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There are no studies that have examined nondietary sources of variability in response to MK intake.
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Shea et al. However, to date, there are few studies that have systematically explored the associations between individual genetic polymorphisms and biochemical measures of vitamin K status. ApoE occurs as 3 isoforms apoE2, E3, and E4 that differ by single amino acid substitutions at positions and Genetic variations in APOE are to known to influence lipoprotein transport and cellular uptake both in vivo and in vitro.
Associations with APOE genotype have been reported for endogenous phylloquinone concentrations and the functional marker percent ucOC, but the results lack consensus. This would be the order predicted if fasting phylloquinone was solely dependent on the rate of clearance of intestinally derived TRL.
A later study in a much larger population of hemodialysis patients did not show any dependence of fasting phylloquinone concentrations on APOE phenotypes, although patients with an APOE4 allele had a significantly higher circulating percent ucOC, suggesting a lower vitamin K status of bone Studies to find out whether APOE -vitamin K relationships exist in healthy populations have also proved contradictory.
In a study of healthy older adults living in the UK or China, Yan et al. Opposite findings to the UK-Chinese study 49 were recently reported in a U. Based on relationships of fasting phylloquinone to APOE genotype in hemodialysis patients, Kohlmeier et al. This suggested that the liver and bone might compete for available amounts of circulating vitamin K carried by lipoproteins. The original postulate 39 , 47 was that if the APOE4 allele promoted faster hepatic uptake of TRL-vitamin K, there might be a sparing effect on the delivery and therefore availability of vitamin K to bone, with opposite effects for the APOE2 allele.
At the cellular level, there is in vitro evidence that apoE4 is the most effective isoform in stimulating [ 3 H]-phylloquinone-labeled TRL uptake into osteoblasts 33 and the defective binding of apoE2 to LDLR is well described 51 , The hypothesis that the APOE4 genotype accelerates the hepatic uptake of phylloquinone was based on 2 assumptions, first that retinyl esters are markers of intestinally derived TRL and second that fasting concentrations of phylloquinone reflect only the rate of clearance of intestinally derived TRL.
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Both these assumptions are open to question. The specificity of the vitamin A fat-loading test for measuring clearance of intestinally derived TRL 44 has been questioned, because as postprandial lipemia progresses, increasing proportions of retinyl esters are carried by LDL Furthermore, when apoB and apoB were employed as more specific markers of intestinally and hepatically derived TRL, respectively Figs. Several investigators have also sought to find out whether APOE polymorphisms affected the dose requirements of vitamin K antagonists.
The main working hypothesis was that if the APOE4 allele enhanced hepatic uptake of vitamin K 39 , 47 , the warfarin dose would be expected to be higher for APOE4 carriers than for other genotypes.
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The results have been mixed and often population dependent. For the APOE4 allele, some studies have shown the expected increased warfarin dose requirement 54 , 55 , but other studies have shown a lower requirement 56 , For the APOE2 allele, a lower warfarin dose requirement has been reported Usually, the contribution of APOE genotype to warfarin dose requirements is small. In summary, the results of the effect of APOE genotype on vitamin K metabolism suggest that the hypothesis of apoE-dependent mechanisms that lead to liver and bone competing with each other for available circulating vitamin K is too simplistic.
Of note is the conflicting evidence that individuals with the APOE4 allele either had the lowest 47 or highest 49 phylloquinone concentrations. Another interpretative problem is that the effect of the APOE4 allele on the clearance of intestinally derived TRL is itself contradictory, being either accelerated 44 or delayed 53 according to how this is measured. Although larger population studies may help to clarify any genetic influences of apoE on vitamin K metabolism, detailed studies measuring the clearance of TRL-bound phylloquinone in the same way as has been carried out for vitamin A are also warranted.
A potential complication to any consideration of the relationship of vitamin K metabolism to human requirements is a pathway by which phylloquinone can be converted in the body to MK Although the existence of this pathway has been known since the s, the biochemistry of this transformation has remained elusive. It was previously shown that this conversion of phylloquinone to MK-4 could occur in germ-free rats; this together with the human findings of the dependence on the oral route and the rapid appearance of menadione in the urine pointed to the possibility that the release of menadione may have occurred during intestinal absorption within the enterocyte If this is true, it would obviously have implications to our current understanding of the human requirements for phylloquinone, which hitherto have always been considered independently of the possibility of its conversion to MK The same is true for MK such as MK-7, which was also shown to release urinary menadione The vitamin K-epoxide cycle is pivotal to both the function of vitamin K and to the conservation of the microsomal cellular stores of vitamin K.
Evidence suggests that both these enzymes are part of a concerted mechanism for the efficient oxidation and reduction of membrane-bound vitamin K Several common polymorphisms have been reported within the VKORC1 gene and have been attributed to the inter-individual variability in warfarin dose Similarly, the GGCX gene exhibits common polymorphisms that have been linked to variability in warfarin dose, although the data are less consistent compared to VKORC1 68 — However, there were no detectable genotype effects on the response to 3 y of phylloquinone supplementation.
This may have been in part a consequence of the overall health of the study participants and, hence, lack of phenotypic responses, a common phenomenon in randomized clinical trials Humans excrete phylloquinone and MK by a common degradative pathway whereby the polyisoprenoid side chain is first shortened to 2 major carboxylic acid metabolites with 7- and 5-carbon side chains, respectively; the metabolites are then conjugated, mainly with glucuronic acid, and excreted in the bile and urine 75 , Recently, searches for genetic polymorphisms of cytochrome P that might influence warfarin dosage led to the discovery of a DNA variant rs; VM of cytochrome P 4F2 CYP4F2 that caused an increase in warfarin dose requirements in a European-American cohort of patients The significance of the VM polymorphism was shown by findings that human liver microsomes obtained from carriers of this variant had a reduced ability to oxidize phylloquinone and lower protein concentrations of CYP4F2 The reason why carriers of the CYP4F2 VM allele required higher doses of warfarin could therefore be explained by invoking their lower capacity to metabolize vitamin K, leading to presumed higher hepatic concentrations.
Although there is as yet no direct proof, one predictive outcome relevant to the setting of human requirements is that carriers of this VM variant should require lower dietary intakes of vitamin K compared to noncarriers to maintain an equivalent vitamin K status. One notable feature of vitamin K metabolism compared to other fat-soluble vitamins is that the most abundant dietary form, phylloquinone is poorly retained in the body.
The recent development of methods for measuring endogenous concentrations of these urinary metabolites has enabled their measurement in h collections in response to varying intakes of phylloquinone diets in a dietary controlled residential environment A potential advantage of measuring urinary excretion is that the catabolic pathway is common to all K vitamins so that the excretion of the 2 terminal metabolites represents turnover and losses of the total body pool of vitamin K As such, it represents a global biomarker of vitamin K metabolism with the caveat that a larger proportion of dietary vitamin K is excreted in the bile Despite the many efforts in recent years to demonstrate the disease-preventing roles of the plethora of Gla proteins that are present in the human body, the only disease outcome of clinical concern that can be shown to specifically relate to a nutritional deficiency of vitamin K in otherwise healthy individuals occurs during early infancy.
This is a bleeding disorder previously known as hemorrhagic disease of the newborn and now renamed VKDB Perhaps to this definition of a condition being caused by an acute deficiency should be added the rare but now fairly well-characterized cases of severe vitamin K maternal deficiency during pregnancy that result in infants being born with a condition known as chondrodysplasia punctata 81 , Less clear is the relationship of vitamin K status with chronic diseases such as osteoporosis and cardiovascular disease for which vitamin K research has centered on the possible health roles of osteocalcin and MGP, respectively More recently, there has been interest in the possible role of osteocalcin and vitamin K status in glucose homeostasis There is a narrow window from birth to 6 mo of life when the human infant is exposed to a small but potentially life-threatening risk of bleeding In late onset VKDB, with a peak incidence between 3 and 8 wk, infants typically present with intracranial bleeding, which may result in death or permanent neurological damage.
The major nutritional risk is to those infants who are exclusively breastfed. Greer et al. When expressed per kilogram body weight, the average daily intakes at 6 and 12 wk were 9. While the generally low, weight-adjusted intakes of phylloquinone in breast-fed infants account for the much higher prevalence of VKDB in breast-fed infants as a group, knowledge of the precipitating factors that trigger VKDB in an individual infant are less well understood. In some infants, underlying pathologies that cause cholestasis with resultant malabsorption of vitamin K may be identified, but in a substantial proportion no predisposing factor is found This is most accurately exemplified by comparing the incidence of VKDB between countries that have published data from nationally representative surveillance programs such as those carried out in the UK, The Netherlands, Germany, Switzerland, Australia, New Zealand, and Japan Care needs to be taken in comparing incidence data because of the different methodologies and case definitions.
The AI for infants aged 0—6 mo is based on an average daily intake of milk of 0. This gives an AI of 2. The weak link in this calculation as a precise AI value lies with the fairly wide variations in the reported concentrations of phylloquinone in breast milk, for which the largest component contributing to variability is likely to be caused by methodological differences rather than to differences between the populations studied.
Thus, the data used for this calculation 1 included 4 individual studies from 2 groups in the US, one of which reported average concentrations in mature breast milk that ranged from 0. Notably, the nonoverlapping, quite tight range of average values for mature milk reported by each laboratory were obtained over 4 similar time points taken over 6 mo. It is generally agreed that the vitamin K coagulation status of the healthy newborn infant is brittle. This conclusion is based on both tissue analyses of K vitamins and on sensitive functional assays such as PIVKA-II that can detect undercarboxylated species of factor II well before there are any changes in global coagulation assays such as the prothrombin time.
Whereas detectable concentrations of PIVKA-II are rarely detected in healthy adults, elevated concentrations are fairly common in the cord blood of healthy newborns. In the same Thai study, infants categorized as high risk according to birth weight and delivery type had a higher median detectable PIVKA-II concentration than infants categorized as normal risk as well as a higher prevalence of PIVKA-II concentrations considered to be clinically relevant Analysis of dietary intakes of vitamin K in a subgroup of mothers showed that those Thai mothers who had phylloquinone intakes below the US.
In the largest study 88 , the median hepatic concentration of phylloquinone in infants at term was 2. This slow buildup of hepatic MK would be consistent with the colonization of the neonatal gut by MK-producing bacteria, although some dietary contribution cannot be ruled out.
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The implication that low hepatic reserves of MK may be a major contributory factor to the brittleness of neonatal vitamin K status is enticing but presently lacks hard evidence. The American Academy of Pediatrics has recommended the parenteral administration of the natural plant form phylloquinone for the prevention of VKDB since Before , the only vitamin K compounds available for vitamin K prophylaxis had been water-soluble derivatives of menadione that in large doses or in certain hereditary conditions were shown to be associated with hemolytic anemia, hyperbilirubinemia, and kernicterus No such toxicity was found for the naturally occurring phylloquinone.
The routine application of vitamin K prophylaxis to all newborns has had a checkered history in some countries more than others that includes the problem with toxicity of menadione derivatives, ignorance of the incidence of VKDB leading to beliefs that prophylaxis was unnecessary, and a subsequently unsubstantiated concern of an association between intramuscular phylloquinone prophylaxis and later childhood cancer In the last 20 y, and especially with incidence data gathered from active surveillance of VKDB, there has been a growing consensus that vitamin K prophylaxis is required for all newborn infants.
This consensus cuts across both developed and developing countries and has been reinforced by the conclusions of expert committees However, there still remains a lack of consensus of the most effective dose regimen that would protect almost all infants from VKDB. It is generally agreed that the i. The i. In other countries such as Germany and The Netherlands, oral regimes are more popular. In the UK, the choice of prophylactic regime is made locally and has been described as chaotic Another potential concern of some prophylactic regimens, which particularly applies to preterm infants, is the markedly supraphysiological tissue concentrations that for serum can be several fold higher than normal A recent study provided evidence that the combination of a raised serum vitamin K epoxide concentration with an increased proportional excretion of the 7-carbon side chain urinary metabolite may together indicate a metabolic overload of both vitamin K recycling and catabolic pathways This is an example of how specific measurements of vitamin K metabolites might help to set optimal dosage guidelines for the prevention of VKDB.
As reviewed elsewhere in this volume, vitamin K is an emerging factor in the regulation of calcification in multiple tissues, including vessel walls and cartilage 31 , and the recent identification of a new enzyme UBIAD1 involved in vitamin K metabolism provides evidence for potential novel physiological roles for vitamin K Despite these exciting developments, the gaps in knowledge regarding vitamin K metabolism and function impede the ability to establish optimal dietary recommendations for vitamin K. To establish dietary requirements for vitamin K, it is essential to have a biomarker or clinical endpoint that reflects the consequence of vitamin K adequacy.
When compared globally, dietary recommendations for vitamin K have a 2-fold range among adults Table 1. This range reflects the lack of consensus on a suitable endpoint or biomarker of adequacy from which to base recommendations. The Dietary Reference Intakes for vitamin K in adults 1. The best understood role of vitamin K is as an enzyme cofactor.
Coagulation proteins are the best characterized Gla proteins, and although a hemorrhagic event is the classical sign of vitamin K deficiency, frank vitamin K deficiency is extremely rare in the adult population 1. Furthermore, measurements of coagulation are insensitive measures of vitamin K status and have limited value in establishing dietary recommendations Despite this, the first attempts at establishing dietary requirements were based on the amount of vitamin K that was required to restore abnormal coagulation in hospitalized elderly male patients This gave rise to an initial estimate of 0.
In the last 2 decades, there has been growing interest in Gla proteins in bone, specifically osteocalcin. There has been much controversy regarding the role of vitamin K in bone health, because dietary intakes of vitamin K, and concomitant changes in biomarkers of vitamin K status, are indicative of a healthy diet and lifestyle Observational studies that report associations between vitamin K and bone health have been unable to isolate the effect of vitamin K from that of a healthy diet , Critical evaluation of the randomized clinical trials, as reviewed elsewhere in this volume, does not support the use of bone outcomes, including percent ucOC, as a physiological measure from which to derive vitamin K dietary requirements.
It is now emerging that vitamin K and vitamin K-dependent proteins have potential physiological roles beyond coagulation and bone metabolism Putative regulatory roles include: calcification processes in multiple tissues 31 , key enzymes involved in sphingolipid metabolism , energy metabolism and inflammation 31 , and the prevention of oxidative injury in vivo However, these potential roles for vitamin K require confirmation in controlled dose-response trials, with validation of suitable biomarkers or clinical endpoints in order to determine vitamin K requirements for optimal health.
The importance of MK to adequacy is unknown and has not been considered to date in forming dietary recommendations. The extent to which endogenous MK production contributes to the daily requirement for vitamin K is not known 17 , A decade after the US Food and Nutrition Board 1 considered vitamin K requirements, it is reasonable to ask to what extent our knowledge of nutritional concepts and metabolism of vitamin K has advanced.
At that time, there had been no stable isotope studies of vitamin K and our knowledge of bioavailability was poor. Since then, there have been a number of studies in which stable isotope methodologies have been applied to the assessment of the bioavailability of phylloquinone in its free state and, more importantly, when incorporated into a plant matrix. This is still a difficult area for research because of the low tissue concentrations and the variety of molecular forms. There is a clear need for stable isotope techniques with enhanced sensitivity to be able to answer the many outstanding questions.
A good illustration of the limitations of using unlabeled K vitamins is in lipoprotein transport and cellular uptake, because it is not possible to differentiate between the vitamer originating from the administration of the original dose from the stores already in the body and at later times new intakes from food sources. Suggested function from deprivation effects or active metabolic handling, but no clearly-identified biochemical function in humans.
Limited circumstantial evidence for trace benefits or biological action in mammals. No evidence for biological action in mammals, but essential in some lower organisms.
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In the case of lanthanum, the definition of an essential nutrient as being indispensable and irreplaceable is not completely applicable due to the extreme similarity of the lanthanides. The early lanthanides up to Sm are known to stimulate the growth of various lanthanide-using organisms. Food portal. Zoroddu; J. Aashet; G. Crisponi; S. Medici; M. Peana; V. Nurchi June Journal of Inorganic Biochemistry. Handbook of Nutrition and Food 3rd ed.
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Effect of Bioactive Nutriments in Health and Disease: The Role of Epigenetic Modifications
European Food Safety Authority. September 18, Retrieved March 20, Angewandte Chemie International Edition. Retrieved 15 June Food and Drug Administration Food Sources of Potassium". United States Department of Agriculture. The American Journal of Clinical Nutrition. Retrieved November 8, Amsterdam: Elsevier Science Pub Co. Retrieved National Institutes of Health. Williams' Essentials of Nutrition and Diet Therapy. Elsevier Health Sciences. Retrieved 15 July Larry; De Groot, Leslie J.
Endocrinology: Adult and Pediatric. Retrieved 14 July Human Nutrition. Retrieved 10 July Advanced Nutrition and Human Metabolism. Cengage Learning. Nutr Clin Pract.
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