Compounds with vitamin K activity all have a common. Vitamin K in Parenteral Nutrition. Metabolic Function

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1 GASTROENTEROLOGY 2009;137:S105 S118 Vitamin K in Parenteral Nutrition MARTIN J. SHEARER Centre for Haemostasis and Thrombosis, St Thomas Hospital, London, United Kingdom Vitamin K (as phylloquinone and menaquinones) is an essential cofactor for the conversion of peptidebound glutamate to -carboxy glutamic acid (Gla) residues in a number of specialized Gla-containing proteins. The only unequivocal deficiency outcome is a bleeding syndrome caused by an inability to synthesize active coagulation factors II, VII, IX, and X, although there is growing evidence for roles for vitamin K in bone and vascular health. An adult daily intake of about 100 g of phylloquinone is recommended for the maintenance of hemostasis. Traditional coagulation tests for assessing vitamin K status are nonspecific and insensitive. Better tests include measurements of circulating vitamin K and inactive proteins such as undercarboxylated forms of factor II and osteocalcin to assess tissue and functional status, respectively. Common risk factors for vitamin K deficiency in the hospitalized patient include inadequate dietary intakes, malabsorption syndromes (especially owing to cholestatic liver disease), antibiotic therapy, and renal insufficiency. Pregnant women and their newborns present a special risk category because of poor placental transport and low concentrations of vitamin K in breast milk. Since 2000, the Food and Drug Administration has mandated that adult parenteral preparations should provide a supplemental amount of 150 g phylloquinone per day in addition to that present naturally, in variable amounts, in the lipid emulsion. Although this supplemental daily amount is probably beneficial in preventing vitamin K deficiency, it may be excessive for patients taking vitamin K antagonists, such as warfarin, and jeopardize their anticoagulant control. Natural forms of vitamin K have no proven toxicity. Compounds with vitamin K activity all have a common 2-methyl-1, 4-naphthoquinone ring structure (trivial name menadione) with those found in nature having a variable alkyl substituent at the 3 position. Naturally occurring forms are classified according to whether they are synthesized by plants or bacteria. Plants, almost invariably, synthesize only 1 chemical form called phylloquinone (vitamin K 1 ), whereas bacteria synthesize a plethora of isoprenologues called menaquinones (vitamins K 2 ). 1 3 These differ from phylloquinone in that the alkyl side chain comprises, for the most part, a polymer of repeating unsaturated prenyl units rather than the phytyl side chain of phylloquinone, which has only 1 unsaturated bond. Most menaquinones that contribute to human requirements have 4 12 prenyl units (abbreviated MK-4 to MK-12). 3 Menadione itself only possesses biological activity because of the ability of animals to add on a geranylgeranyl side chain to produce MK-4. In most countries, patients are treated with pharmaceutical preparations of phylloquinone, also known as phytomenadione (Europe) or phytonadione (United States). Metabolic Function Until the mid 1970s, the only known role of vitamin K was as an essential antihemorrhagic factor, which was known to promote synthesis of the active forms of prothrombin (factor II), and factors VII, IX, and X. 1 Collectively, these 4 proteins, all synthesized in the liver and then released into the circulation, are known as the classical vitamin K-dependent coagulation proteins. At that time, clinical interest in vitamin K had been restricted to its value in the prevention of coagulopathy induced by vitamin K deficiency often found in malabsorption states, its prophylactic role for the prevention of vitamin K-deficiency bleeding (VKDB) in early infancy, and for its role in the management of patients treated with oral anticoagulant drugs, such as warfarin. In 1974, comparative studies between the normal prothrombin and the abnormal prothrombin molecule present in blood of warfarin-treated animals showed that normal prothrombin contained a hitherto unknown modification in which peptide-bound glutamate residues had been transformed into -carboxy glutamic acid (Gla). 4 This soon led to the discovery that vitamin K acted as an essential cofactor for a hepatic microsomal enzyme, vitamin K-dependent -carboxylase that as predicted acted not only on prothrombin (factor II), but factors VII, IX, Abbreviations used in this paper: AI, adequate intake; ALF, acute liver failure; BMC, bone mineral content; BMD, bone mineral density; Gla, -carboxy glutamic acid; GluOC, undercarboxylated osteocalcin; INR, international normalized ratio; MGP, matrix Gla protein; MK, menaquinone; PIVKA, proteins induced by vitamin K absence or antagonism; PN, parenteral nutrition; PT, prothrombin time; VKDB, vitamin K-deficiency bleeding by the AGA Institute /09/$36.00 doi: /j.gastro

2 S106 MARTIN J. SHEARER GASTROENTEROLOGY Vol. 137, No. 5 and X as well. 4 With this mechanistic knowledge, new vitamin K-dependent proteins (now known as Gla proteins) were discovered. Within the coagulation milieu, newly isolated proteins with Gla domains were proteins C and S that are now known to play a feedback anticoagulant role in hemostasis by reducing thrombin generation and procoagulant activity. 5 The subsequent discovery of several other Gla proteins that are expressed in virtually every tissue of the body has led to a reevaluation of the health role of vitamin K. 6,7 The nomenclature, site of synthesis and putative roles of these Gla proteins are shown in Table 1; they include the protein periostin, which was already known to have a key role in several physiologic and pathologic processes, but was only discovered to be a Gla protein in 2008 by proteomic analysis of the secretome of bone marrowderived mesenchymal stromal cells. 8 Apart from the coagulation proteins, the precise physiologic function of many of these newly discovered Gla proteins is poorly understood, as are the consequences of vitamin K deficiency. One exception is matrix Gla protein (MGP) which, through a variety of techniques that included gene deletion and in vivo mutagenesis in mice, was found to be a central inhibitor and regulator of calcification in cartilage and arteries; Gla residues were essential for the antimineralization function. 9,10 In humans, an embryonic skeletal condition known as chondrodysplasia punctata and characterized by abnormal calcification of cartilage has been linked with both MGP malfunction and vitamin K deficiency. 11 This is evidenced by the association of chondrodysplasia punctata with mutations of MGP or vitamin K epoxide reducatase, or to the use of oral anticoagulants or dietary vitamin K deficiency in pregnancy. This illustrates the functional necessity of Gla residues within MGP. The possible requirement of vitamin K to promote optimal bone health remains a subject of ongoing study, and originally stemmed from the discovery that osteocalcin was an important noncollagenous protein in skeletal extracellular matrix. Osteocalcin has 3 Gla residues that have been highly conserved throughout vertebrate evolution. This is probably because their location and spatial orientation are exquisitely suited to high-affinity binding to bone hydroxyapatite, 12 a property diminished by either vitamin K deficiency or oral anticoagulants. Although the precise physiologic role remains unclear, current evidence suggests that osteocalcin plays a role in bone remodelling and mineralization. 13 Very recently, an unexpected role for osteocalcin as a hormone that regulates glucose metabolism and fat mass was proposed, but even more surprising was the suggestion that hormonal activity seemed to be associated with undercarboxylated rather than carboxylated osteocalcin. 14 In addition to their well-known function as cofactors for -glutamyl carboxylase, there is a growing body of evidence, recently reviewed, 15 that members of the vitamin K family have direct effects on cellular functions. Much of this evidence concerns the specific molecular form, MK-4, which is also unusual, for it can be synthesized in humans from menadione and phylloquinone. 15 MK-4 seems to elicit a number of diverse functions in a variety of cell types and modulates the expression patterns of several genes, investigated primarily in bone. 15 Other reported non co-factor roles for vitamin K include suppression of inflammation, Table 1. Diversity and Roles of Vitamin K-Dependent (Gla) Proteins Gla protein Tissue Role Factors II, VII, IX, and X Liver (then blood plasma) Blood coagulation (procoagulants). Protein C Liver (then blood plasma) Blood coagulation (anticoagulant). Activated protein C inhibits inflammation, apoptosis, and endothelial barrier breakdown (protective effect in sepsis). Protein S Liver (then blood plasma) Extrahepatic tissues (brain, spleen, bone, endothelial cells, etc.) Cofactor for protein C (anticoagulant). Ligand and activator of TAM (Tyro3, Axl, Mer) tyrosine kinase receptors. Regulatory role in immune response and phagocytosis. Protein Z Liver (then blood plasma) Protein Z may play a cofactor role in down-regulation of coagulation. Osteocalcin (bone Gla protein) Bone and dentin Bone remodelling and mineralization. New role proposed as hormone that regulates glucose metabolism and fat mass. Matrix Gla protein Most tissues (especially bone and vessel wall) Powerful inhibitor of calcification (cartilage and arteries). Periostin Bone marrow mesenchymal stromal cells Implicated in bone development and in maintenance and repair of bone and heart. Gas6 Most tissues Ligand and activator of TAM (Tyro3, Axl, Mer) tyrosine kinase receptors. Promotion and regulation of cell survival and proliferation, cell migration, cell cell adhesion, platelet signaling, immune response. Regulatory role in phagocytosis. Proline-rich Gla proteins Most tissues (transmembrane proteins) Unknown (?cell-surface receptors).

3 November Supplement 2009 VITAMIN K IN PN S107 prevention of oxidative brain damage, and a role in sphingolipid synthesis. 15 Assessment of Vitamin K Deficiency Coagulation Tests Traditional screening tests for vitamin K deficiency are based on global coagulation assays that include the prothrombin time (PT) and the activated partial thromboplastin time. These tests are simple to perform, but a prolonged PT is not specific to vitamin K deficiency. The most useful confirmatory test is restoration of a normal PT (and individual factors) by vitamin K administration. Inherent to the PT is its insensitivity to vitamin K deficiency; it can predict an imminent bleeding tendency, but is not useful for the diagnosis of subclinical deficiency. 16 Serum Vitamin K Concentrations The major dietary and circulating form of vitamin K is phylloquinone, and measurement of this form in serum is a useful indicator of vitamin K. The majority of circulating phylloquinone is carried by triglyceride-rich lipoproteins, 15 and therefore the measurement of triglyceride-rich lipoprotein borne phylloquinone reflects recent dietary intake and ideally should be determined in fasting individuals. Fasting phylloquinone reference values in healthy adults range from 0.15 to 1.0 g/l (median 0.5 g/l). The common hepatic forms of longchain menaquinones (MKs 9 13) have not been detected in plasma, although MK-7 may be detectable. Well-controlled metabolic studies have shown the fasting phylloquinone concentration reflects both dietary depletion and repletion. 17 Infants are born with undetectable cord blood phylloquinone ( 0.05 g/l), but thereafter, until weaning, their circulating concentrations are usually lower or higher than in adults, depending on whether they are predominately breast fed or formula fed, respectively. 18 There are several studies that describe a high prevalence of low phylloquinone concentrations in hospitalized patients (see the section on vitamin K status of hospitalized patients). Undercarboxylated Serum Vitamin K-Dependent Proteins When the supply of vitamin K is either insufficient or abnormal, functionally defective vitamin K- dependent protein molecules are produced at their site of synthesis and in some species, including humans, are released into the bloodstream. These abnormal molecules comprise a heterogeneous spectrum of undercarboxylated or partially carboxylated molecules. The historical collective term for these undercarboxylated species is Proteins Induced by Vitamin KAbsence or Antagonism (PIVKA). Methods now exist to measure undercarboxylated proteins or peptides for Gla proteins, synthesized and released by the liver (factor II), bone (osteocalcin), and vasculature (MGP). Potentially, these assays are true functional biomarkers of the -carboxylation status of individual Gla proteins. Because the synthesis of many Gla proteins is tissue specific, PIVKA assays also offer a method for the determination of local vitamin K status. 6 Assays for undercarboxylated factor II (PIVKA-II) have proved an extremely useful biomarker of subclinical vitamin K deficiency for at-risk patient groups, 16 including infants 22 and patients with malabsorption. 23 The most sensitive assays are enzyme immunoassays that use antibodies to recognize PIVKA-II, but do not cross-react with native factor II. 24,25 The measurement of undercarboxylated osteocalcin (GluOC) is also widely used as a surrogate marker of the vitamin K reserves of bone. 6 Its advantages include the fact that osteocalcin is expressed only by osteoblasts (and odontoblasts); it has been well studied as a marker of bone formation. Its disadvantages include the variability of different assay methodologies and the fact that serum osteocalcin concentration, including the GluOC fraction and various fragments, also reflect bone turnover. 6 For this reason, GluOC concentration is usually expressed as a percentage of total osteocalcin. Miscellaneous Vitamin K Status Indicators Other biomarkers that have been used to assess vitamin K status include urinary measurements of free Gla and vitamin K metabolites, which reflect whole body turnover of Gla proteins and vitamin K, respectively. Urinary Gla represents the final catabolic product of all Gla-containing proteins and is diminished in states of vitamin K insufficiency. 26 The rationale for measuring vitamin K metabolite excretion is that the side chains of phylloquinone and menaquinones are catabolized via a common degradative pathway so that measurement of the 2 major urinary metabolites reflects turnover and excretion of all K vitamins. 27 It was recently shown that urinary vitamin K excretion responds to both vitamin K depletion and repletion. 28 Practical Assessment of Vitamin K Status In our hospital, we find the most practical way to assess vitamin K status in most patient groups is to measure both serum phylloquinone and PIVKA-II, combining the marker of tissue reserves with the functional marker of coagulation, respectively. We use a sensitive immunoassay for PIVKA-II that has a lower threshold of detection of 200 g/l, and that represents only 0.2% of total circulating native factor II. 25 This threshold is well below the reduction of approximately 50% in circulating concentration of active total factor II that is needed to trigger a detectable change in the PT. 16 The finding of a low serum phylloquinone ( 0.15 g/l) alone often serves as a warning of low tissue stores. The combination

4 S108 MARTIN J. SHEARER GASTROENTEROLOGY Vol. 137, No. 5 of low serum phylloquinone combined with an elevated PIVKA-II usually indicates a subclinical vitamin K-deficient state that can be confirmed by the disappearance of PIVKA-II when vitamin K supplementation is initiated. The half-life of PIVKA-II is similar to native factor II ( 60 hours) so that PIVKA-II may remain detectable for several days after correction of vitamin K deficiency. This slow clearance is often useful in the retrospective diagnosis of vitamin K deficiency after vitamin K has already been administered. It is important to recognize, however, that PIVKA-II is occasionally elevated in some liver disorders, although high serum concentrations are usually only found in hepatocellular carcinoma. 29 Dietary Intakes in Healthy Populations The major form of vitamin K in most diets is phylloquinone from plant sources. Food frequency questionnaire derived estimates of relative intakes of phylloquinone and menaquinones in The Netherlands suggest that about 90% of total vitamin K intakes are provided by phylloquinone, 7.5% by MK-5 10, and 2.5% by MK In Europe and the United States, at least half of total phylloquinone intakes come from vegetables and vegetable products, of which one quarter to one third comprises green leafy vegetables With the exception of animal livers, the most common dietary sources of long-chain MKs are fermented foods, such as cheeses and natto. 34,35 National surveys reveal considerable variations in phylloquinone intakes within the same population In 2 UK surveys of older 32 and younger people, 33 there was an approximate 10-fold difference between the lower 5th and the upper 95th percentiles, although the arithmetic means were similar at approximately 80 g/day. Average intakes in the United States are comparable, but with a trend toward higher intakes in older adults. 31 Vitamin K Body Stores Conventional dogma is that the liver, the site of Gla coagulation factor synthesis, is also the major storage site of vitamin K, but it is now known that other organs have some storage capacity, that for phylloquinone and MK-4 probably exceed the size of their hepatic pools. 15 The median liver storage pool of phylloquinone in adults is of the order of 20 nmol (9 g), but varies widely. 15 A high turnover rate of phylloquinone is suggested by isotopic studies showing that 60% 70% of an oral dose of phylloquinone is lost to the body by excretion within a few days. 34 The liver is unusual compared with other tissues because it contains a much larger pool of menaquinones, mostly long-chain forms, which together account for some nmol, which represents about 90% of total liver vitamin K stores. 15 There is evidence that hepatic menaquinones have a very slow metabolic turnover and therefore would be expected to provide a buffer against vitamin K deficiency when the more labile phylloquinone stores are depleted. 15 However, the extent to which hepatic menaquinones are metabolically available for coagulation synthesis is controversial, 3,36 especially because low intakes of phylloquinone alone are sufficient to induce significant increases in PIVKA-II in healthy subjects within 15 days. 3,15,17 This storage pool of long-chain menaquinones is unique to the liver. 15 However, some extrahepatic tissues, such as brain, kidney, and pancreas, possess unusually high concentrations of MK-4 that are thought to be derived by endogenous synthesis from phylloquinone. 15 Vitamin K Requirements Requirements for Coagulation Function Older recommendations of the daily requirements for vitamin K were based on limited metabolic studies in a few individuals in whom a coagulopathy had been deliberately induced by dietary depletion, usually accompanied by antibiotic therapy in an attempt to reduce intestinal synthesis of menaquinones. 16,37 Such studies were hampered by lack of sensitivity of coagulation assays as a measure of vitamin K sufficiency, but suggested that a conservative estimate of the curative dose of phylloquinone required to maintain coagulation factor synthesis in depleted individuals was of the order of 1 g/kg body weight per day, 16 and very likely significantly below this level. 38 The development of sensitive biomarkers of vitamin K status and methods to accurately measure vitamin K in foods and tissues has led to a greater understanding of the relationship between intakes and vitamin K sufficiency. 17,31 Data from metabolic studies in healthy volunteers have shown that dietary intakes 40 g/d taken for days in initially replete individuals causes changes in 1 established biomarkers of tissue or functional status (eg, serum phylloquinone, PIVKA-II, GluOC, urinary free Gla, or vitamin K metabolites). In 2001, a reevaluation of the US recommendations led to abandonment of the previous recommended daily allowance of 1 g/kg per day in favor of the setting of an Adequate Intake (AI) based on median intakes for men and women reported by the Third National Health and Nutrition Examination Survey. 39 A summary of the recommendations for various age groups is shown in Table 2. The AIs for men and women are 120 and 90 g/d, respectively. 39 There is evidence that a substantial proportion of people in several countries fail to meet their national dietary guideline intakes for vitamin K. 17 The AI for infants in the first 6 months of life is 2 g/d and is based on intakes from human milk. 39 Because of low concentrations of vitamin K in human milk, this AI is considerably lower on a body weight basis than adults but assumes that all infants also receive a prophylactic dose(s) of phylloquinone at birth to prevent the rare but potentially fatal syndrome known as VKDB of early infancy. 18

5 November Supplement 2009 VITAMIN K IN PN S109 Table 2. Dietary Reference Intakes for Vitamin K (Phylloquinone) Population Age Adequate intake, g/day (AI)* Tolerable upper limit Infants 0 6 months 2.0 Insufficient data 7 12 months 2.5 Insufficient data Children and adolescents 1 3 years 30 Insufficient data 4 8 years 55 Insufficient data 9 13 years 60 Insufficient data years 75 Insufficient data Adults (men) 19 years 120 Insufficient data Adults (women) 19 years 90 Insufficient data Pregnancy and lactation years 75 Insufficient data years 90 Insufficient data Data from Institute of Medicine, Food & Nutrition Board. 39 *Except for infants, AI values are based on median intake data from NHANES III ( ). AI based on human milk intakes but assumes that all infants receive vitamin K prophylaxis at birth (usually single IM dose of 1 mg phylloquinone) to prevent vitamin K deficiency bleeding of early infancy. Requirements for Putative Noncoagulation Functions (Bone Health) It is important to emphasize that the current AI values for healthy populations refer only to the coagulation function of vitamin K rather than to the requirements for the putative roles in bone and vascular health. Whereas the US committee noted the interest in new indicators sensitive to vitamin K intake, such as GluOC, they considered that the uncertain physiologic significance of such biomarkers precluded their use for the establishment of a recommended daily allowance. 39 There are several lines of evidence that relate low intakes or impaired status of vitamin K to indices of poor bone health, including fracture rates. Population studies in different healthy groups have found low dietary consumption of vitamin K is associated with increased fracture risk 40,41 or a lower bone mass 42 and that an impaired vitamin K status is associated with low bone mass 43 or increased bone turnover. 44 A limitation of these findings is that they are not consistent for the same outcome measures of fractures and bone mineral density (BMD), or for age, or gender. This may reflect a weak association between vitamin K intakes and bone health, or indicate that certain population groups are more vulnerable to vitamin K deficits than others. Another limitation is that low dietary intakes of phylloquinone could reflect a poor diet in general, and may merely reflect deficiencies of other nutrients important to bone health. Epidemiologic studies have found that high circulating GluOC concentrations constitute an independent risk factor for bone fracture and low BMD. 48,49 The strength of these studies is that GluOC is an accepted functional marker of the vitamin K status of the bone matrix and that this association has been found in 1 country with different methodologies for measuring GluOC. Most bone health intervention trials with vitamin K have been carried out in Japan using MK-4 at high doses (45 mg/d) and, although a meta-analysis revealed an apparently striking reduction of hip and vertebral fractures, this conclusion needs to be regarded cautiously. 50 As recently reviewed, 51 several randomized controlled intervention trials have now been published testing the effect of lower doses of phylloquinone in European and North American populations. The end point for such trials was generally BMD or bone mineral content (BMC) with most trials showing little or no effect of phylloquinone supplementation on these measures. 51 However, if osteocalcin is responsible for subtle changes in the mineralization process and maturation of bone mineral crystals, 13 it is feasible that the effect of vitamin K is on bone quality rather than on bone density. 52 This hypothesis is supported by recent evidence of an association between vitamin K status or supplementation with improved hip bone geometry and bone strength indices. 53,54 Vitamin K Status of Hospitalized Patients Historically, the extent of vitamin K deficiency in hospitalized patients has been difficult to evaluate because of reliance on global coagulation tests, which lack both sensitivity (factor II concentrations need to fall to 50% of normal before there is any change in the PT) and specificity. 16 Specificity is improved by assessing the response of a prolonged PT or activated partial thromboplastin time to intravenous vitamin K. Using this criterion, Alperin 55 was able to make an accurate diagnosis of coagulopathy due to vitamin K deficiency in 42 critically ill, hospitalized patients, most of whom had been misdiagnosed as having disseminated intravascular coagulation. Data for this study had been collected over 9 years, so the prevalence of vitamin K deficiency was not evaluated but common factors were inadequate diet, malabsorption, antibiotic therapy, renal insufficiency, hepatic dysfunction, recent major surgery, and lack of prophylactic vitamin K supplementation. 55 It is noteworthy that 26 patients (62%) reported reduced dietary intake for periods of 1 7 weeks before hospitalization. The coagulopathies occurred between days 12 and 22 of hospitalization, and 21 patients (50%) had undergone major surgery 3 12 days before vitamin K deficiency was diagnosed. Two recent British studies have employed

6 S110 MARTIN J. SHEARER GASTROENTEROLOGY Vol. 137, No. 5 serum phylloquinone and PIVKA-II measurements as more sensitive and specific markers of the prevalence of vitamin K insufficiency in critically ill patients in the settings of either intensive 19 or palliative care. 20 In the intensive care setting, 15 of 35 (43%) admitted adult patients had low tissue stores of vitamin K as evidenced by a low plasma phylloquinone and 12 of 35 patients (34%) had a disturbance of -carboxylation as evidenced by an elevated PIVKA-II. 19 In the palliative care setting, 13 of 46 (28%) had a low phylloquinone concentration and 36 of 46 (78%) had an elevated PIVKA-II. 20 However, in both studies, patients with an elevated PIVKA-II did not always show a low phylloquinone and vice versa. There are several possible explanations for this lack of synchronicity, including a raised PIVKA-II reflecting liver dysfunction, independent of vitamin K insufficiency, the delay between the finding of a low serum phylloquinone and the onset of an impaired -carboxylation in the liver (that does not take into account any contribution to -carboxylation from menaquinones), and the long half-life of PIVKA-II in the circulation. However, a low serum phylloquinone concentration may be regarded as a danger sign of an impending functional deficiency. 19 A Japanese study directly addressed the question of how sudden and severe dietary vitamin K depletion affects both circulating and liver concentrations in patients before and after undergoing gastrointestinal surgery. 21 After receiving the standard hospital diet for 4 days, the patients were divided into 2 groups according to whether they were then given a low-vitamin K diet (5 g phylloquinone per day) or standard diet ( g phylloquinone per day) for 3 days before the operation. Preoperatively, the mean plasma phylloquinone fell by 50% in the group on the low-vitamin K diet over 3 days, whereas concentrations fell only slightly on the standard diet. After gastrointestinal surgery, all patients received only electrolytes, water-soluble vitamins, and antibiotics for 3 days. Postoperatively, plasma phylloquinone fell precipitously by about 70% during the first 24 hours of the 3-day postoperative fasting period in the group who had received the standard diet; thereafter, the concentrations declined only slightly and had plateaued by 3 days, at which time the plasma levels were equally low in both groups. However, the most significant findings came from liver biopsy analyses showing that the livers from patients who had received the low-vitamin K diet contained only 25% of the phylloquinone content of those receiving the standard diet. In contrast, the hepatic concentrations of menaquinones remained essentially unchanged. This study provides direct evidence that phylloquinone stores are very labile and readily depleted after only a few days of dietary depletion. The negligible decline in menaquinones over 3 days is in keeping with animal studies. It is important to note that the PT values remained within the reference range, although there was a nonsignificant trend for a postoperative increase in both groups. Unfortunately, no sensitive functional marker of hepatic vitamin K status such as PIVKA-II was employed to assess hepatic -carboxylation changes. This may have helped to resolve the long-standing question of the availability of the hepatic MK stores to maintain -carboxylation of the coagulation factors during drastic dietary depletion. Vitamin K in Liver Disease It is well recognized that the intestinal uptake of vitamin K is dependent on its solubilization by bile salts and that diseases resulting in bile salt deficiency pose a high risk for the rapid development of severe vitamin K deficiency and resultant coagulopathy. 36,56 Subclinical vitamin K deficiency is common in patients presenting with cholestatic liver disease. In a small, prospective trial on patients admitted to hospital with obstructive jaundice, 20% had an abnormal PT but 64% had subnormal phylloquinone concentrations. 57 Likewise in a prospective study of 44 infants admitted to hospital with conjugated hyperbilirubinemia, 8 infants (18%) had low phylloquinone concentrations and 18 (41%) had elevated PIVKA-II at presentation. 58 In the same cholestatic infants, it was shown that the administration of an oral dose of 2 mg phylloquinone showed an impaired and erratic intestinal absorption, with only 17% achieving a satisfactory incremental rise in serum phylloquinone. 58 Therefore, patients with cholestasis are best protected from vitamin K deficiency by the timely prophylactic administration of parenteral phylloquinone preparations. Prophylaxis needs to be given on a regular basis because of the poor hepatic storage of phylloquinone. Patients with severe acute liver failure (ALF) commonly present with a complex, multifactorial coagulopathy that includes a reduction in circulating concentrations of both vitamin K-dependent and -independent coagulation proteins. The possible contribution of vitamin K deficiency to this picture was examined in a series of 49 adults admitted to the hospital with ALF. 59 Thirteen patients (27%) presented with either low phylloquinone or elevated PIVKA-II concentrations indicative of vitamin K insufficiency, with 2 patients presenting with very high PIVKA-II concentrations in the range found in warfarin-anticoagulated patients. 59 This insufficiency was reliably corrected by a single intravenous dose of 10 mg phylloquinone but not by a dose of 10 mg of phylloquinone given by mouth or nasogastric tube. After the intravenous dose, the usual rapid clearance of phylloquinone from the circulation was markedly prolonged, suggesting that the hepatic damage also impaired the catabolism of vitamin K. This resulted in the maintenance of plasma phylloquinone at supraphysiologic concentrations for 1 week. This study concluded that it is

7 November Supplement 2009 VITAMIN K IN PN S111 prudent to give prophylactic vitamin K to patients admitted with ALF and that a single intravenous bolus of 10 mg phylloquinone seems to be sufficient for 1 week. However, in most patients the deranged coagulation seen in ALF remains unresponsive to vitamin K, reflecting either a decreased synthesis, increased consumption of coagulation factors, or both. Intakes and Use of Vitamin K in Parenteral Nutrition At present, the only generally accepted clinical risk of providing too little vitamin K to patients receiving parenteral nutrition (PN) is the risk of bleeding due to reduced synthesis of factors II, VII, IX, and X. Other putative risks of PN-associated vitamin K insufficiency with other clinical outcomes, such as increased fracture rates and cardiovascular calcification, are presently unquantifiable. The natural source of vitamin K in parenteral feeds is phylloquinone contained in the lipid emulsion. As highlighted by Singh and Duerksen 60 the natural phylloquinone content of commercial PN products varies widely depending on the oil source with, for example, high levels in soybean oil ( g per 100 g) and relatively low levels in safflower oil (6 12 g per 100 g). Duerksen and Papineau carried out 2 separate studies comparing the prevalence of coagulation abnormalities in 2 groups of PN patients who received intravenous lipid emulsions that contained either low ( 1 g per 100 ml) 61 or high ( 30 g per 100 ml) 62 amounts of phylloquinone for a mean duration of or days, respectively. Using the same criterion for significant change (international normalized ratio [INR] 0.2 above baseline) the prevalence of coagulation defects was approximately 5-fold higher in those patients who received the low-phylloquinone emulsion than in those who received the high-phylloquinone emulsion (20% vs 3.6%, respectively). 61,62 Although the incremental increases in INR from either formulation did not pose a significant bleeding risk, 61,62 the INR is an insensitive measure of vitamin K status, and extrahepatic Gla proteins such as osteocalcin and MGP are affected to a greater degree by marginal vitamin K intakes than the hepatic coagulation factors. 6 One of the few studies to have assessed the long-term relationship between vitamin K intake from lipid emulsions on plasma phylloquinone concentrations showed that an average weekly intravenous supply of 255 g (36 g/d) was sufficient to maintain phylloquinone concentrations within the reference range in patients that received home PN because of severe malabsorption. 63 Furthermore, in a group of patients with an initially low plasma phylloquinone concentration, an average weekly dose of 418 g (60 g/d) was sufficient to both restore and maintain plasma phylloquinone within the normal range. 63 Although the number of patients in the study was small, its virtue was that patients were followed up for up to 5 years and no coagulation abnormalities were recorded. 63 In 2000, the US Food and Drug Administration (FDA) revised their guidelines and mandated that adult parenteral multivitamin preparations should provide 150 g phylloquinone per day. 64 This amount is in addition to that provided naturally by the lipid emulsion, and so a patient receiving 50 g of lipid per day from a high vitamin K emulsion could easily have a daily phylloquinone intake in excess of 300 g. 60 One study showed that daily intakes of 300 g phylloquinone from a lipid emulsion alone (Intralipid 20%) raised serum phylloquinone levels by 3- to 30-fold after 4 days of lipid infusion with no evidence of a plateau being reached. 65 The likely impact of this revised guideline change on the management of PN patients has been reviewed and, although an increased and regular provision of vitamin K may be beneficial to most patients, it may be detrimental to others, such as neonates and patients being treated with oral anticoagulants. 60,66 For patients on warfarin, such high intakes are almost certain to result in a degree of warfarin resistance. Therefore, as stated by Singh and Duerksen, 60 it is imperative that nutrition support teams be aware of the vitamin K content of the lipid emulsion and the multivitamin preparations in their institutions. Modification for Special High-Risk Patient Groups Certain patient groups have enhanced risk of developing vitamin K deficiency that may be due to malabsorption resulting from physical (eg, short bowel syndrome) or pathophysiologic factors (eg, cholestasis), or owing to associated treatment (eg, antibiotics). In addition certain metabolic states (eg, fever) may be associated with an increased requirement owing to the increased turnover of the vitamin K-dependent coagulation proteins or the vitamin itself. As discussed, the most severe malabsorption of vitamin K is seen in cholestatic liver disease. There are few studies that have carried out quantitative assessments of vitamin K requirements in such high-risk groups, but if given parenterally rather than orally, the current FDA recommendation of 150 g phylloquinone per day is more than sufficient to protect against vitamin K deficiency. Importance of Diet Versus Colonic Bacterial Synthesis as Sources of Vitamin K The colon contains a large reservoir of bacterial menaquinones; limited quantitative data suggest the average pool size is 2 mg (range, mg). 3,67 Even for the lower estimate of 0.5 mg, it would only need a small fraction ( 10%) to be absorbed to satisfy human vitamin K requirements for coagulation. However, there are several lines of evidence of poor bioavailability that argue against the concept of the colon as a significant

8 S112 MARTIN J. SHEARER GASTROENTEROLOGY Vol. 137, No. 5 provider of vitamin K. They include the fact that bile salts are obligatory for significant absorption of vitamin K, yet are absent from the colon; this argument is reinforced by clinical observations that intestinal synthesis is insufficient to prevent the common cause of vitamin K deficiency arising from biliary obstruction (even without other pathology). Another factor is that the vast majority of menaquinones in the colon are simply not bioavailable because they are locked in bacterial membranes from which little is released for absorption. 3,67 However when free menaquinones were introduced into the ileum, absorption of menaquinones was demonstrated, but this uptake was presumed to be mediated by incorporation into ileal bile salt micelles. 67 Direct evidence that bacterial MK cannot completely maintain Gla protein synthesis comes from the use of sensitive biomarkers that have consistently demonstrated that relatively mild dietary restriction leads to significant decreases in the -carboxylation status of both hepatic and bone Gla proteins in a short time. 3,15,17 Overall, the weight of evidence suggests that although menaquinones do make some contribution to vitamin K requirements, they are less important than has often been presumed. 3,36 Moreover, absorption from the colon is probably minimal, with menaquinones present in the distal ileum representing a more likely source. 67 Although antibiotics are a well-known contributory risk factor to vitamin K deficiency, evidence that the mechanism is due to decreased MK synthesis remains unproven and, in fact, some antibiotics have been shown to be weak inhibitors of vitamin K metabolism. 3,36 In conclusion, patients who lack an intact colon should not require extra supplementation beyond what is already recommended for enteral or parenteral preparations. Patients at greatest risk remain those on enteral nutrition with short bowel syndrome who cannot absorb vitamin K from the small intestine owing to disorders of bile acid secretion or metabolism. Pregnancy and Newborns Pregnant women who require PN should be considered a high-risk group with respect to the vitamin K requirements of their fetus because of several case reports that have documented maternal PN without supplemental vitamin K as a causative factor for either fetal intracranial hemorrhage or skeletal deformities of chondrodysplasia punctata. 71 These risks occur throughout pregnancy, with the skeletal phenotype being a manifestation of early maternal vitamin K deficiency, and fetal bleeding a risk in later pregnancy. It is important to realize that severe fetal vitamin K deficiency can develop even when maternal deficiency is mild. 68 The reason for the much greater risk to the fetus is probably poor placental vitamin K transport, which leads to relatively impaired vitamin K status, even in healthy newborns. 18,72 In most countries, all newborns receive vitamin K prophylaxis (usually at a dose of 1 mg intramuscularly) to prevent the rare but potentially fatal VKDB of early infancy. 18 The period of greatest risk for bleeding is the first 6 months of life. The FDA regulation of 150 g phylloquinone per day does not apply to infants, but it has been demonstrated that pediatric patients who received 200 g per day phylloquinone in their PN feed had serum phylloquinone concentrations 10-fold higher than controls who did not receive PN. 73 Greater concerns surround excessive vitamin K given to premature infants who receive PN. At 2 weeks of age, plasma phylloquinone concentration in preterm infants strongly reflects gestational age and declines with increasing maturity. 74 For a gestational age 28 weeks, the average circulating serum phylloquinone concentration in 2-week-old infants who received 70 g/kg phylloquinone per day via PN was 250-fold higher than the average adult concentration of 0.5 g/l. 74 The authors suggested that an intake of 10 g/kg phylloquinone per day would be more than enough for premature infants. 74 Another study demonstrated similarly elevated serum phylloquinone concentrations in preterm infants, and on day 10 were about 10-fold higher relative to previously documented day 5 plasma values of full-term infants who had received a single intramuscular injection of 1 mg phylloquinone at birth. 75 These authors also called for lower intake from PN for premature infants. 75,76 Although evidence of toxicity from such high doses is lacking, there is evidence that premature infants given high prophylactic doses cannot efficiently recycle the metabolite vitamin K epoxide to vitamin K needed for -carboxylation. 25 The doserelated detection of this metabolite in serum provides biochemical evidence that the vitamin K epoxide cycle may be overloaded by current prophylactic and PN regimens. 25 Patients Taking Warfarin for Prevention of Thromboembolism Several authors have expressed reservations of the potential impact of the 150 g level of fortification of multivitamin preparations on those patients who are also taking vitamin K antagonists, such as warfarin. 62,66,77,78 These reservations apply to both conventional-dose and low-dose (minidose) anticoagulant therapy. Conventional Oral Anticoagulation Therapy For conventional anticoagulation therapy, a major concern is that the combination of phylloquinone intakes from the multivitamin preparation and the lipid formulation may be excessive and jeopardize anticoagulant control. As discussed, depending on the lipid source, the total daily intake from both sources may range from a minimum of 150 g to 400 g phylloquinone. The impact of different levels of phylloquinone intakes on the control and stability of conventional anticoagulation

9 November Supplement 2009 VITAMIN K IN PN S113 therapy has recently been reviewed. 15,79 An intervention study in healthy subjects evaluated the response to incremental doses of vitamin K supplements ( g phylloquinone each dose taken daily for a week) on the stability of anticoagulation. 80 The threshold dose that caused significantly lowering of the INR was 150 g/d, and in 25% of the subjects the INR change would have been sufficient to warrant dose adjustment. At a daily dose of 500 g of phylloquinone the mean starting INR of had fallen to Although this study was conducted in healthy volunteers, they generated the first quantitative data on which the potential benefit of vitamin K supplementation in patients can be based. The rationale for vitamin K supplementation is the evidence that patients with a low dietary intake of vitamin K have more unstable anticoagulation. 81 Vitamin K supplementation studies have now been extended to patients at thrombotic risk and provided evidence that daily oral supplements of g phylloquinone improves the stability of anticoagulant control. 82,83 The applicability of data from the above studies to patients on PN suggests that, whereas patients would benefit from a constant daily intake of phylloquinone, serious consideration needs to be given to the level of supplementation, particularly when the total intake exceeds 150 g/d. Apart from causing nutritional resistance, 1 particular danger is to patients who have been started on oral anticoagulant therapy while taking PN and who subsequently are taken off PN and resume their normal diet. 62 Such patients need careful supervision to prevent an excessive INR developing during the transition to an inevitably much lower vitamin K intake. Low-Dose (Minidose) Anticoagulation Therapy High vitamin K intakes are also contraindicated for patients on low-dose anticoagulation therapy. 77,78 The American Society for Parenteral and Enteral Nutrition has recommended 84 that low-dose anticoagulation therapy should be used to prevent complications in patients requiring long-term catheterization during PN, although the extent to which this advice is followed is unclear. The perceived advantage, particularly for home use, is that low-dose anticoagulation (usually with 1 2 mg/d warfarin) should not require monitoring of the INR. Several, but not all trials, have reported that lowdose warfarin is effective in reducing the prevalence of thrombosis in the central venous catheter. 77,85 The protective mechanism is unclear but it is assumed that lowdose warfarin induces a very mild hypoprothrombinemia, even though this is not discernible by global coagulation assays. Some support for this mechanism comes from a study in healthy volunteers eating a normal diet in which a daily dose of 1 mg warfarin induced increases in undercarboxylated proteins PIVKA-II and osteocalcin. 86 The increase in PIVKA-II was slight and could not be detected by a typical barium citrate binding assay, but was detected by a sensitive immunoassay. 86 The problem in interpretation of the original minidose trials in patients receiving PN is that no measures of vitamin K intakes or status were made. However, it is likely that the vitamin K status of the patients of the first catheter trial who had metastatic carcinoma 85 would have been inferior to healthy subjects and that the minidose regimen would have caused a significantly greater inhibition of thrombosis potential. It is also reasonable to assume that the clinical efficacy of minidose warfarin is dependent on vitamin K intakes and that clinical efficacy may be compromised by intakes of 150 g/d and higher. Clearly as recommended by Duerksen 78 further studies are needed in this area. Toxicity of Vitamin K Reports of toxicity for phylloquinone, the form of vitamin K almost universally used in injectable and parenteral formulations, are rare and generally attributed to the vehicle of solubilization or other component rather than to vitamin K itself. The most serious reaction to vitamin K is anaphylactoid reactions after parenteral administration. A large, worldwide surveillance of adverse effects of 2 commercial (Hoffmann-La Roche Ltd, Nutley, NJ) phylloquinone formulations (Konakion Cremophor versus Konakion MM) showed that 96% of the rare adverse events were associated with the older formulation containing Cremophor EL (BASF Corp, Ludwigshafen, Germany), an emulsifier previously implicated as the cause of anaphylactoid reactions for other drugs. 87,88 Rare case reports of anaphylaxis have been reported for another formulation (AquaMephyton, Merck & Co, Whitehouse Station, NJ) containing a polyoxyethylated fatty acid derivative as the emulsifying agent. 88 In the early 1990s, there was considerable worldwide alarm arising from the publication of 2 epidemiologic studies in the United Kingdom that reported an unexpected association between the intramuscular injection of phylloquinone given to newborns with later childhood cancer (for reviews see Shearer 18 and IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 88 ). The magnitude of concern was that intramuscular injections of phylloquinone were given as routine prophylaxis to prevent VKDB in many developed countries. However, many subsequent studies have failed to substantiate the link between vitamin K prophylaxis and risk of cancer. 18 Menaquinones are not used for parenteral administration, but large pharmacologic doses (45 mg/d) of MK-4 are given orally in Japan as an anti-osteoporotic agent without evidence of adverse effects. 89 Summary Recommendations Although a weekly intravenous supply of g phylloquinone is sufficient to maintain effective

10 S114 MARTIN J. SHEARER GASTROENTEROLOGY Vol. 137, No. 5 coagulation in most patients on PN, a daily injection of 150 g phylloquinone should cover the requirements of all patients and will be also more effective in maintaining the -carboxylation status of noncoagulation Gla proteins. Lipid emulsions provide a variable amount of phylloquinone according to the type of oil, and this source of vitamin K needs to be factored into requirement calculations. Pregnant women present a special risk category because of the poor placental transport of vitamin K and consequent danger that even subclinical maternal vitamin K deficiency can result in severe bleeding or skeletal defects in the fetus. The phylloquinone content of present PN formulations may cause vitamin K overload in premature infants. Consideration needs to be given to administer lower amounts of phylloquinone to preterm infants, especially in the first 2 weeks of life. Although anticoagulant control in patients taking vitamin K antagonists such as warfarin may be improved by a regular vitamin K intake, the current FDA recommendations for multivitamin preparation (150 g/d) and variable amount from lipid emulsions (up to 400 g/d) may cause warfarin resistance. Such high phylloquinone intakes are likely to completely negate any antithrombotic effects of low-dose (minidose) warfarin therapy. Research Priority Recommendations Are there any long-term pathologic consequences of suboptimal vitamin K status mediated by nonfunctional extrahepatic Gla proteins (eg, osteocalcin in fracture risk and MGP in vascular calcification)? How do varying vitamin K intakes affect the control and stability of conventional anticoagulant therapy in patients on PN? More in-depth studies (using sensitive methodologies of haemostatic capacity and vitamin K status) are needed to confirm or refute the proposed antithrombotic mechanism of low-dose anticoagulant therapy for patients with central venous catheters. Question and Answer Session DR BUCHMAN: Martin, what in your opinion is the role, if there is any, for insufficient vitamin K in the low turnover bone disease that patients get on PN? Do you think the potential role for vitamin K has been overplayed or do you think that it had a role that perhaps has been eliminated because now most all adults are getting vitamin K? Is a higher dose necessary to maintain bone health than that which may be necessary for synthesis of coagulation factors? DR SHEARER: Historically, the issue began with the Japanese who patented menatetranone, which is MK-4. This is not a common dietary form of vitamin K, although it can be synthesized in the human body from vitamin K 1. They used a dose of 45 mg/d in postmenopausal women with osteoporosis and claimed it was beneficial. However, in a meta-analysis published in the Archives of Internal Medicine it was shown that most studies outside of Japan failed to demonstrate any benefit on bone from vitamin K supplementation. We found a minor improvement in BMC but only at the ultradistal radius in Scottish women given vitamin K at a dose of 200 g/d, which is almost the dietary dose. Therefore, I don t think that given the present state of our knowledge there would be any benefit in giving extra vitamin K to treat or prevent osteoporosis in patients on PN. DR HOWARD: Dr Shearer, we ve heard that the trace element amounts vary considerably in the different parenteral products, and you mentioned that the source of oil will affect the amount of vitamin K that the lipid solution might provide. What is the degree of interbatch variation? DR SHEARER: I don t know. You d have to ask the manufacturers that. Duerkson gave a range for soybean oil of g vitamin K 1 per 100 g, but the true variation might even be greater. DR MOUKARZEL: Every newborn is administered vitamin K supplementation to prevent vitamin K deficiency. Because breastfed infants do not get sufficient vitamin K from human milk, can you speculate why Mother Nature failed to put adequate vitamin K in breast milk? DR SHEARER: The incidence of vitamin K deficiencyrelated bleeding is low and approximately 1 per 10,000 in the Western hemisphere (greater in Asia). This can be reduced to 3 4 cases per 100,000 with vitamin K prophylaxis. The concern is to prevent an intracranial hemorrhage (80% of bleeding between the ages of 2 weeks and 6 months), which can be catastrophic. The problem is not completely eliminated because sometimes the mother refuses the vitamin K. In addition, some bleeds occur because the infants develop cholestasis or may be born with a metabolic defect such as biliary atresia, which is only detected later. I do think, however, that in general breast milk has sufficient vitamin K. An underlying pathology is often detected in infants who bleed. DR FORBES: I remain confused about the situation in an anticoagulated patient. We generally rely on the phyllo vitamin K from the lipid emulsion to provide what we think is an adequate amount of vitamin K. But if the patient requires anticoagulation and they re on warfarin, as you said, you generally end up in a situation where you need to give more warfarin to establish a suitable INR. Having given more warfarin, aren t we undoing the benefit of the vitamin K, and in effect rendering the patient

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