Vitamin K and PIVKAII profile
Vitamin K forms and function:
There are a number of structurally similar, naturally occurring compounds which have vitamin K activity. The major plant form is phylloquinone (vitamin K1; usually abbreviated to K1). The menaquinones (vitamins K2; usually abbreviated to MK) are predominately of bacterial origin. While K1 has a 20-carbon phytyl side chain, the MKs have multiple prenyl side chains, their number being indicated by a suffix (i.e. MK-n).
In the typical Western diet, K1 and MK-n account for 90% and 10% of the vitamin K intake, respectively . Dietary MK-n consists of MK-4, MK-7, MK-8, and MK-9 , although MKs with longer side chains up to MK-13 can be found in the human liver [3,4]. Menadione (usually abbreviated to K3) is a synthetic vitamin K homolog which, despite toxicity concerns and restricted biological activity, is available in some countries as a pharmaceutical vitamin K preparation . The biological activity of K3 in vivo depends entirely on its conversion to MK-4 [6,7].
At the cellular level, the co-factor role of vitamin K for the conversion of peptide-bound glutamate to gamma-carboxyglutamate (Gla) is well established, as is the associated metabolic cycle whereby the vitamin K 2,3-epoxide metabolite generated during gamma-glutamyl carboxylation is salvaged and re-cycled to active vitamin K [8, 9].
The liver synthesises seven vitamin K-dependent proteins that have a crucial role in blood coagulation (factors II, VII, IX and X, proteins C, S, and Z). Other vitamin K-dependent proteins (Gla proteins), with a widespread tissue distribution, have also been identified; this has led to a re-evaluation of the general physiological function of vitamin K and its role in human health. Putative roles of Gla proteins now extend to a diversity of functions, such as the regulation of bone turnover and calcification [10,11], inhibition of vascular calcification , and roles in vascular repair processes , cell cycle regulation, cell-cell adhesion and signal transduction . Of particular note is the accumulating body of evidence that has linked sub-optimal vitamin K reserves in bone to an increased risk of osteoporotic fracture [15,16] or to reduced bone mineral density .
Vitamin K deficiency
Vitamin K1 is found chiefly in green leafy vegetables, while MK is present in animal tissues. Like other fat-soluble vitamins, vitamin K is absorbed from the duodenum, where it is dependent on bile and pancre-atic secretions for solubilisation. Any condition causing the intestinal malabsorption of fat will therefore lead to a secondary deficiency of fat-soluble vitamins, including vitamin K.
Deficient absorption of vitamin K leads to the depletion of its tissue stores, which is indicated by a decrease in circulating levels of the vitamin long before pathological changes develop. Vitamin K deficiency is more prevalent than generally supposed. Cases are often missed, or detected late, due to the use of inappropriate laboratory markers of vitamin K status - commonly the International Normalised Ratio (INR). The INR, which is based on the prothrombin time, is designed to detect bleeding tendencies and is a very insensitive marker of vitamin K status.
Vitamin K status assessment:
Tissue stores of vitamin K are evaluated by the direct measurement of circulating K1. This is supported by the analysis of PIVKA-II (under-carboxylated prothrombin - an abnormal species of Factor II that is only detectable in the circulation of patients with suboptimal vitamin K status). By running these two assays in tandem we are able to monitor the two most important determinants of vitamin K status - availability and utilisation.
The serum concentration of K1 reflects its storage and transport. K1 is measured using a modified HPLC method with postcolumn chemical reduction and fluorescence detection . In healthy, normolipaemic adults the non-fasting reference range for K1 is 0.15-1.55 ug/L.
Serum PIVKA-II is determined using a monoclonal antibody (C4B6) to PIVKA-II in an ELISA [19,20]. The C4B6 MAb used in this assay is conformation-specific such that, in the presence of calcium ions, it binds only to the under-carboxylated species of prothrombin and does not cross-react with fully carboxylated prothrombin. Results are expressed as arbitrary units (AU) per millilitre, where 1 AU is equivalent to 1 ug of multiple PIVKA-II species purified from patients treated with vitamin K antagonists. The upper limit of the reference range for PIVKA-II in adults is 0.2 AU/ml (200 ng/ml).
Patients should fast for 12 hours before taking blood for the assessment of vitamin K status and should have refrained from taking nutritional supplements for 24 hours prior to venipuncture.
Please note that vitamin K cannot be measured without the PIVKAII test.
Cardiovascular disease and osteoporosis.
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1. Schurgers LJ, Geleijnse JM, Grobbee DE, Pols HAP, Hofman A, Witteman JCM, and Vermeer C. 1999. Nutritional intake of vitamin K-1 (phylloquinone) and K-2 (menaquinone) in The Netherlands. J. Nutr. Environ. Med. 9: 115-122.
2. Schurgers LJ and Vermeer C. 2000. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis. 30: 298-307.
3. Shearer MJ. 1992. Vitamin K metabolism and nutriture. BloodRev. 6: 92-104.
4. Suttie JW. 1995. The importance of menaquinones in human nutrition. Annu. Rev. Nutr. 15: 399-417.
5. British National Formulary. 2004. British Medical Association and Royal Pharmaceutical Society of Great Britain. No. 48 (September).
6. Martius , and Esser HO. 1958. Uber die Konstitution des im Tierkorper aus Methylnaphthochinon gebildeten K-Vitamines. Biochem. Z. 331: 1-9.
7. Taggart WV and Matschiner JT. 1969. Metabolism of menadione-6,7-3H in the rat. Biochemistry. 8: 1141-1146.
8. Olson RE. 1999. Vitamin K. In Modern Nutrition in Health & Disease. 9th ed. M. E. Shils, J. A. Olson, M. Shike, and A. C. Ross, editors. Williams & Wilkins, Baltimore, MD. 363-380.
9. Suttie JW. 1992. Vitamin K and human nutrition. J. Am. Diet. Assoc.92: 585-590.
10 Vermeer C, Knapen MH, and Schurgers LJ. 1998. Vitamin K and metabolic bone disease. J. Clin. Pathol. 51: 424-426.
11 Shearer, M. J. 2000. Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Curr. Opin. Clin. Nutr. Metab. Care. 3: 433-438.
12. Shanahan CM, Proudfoot D, Farzaneh-Far A, and Weissberg PL. 1998. The role of Gla proteins in vascular calcification. Crit.Rev. Eukaryot. Gene Expr. 8: 357-375.
13. Benzakour O and C. Kanthou. 2000. The anticoagulant factor, protein S, is produced by cultured human vascular smooth muscle cells and its expression is up-regulated by thrombin. Blood. 95: 2008-2014.
14. Tsaioun KI. 1999. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr. Rev. 57: 231-240.
15. Szulc P, Chapuy MC, Meunier PJ, and Delmas PD. 1993. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J. Clin. Invest. 91: 1769-1774.
16. Luukinen H, Kakonen SM, Pettersson K, Koski K, Laippala P, Lovgren T, Kivela SL, and Vaananen HK. 2000. Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J. Bone Miner. Res. 15: 2473-2478.
17. Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, and Delmas PD. 1994. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J. Bone Miner. Res. 9: 1591-1595.
18. Davidson KW, Sadowski JA. 1997. Determination of vitamin K compounds in plasma or serum by high-performance liquid chromatography using postcolumn chemical reduction and fluorimetric detection. Methods Enzymol 282:408-21.
19. Belle M, Brebant R, Guinet R, et al. 1995a.Production of a new monoclonal antibody specific to human des-gamma-carboxyprothrombin in the presence of calcium ions. Application to the development of a sensitive ELISA test. J Immunoassay 16:213-29.
20. Belle M, Leclercq M, Vignal B, et al. 1995. Application of an ELISA test to vitamin K deficient conditions using a new monoclonal antibody against human des-gammacarboxy-prothrombins (DCP). In: Sutor AH, Hathaway WE, eds. Vitamin K in infancy. New York: Schattauer:123-37.
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