of Medicine Dietary Reference Intakes. (2001).FNB Institute of Medicine
  5. van Summeren, M., L. Braam, F. Noirt, W. Kuis, and C. Vermeer, (2007) ‘Pronounced elevation of undercarboxylated osteocalcin in healthy children.’ Pediatr Res. 61(3): p. 366-70.
  6. O’Connor, E., C. Molgaard, K.F. Michaelsen, J. Jakobsen, C.J. Lamberg-Allardt, and K.D. Cashman, (2007) ‘Serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, and its relationship to bone health indices in Danish girls.’ Br J Nutr. 97(4): p. 661-6.
  7. van Summeren, M.J., S.C. van Coeverden, L.J. Schurgers, L.A. Braam, F. Noirt, C.S. Uiterwaal, W. Kuis, and C. Vermeer, (2008) ‘Vitamin K status is associated with childhood bone mineral content.’ Br J Nutr. 100(4): p. 852-8.
  8. Booth, S.L., K.E. Broe, D.R. Gagnon, K.L. Tucker, M.T. Hannan, R.R. McLean, B. Dawson-Hughes, P.W. Wilson, L.A. Cupples, and D.P. Kiel, (2003) ‘Vitamin K intake and bone mineral density in women and men.’ Am J Clin Nutr. 77(2): p. 512-6.
  9. Feskanich, D., P. Weber, W.C. Willett, H. Rockett, S.L. Booth, and G.A. Colditz, (1999) ‘Vitamin K intake and hip fractures in women: a prospective study.’ Am J Clin Nutr. 69(1): p. 74-9.
  10. Braam, L.A., M.H. Knapen, P. Geusens, F. Brouns, K. Hamulyak, M.J. Gerichhausen, and C. Vermeer, (2003) ‘Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.’ Calcif Tissue Int. 73(1): p. 21-6.
  11. Thijssen, H.H., M.J. Drittij, C. Vermeer, and E. Schoffelen, (2002) ‘Menaquinone-4 in breast milk is derived from dietary phylloquinone.’ Br J Nutr. 87(3): p. 219-26.