Vitamin K nutrition, metabolism, and requirements: current concepts and future research.

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.

[1]  P. Frick,et al.  Dose response and minimal daily requirement for vitamin K in man. , 1967, Journal of applied physiology.

[2]  R. Blomstrand,et al.  Vitamin K1-3H in man. Its intestinal absorption and transport in the thoracic duct lymph. , 1968, Internationale Zeitschrift fur Vitaminforschung. International journal of vitamin research. Journal international de vitaminologie.

[3]  M. Shearer,et al.  Absorption and Excretion of an Oral Dose of Tritiated Vitamin K1 in Man , 1970, British journal of haematology.

[4]  M. Shearer,et al.  Clearance from Plasma and Excretion in Urine, Faeces and Bile of an Intravenous Dose of Tritiated Vitamin K1 in Man , 1972, British journal of haematology.

[5]  M. Shearer,et al.  Studies on the metabolites of phylloquinone (vitamin K 1 ) in the urine of man. , 1973, Biochimica et biophysica acta.

[6]  M. Shearer,et al.  Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. , 1974, Vitamins and hormones.

[7]  M. Shearer,et al.  Preparative isolation and characterization of the urinary aglycones of vitamin K1 (phylloquinone in man. , 1980, Biochemical medicine.

[8]  R. Mahley,et al.  Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. , 1981, The Journal of clinical investigation.

[9]  R. Mahley,et al.  Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. , 1982, The Journal of biological chemistry.

[10]  M. Shearer,et al.  Vitamin K1 Content of Maternal Milk: Influence of the Stage of Lactation, Lipid Composition, and Vitamin K1 Supplements Given to the Mother , 1987, Pediatric Research.

[11]  M. Weintraub,et al.  Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. , 1987, The Journal of clinical investigation.

[12]  J. Cortner,et al.  Kinetics of chylomicron remnant clearance in normal and in hyperlipoproteinemic subjects. , 1987, Journal of lipid research.

[13]  E. Schaefer,et al.  Postprandial Changes in the Plasma Concentration of α- and γ-Tocopherol in Human Subjects Fed a Fat-Rich Meal Supplemented with Fat-Soluble Vitamins , 1989 .

[14]  R. Mahley,et al.  Chylomicron metabolism. Chylomicron uptake by bone marrow in different animal species. , 1989, The Journal of biological chemistry.

[15]  R. Mahley,et al.  Chylomicron-chylomicron remnant clearance by liver and bone marrow in rabbits. Factors that modify tissue-specific uptake. , 1989, The Journal of biological chemistry.

[16]  E. Schaefer,et al.  Postprandial changes in the plasma concentration of alpha- and gamma-tocopherol in human subjects fed a fat-rich meal supplemented with fat-soluble vitamins. , 1989, The Journal of nutrition.

[17]  R. Russell,et al.  Postprandial plasma vitamin A metabolism in humans: a reassessment of the use of plasma retinyl esters as markers for intestinally derived chylomicrons and their remnants. , 1990, Metabolism: clinical and experimental.

[18]  C. Garza,et al.  Vitamin K in colostrum and mature human milk over the lactation period--a cross-sectional study. , 1991, The American journal of clinical nutrition.

[19]  J. Cherry,et al.  Vitamin K status of lactating mothers, human milk, and breast-feeding infants. , 1991, Pediatrics.

[20]  R. Mahley,et al.  Chylomicron and chylomicron remnant catabolism , 1991 .

[21]  J. Golding,et al.  Childhood cancer, intramuscular vitamin K, and pethidine given during labour. , 1992, BMJ.

[22]  M. Shearer Vitamin K metabolism and nutriture. , 1992, Blood reviews.

[23]  W. Webster,et al.  Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis. , 1992, Australian dental journal.

[24]  Mandating vitamin K prophylaxis for newborns in New York State. , 1993, American journal of public health.

[25]  M. Shearer,et al.  Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis. , 1993, The American journal of clinical nutrition.

[26]  K. Karita,et al.  [Relation of fingernail mineral concentrations to bone mineral density in elderly Japanese women]. , 1994, [Nihon koshu eisei zasshi] Japanese journal of public health.

[27]  Y. Yazaki,et al.  Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice. , 1994, The Journal of clinical investigation.

[28]  R. Mahley,et al.  Secretion-capture role for apolipoprotein E in remnant lipoprotein metabolism involving cell surface heparan sulfate proteoglycans. , 1994, The Journal of biological chemistry.

[29]  E. Boerwinkle,et al.  Apolipoprotein E polymorphism influences postprandial retinyl palmitate but not triglyceride concentrations. , 1994, American journal of human genetics.

[30]  J. Suttie The importance of menaquinones in human nutrition. , 1995, Annual review of nutrition.

[31]  C. Vermeer,et al.  Effect of food composition on vitamin K absorption in human volunteers , 1996, British Journal of Nutrition.

[32]  M. Shearer,et al.  Transport of vitamin K to bone in humans. , 1996, The Journal of nutrition.

[33]  P. Loughnan,et al.  Does intramuscular vitamin K1 act as an unintended depot preparation? , 1996, Journal of paediatrics and child health.

[34]  R. Havel,et al.  Prolonged postprandial responses of lipids and apolipoproteins in triglyceride-rich lipoproteins of individuals expressing an apolipoprotein epsilon 4 allele. , 1996, The Journal of clinical investigation.

[35]  L. Sokoll,et al.  Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. , 1996, The American journal of clinical nutrition.

[36]  A. Cooper Hepatic uptake of chylomicron remnants. , 1997, Journal of lipid research.

[37]  R. Mahley,et al.  Uptake of chylomicrons by the liver, but not by the bone marrow, is modulated by lipoprotein lipase activity. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[38]  S. Booth,et al.  Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. , 1997, The Journal of nutrition.

[39]  S. Booth,et al.  Dietary intake and adequacy of vitamin K. , 1998, The Journal of nutrition.

[40]  E. Schaefer,et al.  Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. , 1998, The American journal of clinical nutrition.

[41]  S. Booth,et al.  Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults. , 1999, The American journal of clinical nutrition.

[42]  N. Binkley,et al.  Comparison of phylloquinone bioavailability from food sources or a supplement in human subjects. , 1999, The Journal of nutrition.

[43]  L. Schurgers,et al.  Congenital Deficiency of Vitamin K Dependent Coagulation Factors in Two Families Presents as a Genetic Defect of the Vitamin K-Epoxide-Reductase-Complex , 2000, Thrombosis and Haemostasis.

[44]  S. Booth,et al.  Effects of a hydrogenated form of vitamin K on bone formation and resorption. , 2001, The American journal of clinical nutrition.

[45]  P. Trumbo,et al.  Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. , 1998, Journal of the American Dietetic Association.

[46]  L. Schurgers,et al.  Differential lipoprotein transport pathways of K-vitamins in healthy subjects. , 2002, Biochimica et biophysica acta.

[47]  S. Booth,et al.  Phylloquinone absorption from phylloquinone-fortified oil is greater than from a vegetable in younger and older men and women. , 2002, The Journal of nutrition.

[48]  M. Shearer,et al.  The Uptake of Lipoprotein‐Borne Phylloquinone (Vitamin K1) by Osteoblasts and Osteoblast‐Like Cells: Role of Heparan Sulfate Proteoglycans and Apolipoprotein E , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[49]  S. Booth,et al.  HPLC and GC/MS determination of deuterated vitamin K (phylloquinone) in human serum after ingestion of deuterium-labeled broccoli. , 2002, The Journal of nutritional biochemistry.

[50]  Hong Wang,et al.  Novel Role of Vitamin K in Preventing Oxidative Injury to Developing Oligodendrocytes and Neurons , 2003, The Journal of Neuroscience.

[51]  B. Clevidence,et al.  Isotopic labeling and LC-APCI-MS quantification for investigating absorption of carotenoids and phylloquinone from kale (Brassica oleracea). , 2003, Journal of agricultural and food chemistry.

[52]  D. Kiel,et al.  Vitamin K intake and bone mineral density in women and men. , 2003, The American journal of clinical nutrition.

[53]  S. Booth,et al.  Dietary phylloquinone depletion and repletion in older women. , 2003, The Journal of nutrition.

[54]  D. Kiel,et al.  Associations between vitamin K biochemical measures and bone mineral density in men and women. , 2004, The Journal of clinical endocrinology and metabolism.

[55]  I. Ieiri,et al.  Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. , 2003, Blood.

[56]  S. Booth,et al.  Plasma transport of vitamin K in men using deuterium-labeled collard greens. , 2004, Metabolism: clinical and experimental.

[57]  C. Ponting,et al.  Vitamin K epoxide reductase: homology, active site and catalytic mechanism. , 2004, Trends in biochemical sciences.

[58]  A. Hofman,et al.  Patients with an ApoE ϵ4 allele require lower doses of coumarin anticoagulants , 2005, Pharmacogenetics and genomics.

[59]  J. Manson,et al.  Phylloquinone intake as a marker for coronary heart disease risk but not stroke in women , 2005, European Journal of Clinical Nutrition.

[60]  S. Booth,et al.  Vitamin K and sphingolipid metabolism: evidence to date. , 2005, Nutrition reviews.

[61]  Deborah A Nickerson,et al.  Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. , 2005, The New England journal of medicine.

[62]  M. Wadelius,et al.  Warfarin dose related to apolipoprotein E (APOE) genotype , 2005, European Journal of Clinical Pharmacology.

[63]  Moustapha Kassem,et al.  Expression of LRP1 by Human Osteoblasts: A Mechanism for the Delivery of Lipoproteins and Vitamin K1 to Bone , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[64]  S. Hunt,et al.  Common VKORC1 and GGCX polymorphisms associated with warfarin dose , 2005, The Pharmacogenomics Journal.

[65]  Liya Yan,et al.  Effect of apolipoprotein E genotype on vitamin K status in healthy older adults from China and the UK , 2005, British Journal of Nutrition.

[66]  D. McGee,et al.  Quantitation of vitamin K in human milk , 1990, Lipids.

[67]  Guoying Tai,et al.  The pharmocogenomics of warfarin: closing in on personalized medicine. , 2006, Molecular interventions.

[68]  H. Halkin,et al.  Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin , 2006, Thrombosis and Haemostasis.

[69]  M. Shearer,et al.  Menadione is a metabolite of oral vitamin K , 2006, British Journal of Nutrition.

[70]  Yibo Wang,et al.  VKORC1 Haplotypes Are Associated With Arterial Vascular Diseases (Stroke, Coronary Heart Disease, and Aortic Dissection) , 2006, Circulation.

[71]  F. Kamali,et al.  APOE genotype makes a small contribution to warfarin dose requirements. , 2006, Pharmacogenetics and genomics.

[72]  Lisa M. Miller,et al.  Subclinical vitamin K deficiency in hemodialysis patients. , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[73]  S. Sasaki,et al.  Vitamin K content of foods and dietary vitamin K intake in Japanese young women. , 2007, Journal of nutritional science and vitaminology.

[74]  J. Tripp,et al.  Neonatal vitamin K prophylaxis in Great Britain and Ireland: the impact of perceived risk and product licensing on effectiveness , 2007, Archives of Disease in Childhood.

[75]  L. Schurgers,et al.  Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. , 2007, Blood.

[76]  M. Shearer,et al.  Excretion of the urinary 5C- and 7C-aglycone metabolites of vitamin K by young adults responds to changes in dietary phylloquinone and dihydrophylloquinone intakes. , 2007, The Journal of nutrition.

[77]  G. Williamson,et al.  Nutrients and phytochemicals: from bioavailability to bioefficacy beyond antioxidants. , 2008, Current opinion in biotechnology.

[78]  J. Oldenburg,et al.  The vitamin K cycle. , 2008, Vitamins and hormones.

[79]  D. Stafford,et al.  Structure and function of vitamin K epoxide reductase. , 2008, Vitamins and hormones.

[80]  W. Coward,et al.  A stable isotope method for the simultaneous measurement of vitamin K1 (phylloquinone) kinetics and absorption , 2008, European Journal of Clinical Nutrition.

[81]  M. Irving,et al.  Chondrodysplasia punctata: a clinical diagnostic and radiological review , 2008, Clinical dysmorphology.

[82]  MaaikeKockx,et al.  Regulation of Endogenous Apolipoprotein E Secretion by Macrophages , 2008 .

[83]  M. Shearer,et al.  Metabolism and cell biology of vitamin K , 2008, Thrombosis and Haemostasis.

[84]  C. Thorn,et al.  Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans , 2008, The Pharmacogenomics Journal.

[85]  A. Schilling,et al.  Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function. , 2008, Bone.

[86]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[87]  S. Booth,et al.  Determinants of vitamin K status in humans. , 2008, Vitamins and hormones.

[88]  M. Shearer,et al.  Prevalence of subclinical vitamin K deficiency in Thai newborns: relationship to maternal phylloquinone intakes and delivery risk , 2009, Archives of Disease in Childhood: Fetal and Neonatal Edition.

[89]  S. Booth Roles for vitamin K beyond coagulation. , 2009, Annual review of nutrition.

[90]  C. Prynne,et al.  The effect of different meals on the absorption of stable isotope-labelled phylloquinone , 2009, British Journal of Nutrition.

[91]  M. Rieder,et al.  CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant , 2009, Molecular Pharmacology.

[92]  M. Shearer Vitamin K deficiency bleeding (VKDB) in early infancy. , 2009, Blood reviews.

[93]  P. Tso,et al.  Intestinal Fatty acid Absorption , 2009 .

[94]  S. Booth,et al.  Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylase genes with biochemical measures of vitamin K status. , 2009, Journal of nutritional science and vitaminology.

[95]  R. D'Agostino,et al.  Genetic and non-genetic correlates of vitamins K and D , 2009, European Journal of Clinical Nutrition.

[96]  Xueyan Fu,et al.  Measurement of deuterium-labeled phylloquinone in plasma by high-performance liquid chromatography/mass spectrometry. , 2009, Analytical chemistry.

[97]  K. Nakagawa,et al.  Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme , 2010, Nature.

[98]  P. Clarke,et al.  Urinary Excretion of Vitamin K Metabolites in Term and Preterm Infants: Relationship to Vitamin K Status and Prophylaxis , 2010, Pediatric Research.

[99]  R. Landewé,et al.  Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species , 2010, Thrombosis and Haemostasis.

[100]  D. Baer,et al.  Vitamin K absorption and kinetics in human subjects after consumption of 13C-labelled phylloquinone from kale , 2010, British Journal of Nutrition.

[101]  P. Clarke Vitamin K prophylaxis for preterm infants. , 2010, Early human development.

[102]  E. Strehle,et al.  Evaluation of the acceptability of a new oral vitamin K prophylaxis for breastfed infants , 2010, Acta paediatrica.

[103]  L. Pedersen,et al.  A hetero-dimer model for concerted action of vitamin K carboxylase and vitamin K reductase in vitamin K cycle. , 2011, Journal of theoretical biology.

[104]  M. Morris,et al.  A potential design flaw of randomized trials of vitamin supplements. , 2011, JAMA.

[105]  M. Ijland,et al.  Intracranial bleeding due to vitamin K deficiency: advantages of using a pediatric intensive care registry , 2011, Intensive Care Medicine.

[106]  Lamiaa N. Hammad,et al.  Genetic and nongenetic factors associated with warfarin doserequirements in Egyptian patients , 2011, Pharmacogenetics and genomics.

[107]  Robert M. Russell,et al.  Dietary Reference Intakes for Vitamin A , Vitamin K , Arsenic , Boron , Chromium , Copper , Iodine , Iron , Manganese , Molybdenum , Nickel , Silver , Vanadium , and Zinc , 2022 .