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Vitamin K Status in Nutritionally Compromised Circumstances

  • Mina Yamazaki Price
  • Victor R. Preedy
Living reference work entry

Abstract

Vitamin K deficiency is very rare except in neonatal populations. This is due to dietary sources, particularly plant-derived phylloquinones (vitamin K1) being abundantly distributed in nature and ubiquitously available in common foods. However, there is very little information on the bioavailability of vitamin K from foods. Furthermore, despite the increased understanding of vitamin K’s biological roles, there are difficulties in establishing a causal link between plausible biomarkers of vitamin K deficiency and reproducible health outcome measures. Additionally, with vitamin K there is the added complication that this vitamin is also synthesized in the gastrointestinal tract by gut microflora. As a result, the exact dietary requirements for vitamin K in numerical terms have not been fully established. Clinically significant vitamin K deficiency is almost nonexistence in healthy populations. However, there are states in which it is compromised in some population cohorts other than neonatal populations. This review illustrates some examples of vitamin K insufficiency states, which include eating disorders, undernourished children, inflammatory bowel disease, and chronic kidney disease. It also describes some biomarkers of vitamin K status used in recent studies.

Keywords

Vitamin K Phylloquinones Menaquinones Natto Carboxylation Uncarboxylated Glutamate residues 

List of Abbreviations

BMI

Body mass index

ESRF

End-stage renal failure

IBD

Inflammatory bowel disease

PIVKA-II

Protein induced by vitamin K absence-II

ucMGP

Undercarboxylated matrix Gla protein

ucOC

Undercarboxylated osteocalcin

Introduction

Vitamin K is a one of four fat-soluble vitamins (the other three being vitamin A, D, and E). Vitamin K is categorized into two major forms. They are the plant-derived phylloquinones (vitamin K1) and the bacterial-derived menaquinones (vitamin K2) (Price and Preedy 2015). There are number of vitamers within each form. Some texts describe a third class, namely, menadione (sometimes denoted as vitamin K3), but it does not occur naturally (it is synthesized) and is used in animal feeds (Coombs and McClung 2017). Structurally, they have a common 2-methyl-1, 4-napthoquione ring, and the differences at the three position of the side chain separate the two major forms (phytyl side chain and prenyl side chains, phylloquinones and menaquinones, respectively) (Fig. 1).
Fig. 1

Chemical structure phylloquinone (vitamin K1) and menaquinones (vitamin K2). Fig. A shows phylloquinones (vitamin K1) and B shows menaquinones (vitamin K2). (Source: Rishavy and Berkner 2012)

The nomenclature of vitamin K can be somewhat challenging as they are also denoted by the number of isoprenoid units. For example, phylloquinone-1 is denoted by K-1 and menaquinone-7 is denoted as MK-7 etc. Natto, for example, (Table 1) is particularly high in MK-7. There are a number of phylloquinones and menaquinones, with different biological activities. Coombs and McClung (2017) list six phylloquinones (K-1 - K-6) and six menaquinones (MK-2 - MK-7) in terms of their bioactivity (potency). For example, K-4 is 20 times more potent than K-1. MK-5 is eight times more potent than MK-2 (Coombs and McClung 2017). There are probably about 20 different vitamin K isomers (both phylloquinones and menaquinones) that have been investigated or characterized in depth (see Coombs and McClung 2017).
Table 1

Vitamin K concentrations in some of common foods consumed in the Western diet. The below values show mean values of at least three to six different samples or brands. Natto (fermented soy beans) is not commonly consumed in the Western diet but commonly consumed in Japan. It is listed as an example of extremely high content of menaquinones (Vitamin K2) in fermented foods (Source: Schurgers and Vermeer 2000)

Food group

Food

Phylloquinone (vitamin K1) concentration μg per 100 g

Menaquinone (vitamin K2) concentration μg per 100 g

Vegetables

Kale

817.0

Not detectable

Spinach

387.0

Not detectable

Broccoli

156.0

Not detectable

Sauerkraut

25.1

4.8

Natto (fermented soy beans)

34.7

1088.4

Fruits

Apple

3.0

Not detectable

Banana

0.3

Not detectable

Orange

0.1

Not detectable

Fat and oils

Olive oil

53.7

Not detectable

Margarine

93.2

Not detectable

Sunflower oil

5.7

Not detectable

Butter

14.9

15.0

Dairy

Whole milk

0.5

0.9

Buttermilk

Not detectable

2.5

Whole yoghurt

0.4

0.9

Hard cheese

10.4

76.3

Soft cheese

2.6

56.5

Meat and egg

Beef

0.6

1.1

Chicken breast

Not detectable

8.9

Pork steak

0.3

2.1

Pork liver

0.2

0.3

Salami

2.3

9.0

Goose liver paste

10.9

369.0

Egg yolk

2.1

31.4

Fish and shell fish

Mackerel

2.2

0.4

Herring

0.1

Not detectable

Salmon

0.1

0.5

Prawn

0.1

Not detectable

Bread

Wheaten bread

1.1

Not detectable

Sourdough bread

1.0

Not detectable

Dietary Sources

The main dietary sources of plant-derived phylloquinone are leafy green vegetables, pulses, and certain plant oils. The phylloquinones are synthesized by chloroplasts. Phylloquinone is abundantly distributed in nature and is the primary form in the Western diet (Hayes et al. 2016). On the other hand, dietary sources of bacterial-derived menaquinones are primarily found in animal sources including dairy products and meats including processed meat products. Additionally, menaquinones are synthesized by the gut microflora in the large intestine in humans and then subsequently enter the circulation. Bacterially fermented products such as natto are a rich source of menaquinones. Furthermore, although the biological pathway is unclear, phylloquinone is converted to one form of menaquinone, i.e., menaquinone-4, in vivo which is independent of gut microflora activity (Price and Preedy 2015). Table 1 shows the vitamin K concentrations in some of the common foods consumed in the Western diet. It highlights the ubiquitous distribution of phylloquinones compared to the less common distribution of menaquinones (Schurgers and Vermeer 2000).

Biological Role

The primary or traditionally accepted role of vitamin K, established since the 1970s, is its participation in hemostasis (antihemorrhagic). It acts as a cofactor to facilitate the post-translational carboxylation of specific peptide-bound glutamate residues to γ-carboxyglutamate (in some text the Greek symbol is replaced with the term “gamma”) residues in plasma-clotting proteins, namely, factors II (prothrombin), VII, IX, and X to initiate the coagulation cascade (Price and Preedy 2015).

Proteins which require vitamin K as a cofactor for the posttranslational γ-carboxylation of glutamate residues for its activation are termed as vitamin K-dependent proteins. Further discovery of a number of vitamin K-dependent proteins (a total of 16 proteins including the aforementioned 4) leads to the general consensus that the role of vitamin K extends beyond hemostasis (Price and Preedy 2015). For example, vitamin K is involved in vascular and bone health by protecting against vascular calcification and bone loses, respectively. Table 2 shows a list of vitamin K- dependent proteins and their physiological roles (Berkner and Runge 2004; Booth 2009; Price and Preedy 2015). There is also increasing evidence that vitamin K status has a bearing on bone and cardiovascular health and well-being. Indeed, there is some evidence that supplemental vitamin K may confer a biological advantage in terms of bone health.
Table 2

Vitamin K-dependent proteins and their biological roles. The table shows 16 vitamin K-dependent proteins. Many of biological pathways of roles listed in this table are unclear (Berkner and Runge 2004; Booth 2009)

Name of proteins

Biological role

Prothrombin (factor II)

Hemostasis/coagulation

Factor VII

Hemostasis/coagulation

Factor IX

Hemostasis/coagulation

Factor X

Hemostasis/coagulation

Protein Z

Hemostasis/coagulation

Protein S

Hemostasis/coagulation/anti-inflammatory

Protein C

Hemostasis/coagulation/anti-inflammatory

Osteocalcin

Bone health/regulates bone mineral maturation/possible role in glucose homeostasis

Gla-rich protein

Bone health/regulates extracellular calcium

Periostin

Bone health/involves extracellular matrix mineralization

Matrix Gla protein

Vascular health/inhibits vascular calcification

Gas-6

Vascular health/involves vascular smooth muscle cell apoptosis and movement

Transmembrane Gla 1

unclear/possible role in signal transduction

Transmembrane Gla 2

unclear/possible role in signal transduction

Transmembrane Gla 3

unclear/possible role in signal transduction

Transmembrane Gla 4

unclear/possible role in signal transduction

Dietary Requirements and Recommendations

Despite the increased understanding of vitamin K’s biological roles, its exact dietary requirements in numerical terms have not been fully established. This uncertainty may be due to the difficulties in inducing vitamin K deficiency through dietary deprivation alone or finding individuals who are vitamin K deficient via classical undernutrition studies (DH 1991). Furthermore, there are difficulties in establishing a causal link between plausible biomarkers of vitamin K deficiency and reproducible health outcome measures. This is compounded by the fact that there is very little information on the bioavailability of vitamin K from foods. As a consequence, it is somewhat problematical to derive specific dietary recommendations or reference values for vitamin K (Shearer et al. 2012).

For the UK, the Dietary Reference Values consist of 3 main components as follows:
  • Estimated average requirements (EAR). On the population level, half will require more than the EAR and half less.

  • Lower Reference Nutrient Intake (LRNI). Intakes at the LRNI will only satisfy the few people in a group who have low needs (less than 3% of the population).

  • Reference Nutrient Intake (RNI). Intakes at the RNI will satisfy the needs of the majority of the people in a group (about 97% of the population). The risk of deficiency in the group is very small if intakes Are at the RNI or above.

Occasionally, there is not sufficient information to provide either an EAR, LRNI, or RNI. In these circumstances safe intakes have been derived for UK-based reference values. Safe Intakes are defined as “a term used to indicate intake or range of intakes of a nutrient for which there is not enough information to estimate RNI, EAR or LRNI. It is an amount that is enough for almost everyone but not so large as to cause undesirable effects” (DH 1991).

For a full explanation of these terms, their derivation, and implications for health and disease prevention, one is referred to the original report on the Dietary Reference Values (DH 1991).

In the UK, safe intakes have been derived for vitamin K dietary reference values for adults and infants (in other words and to reiterate a point, there are no EAR, LRNI, nor RNI for vitamin K). In the UK, safe intake for adults for vitamin K is 1 μg per body weight (kg) per day (DH 1991). This equates to about 69–72 and 59–60 μg/day adults, for male and female, respectively (values are calculated based on reference weight for age range between 19 and 54 years) (SACN 2015, Table 3). Safe intake for vitamin K for infants is 10 μg/day in the UK (DH 1991). These values are similar for the USA and Japan (Table 3). Both countries have only values for adequate intake, which is considered to be the UK equivalent of safe intake. In the USA and Japan, for adults, reference intakes are higher, i.e., 150 μg for both genders for the USA and 120 and 90 μg/day in Japanese men and women, respectively. For infants, they are 2.0–2.5 μg/day for the USA and 4–7 μg/day for Japan (NASEM 2016, MHLW 2015). For the definition of infants, it has to be mentioned that there is no age specification for the UK. However, they are defined as 0–12 months, for the USA, and 6–11 months for Japan, respectively (NASEM 2016, MLHW 2004).
Table 3

Reference values of vitamin K, definition of the terminology and current recommendation for adults used in the UK, USA, and Japan

Country

Reference values

Definition

Current recommendation or reference intakes (μg/day)

UK

Safe intake

A term used to indicate intake or range of intakes of a nutrient for which there is not enough information to estimate reference nutrient intake, estimated average requirements or lower reference nutrient intake. It is an amount that is enough for almost everyone but not so large as to cause undesirable effects

68.8–71.5 adult male

59.0–59.9 adult female

10.0 infants

USA

Adequate intakes

A recommended average daily nutrient intake level based on observed or experimentally determined approximations or estimates of mean nutrient intake by a group (or groups) of apparently healthy people. An adequate intakes is used when the recommended dietary allowance cannot be determined

120.0 adult male

90.0 adult female

2.0–2.5 infants

Japan

Adequate intake

A less well-defined value, generally the median of the population without evidence of deficiency

150.0 adult male

150.0 adult female

7.0 infants

The current recommendations or reference intakes for adults shows values 19–50 years in the UK and USA and 19–49 years in Japan. For the UK, figures are calculated based on μg/body weight (kg)/day (DH 1991) using weight for males 19–24 years, 71.5 kg; 25–34 years, 71.0 kg; 35–44 years, 69.7 kg; 45–50 years, 68.8 kg. For females, 19–24 years, 59.9 kg; 25–34 years, 59.7 kg; 45–50 years, 59.0 kg (SACN 2011). For infants, there is no age definition for the UK, for the USA, it is defined as 0–12 month old (4 μg/day for 0–6 month, 2.5 μg/day for 6–12 month); for Japan, it is defined as 6–11 months old. Sources: for the UK (DH 1991); for the USA (NASEM 2016); for Japan (MHLW 2015)

Table 3 shows dietary reference values and definitions of the terminology for vitamin K used in the UK, USA, and Japan.

As mentioned earlier, vitamin K is widely distributed in a variety of foods. Therefore the clinical deficiency caused by dietary deficiency is extremely rare. However, there are states in which it is compromised. In the following text, we describe these compromised states pertaining to vitamin K insufficiency.

Different biomarkers have been used to define reduced vitamin K status. Table 4 summarizes the biomarkers used in studies described in the text below.
Table 4

Vitamin K biomarkers

Biomarker

Rationale

Undercarboxylated osteocalcin

Osteocalcin, a bone matrix protein is exclusively produced by osteoblasts, bone forming cells. Osteocalcin is a bone matrix protein that undergoes a post-translational carboxlylation of protein-bound glutamate residues into gamma-carboxyglutamate which requires vitamin K as a cofactor. Undercarboxylated osteocalcin has no role in bone metabolism

Undercarboxlylated prothrombin

Also called protein induced by vitamin K absence or antagonist -II (PIVA-II). Prothrombin (factor II) is one of four plasma-clotting proteins (other 3 are factor VII, IX, X). Prothrombin undergoes post-translational carboxylation of glutamate residues into gamma-carboxyglutamate which requires vitamin K as a cofactor. Undercarboxylated prothrombin is inactive/defective in blood coagulation

Undercarboxylated matrix Gla protein

Matrix Gla protein is a calcification inhibitor secreted primarily by vascular smooth muscle cells. Gamma-carboxylation of its five glutamate residues requires vitamin K as a cofactor. Undercarboxylated matrix Gla protein does not inhibit the process of vascular calcification

The above biomarkers increase in the circulation in the case of reduced vitamin K availability in vivo (Urano et al. 2015; Nakajima et al. 2011; Lee et al. 2016; Wyskida et al. 2016). These have been selected as they are mentioned in this review in the context of specific studies

Vitamin K and its Deficiency States

Clinically significant vitamin K deficiency is almost nonexistence in healthy populations except for neonatal populations (Lee et al. 2016). Neonatal populations are particularly vulnerable to vitamin K deficiency. Underlying causes include their low hepatic reserve and plasma concentration of vitamin K at birth due to poor placental transport of vitamin K and low levels of vitamin K in breast milk (DH 1991; Mihatsch et al. 2016). Additionally, insufficient gut microflora colonization in the large intestine also likely contributes to endogenous deficiency (Lippi and Franchini 2011). However, some other population cohorts may also be vulnerable to vitamin K deficiency in feeding disorders, starvation, and fat malabsorption, as described below.

Eating Disorders of Anorexia Nervosa and Bulimia Nervosa

Compromised bone health (i.e., osteopenia and osteoporosis) is one of the well- recognized clinical complications of deficiency-related eating disorders and their subtype, such as anorexia nervosa and bulimia nervosa (Howgate et al. 2013). This is because of the essential role that vitamin K plays in bone metabolism (i.e., involvement by the vitamin K-dependent proteins, namely, osteocalcin, Gla-rich protein, and periostin). Urano et al. (2015) investigated vitamin K status of 54 females with eating disorders and 15 age-matched healthy controls (mean age of 28 years).

In their aforementioned study, serum undercarboxylated osteocalcin (ucOC) levels of 4.5 ng/ml or higher were defined as vitamin K deficiency. Osteocalcin is a bone matrix protein which is produced by the osteoblasts, the bone forming cells. Vitamin K is a necessary cofactor for the posttransitional carboxylation of osteocalcin. When the supply of vitamin K is insufficient or abnormal, ucOC, which has no biochemical role in bone metabolism, is released into the blood stream. UcOC is considered as a sensitive biomarker for vitamin K status (Urano et al. 2015).

The 54 subjects included 29 with anorexia nervosa and 25 with bulimia nervosa (Urano et al. 2015). The mean body mass index (BMI) of eating disorder subjects was 14.8 kg/m2 (95% confidence interval 14.1–15.5 kg/m2). BMI of this magnitude indicates severe thinness (BMI less than 16.0 kg/m2) (WHO 2016). The mean BMI of the healthy subjects was 20.1 kg/m2 (95% confidence interval 18.7–21.4 kg/m2). All eating disorder subjects were diagnosed with osteopenia or osteoporosis, and a total of 28% of the eating disorder subjects (anorexia nervosa n = 5, bulimia nervosa n = 10) were found to be vitamin K deficient. The prevalence of vitamin K deficiency within healthy subjects was not shown. However, serum levels of ucOC of bulimia nervosa subjects were statistically significantly higher than healthy subjects (p < 0.05), whereas differences between anorexia nervosa and healthy subjects did not reach statistical significance (Urano et al. 2015).

Interestingly, this study showed significant negative correlation between serum level of ucOC (a surrogate marker of vitamin K deficiency) and dietary vitamin K intake for both types of eating disorder (p < 0.01). The authors argued that the cause of vitamin K deficiency in this cohort was likely multifactorial (Urano et al. 2015). For example, complex behaviors associated with eating disorders such as severe restriction of dietary intake and vomiting/purging behaviors could cause reduction in overall vitamin K status. Regular laxatives misuse could also lead to malabsorption of dietary vitamin K. Furthermore, laxative abuse may cause alterations in the gut microflora populations which could negatively affect in vivo vitamin K synthesis (Urano et al. 2015).

The importance of mentioning the effects of anorexia nervosa and bulimia nervosa is their potential appreciation in understanding the consequence of undernutrition/starvation. In conceptual terms, these two conditions should provide us with information as to the effects of undernutrition/starvation on vitamin K status. However, as the previous text alludes, with vitamin K there is the added complication that this vitamin is also synthesized in the gastrointestinal tract.

Children and Undernutrition

There have been some studies showing positive associations between vitamin K status and childhood bone health, such as total body bone mineral content (van Summeren et al. 2008). However, in children, results are inconclusive in terms of relationships between dietary vitamin K intake and vitamin K status. This could be due to several potential reasons including the large variation in day to day vitamin K intake and difficulties in assessing bioavailability of dietary vitamin K and synthesis by gut microbial population (Cashman 2005).

Recently, Lee et al. (2016) studied 500 children of 6–8 years of age in the southern rural part of Nepal. The study found 100 children (mean age 7.3 years) to be vitamin K deficient. In this study, vitamin K deficiency was defined by plasma concentration of undercarboxylated prothrombin, also known as protein induced by vitamin K absence-II (PIVKA-II) to be more than 2 μg/L. Prothrombin (blood coagulant factor II) is a hepatic vitamin K-dependent protein and abundant in the circulation. PIVKA-II is secreted by the liver when the liver storage of vitamin K is depleted (Lee et al. 2016).

Among the 100 children identified with vitamin K deficiency, 37% and 44% were classified as stunted and underweight, respectively. However, when vitamin K-deficient (n = 100) and vitamin K-sufficient (n = 400) children were compared, the study showed no significant differences in anthropometric measurements (i.e., weight, height, BMI, and mid-upper arm circumference), prevalence of stunting and underweight. The dietary intake of certain foods (i.e., intake of milk, eggs, meat, fish, dark leafy vegetables in the past week) and most of other profiles (e.g., literacy and economics of household) were also not different between vitamin K-deficient (n = 100) and vitamin K-sufficient (n = 400) children. For example, the prevalence of underweight was 44% and 50%, in vitamin K-deficient and vitamin K-sufficient groups, respectively. The authors hypothesized there may be diverse homeostatic responses to subclinical vitamin K status in a generally undernourished young children population (Lee et al. 2016).

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is the collective term for ulcerative colitis and Crohn’s disease. IBD is characterized as a chronic relapsing and remitting inflammation of the digestive tract (Nakajima et al. 2011). Micronutrient deficiency including vitamin K as well as protein energy malnutrition is known to be commonly prevalent in patients with IBD. The prevalence of malnutrition could be as much as 85% of patients regardless of their disease status (i.e., active or remission) (Weisshof and Chermesh 2015). The degree of malnutrition depends on the disease severity including inflammatory processes and, in the case of Crohn’s disease, the area of the gut affected by the disease. Therefore, the etiology of malnutrition in IBD is multifactorial. Common causes of malnutrition include failure to maintain a sufficient dietary intake (poor appetite and imposed dietary restrictions), impaired intestinal absorption (depending on the location and severity of inflammation), and nutrient loss from the inflamed and ulcerated gut (Altomare et al. 2015). Furthermore, nutritional requirements in general increase particularly in the active stages of IBD due to physiological response to inflammation. Moreover, the increased nutritional requirements during the active stages of inflammatory disease may not be coupled with increased nutritional intake for many experiencing physiological symptoms such as abdominal pain, nausea, and diarrhea (Weisshof and Chermesh 2015).

Nakajima et al. (2011) investigated vitamin K status in IBD patients. In their study, vitamin K insufficiency was defined by the comparison of serum concentration of undercarboxylated osteocalcin (ucOC) between IBD patients and healthy subjects. The cutoff value for serum concentration of ucOC to define vitamin K insufficiency was not specified (Nakajima et al. 2011).

Forty seven Crohn’s disease patients, 40 ulcerative colitis patients, and 41 age- and gender-matched healthy subjects were compared (all were Japanese) (Nakajima et al. 2011). Serum ucOC level was statistically significantly higher (p < 0.05) in Crohn’s disease patients when compared to ulcerative colitis patients and healthy subjects. However, when compared ulcerative colitis patients and healthy subjects, serum ucOC level was higher in ulcerative colitis patients compared to healthy subjects, but the differences did not reach of statistical significance.

Although this study did not examine vitamin K dietary intake, the authors argued that insufficient vitamin K intake may not be the main reason to explain the results. This is because, previously, Kuwabara et al. (2009) found vitamin K dietary intake in IBD patients exceeded the daily adequate intake level at the time the study was performed (Kuwabara et al. 2009). The mean vitamin K intake in IBD patients was 131.1 μg in this study (Kuwabara et al. 2009). At the time the adequate intake for vitamin K was 75 μg for adult male and 65 μg for adult female in Japan (MWLH 2004). The adequate intake for vitamin K in Japan was then revised to 150 μg for adult male and female in 2015 (MHLW 2015). Rather than insufficient vitamin K dietary intake, the authors suggested that the statistically higher serum concentration of ucOC found in Crohn’s disease patients compared to the healthy subjects is attributed to reduced dietary fat intake by Crohn’s disease patients. In Japan, Crohn’s disease patients are commonly treated with a fat-reduced diet. The absorption of fat-soluble vitamin K may be compromised in Crohn’s disease patients. Finally, endogenous synthesis of vitamin K by intestinal bacteria may differ between these cohorts, as the bacterial flora composition is significantly altered, particularly in Crohn’s patients, due to inflammation of the gut (Nakajima et al. 2011).

Here, we can suggest that there is a common theme in the aforementioned studies related to children with malnutrition, subjects with anorexia, and patients with IBD. Namely, the microbiological profile of the intestinal tract may complicate the understanding of the relationship between dietary intake of vitamin K and the status of vitamin K sufficiency or deficiency. However, there is little information on the exact amount of vitamin K (menaquinones) produced by intestinal bacteria. Furthermore, some have suggested de novo synthesis of vitamin K (menaquinones) may not be fully dependent on intestinal bacteria as animals lacking a gut microflora still synthesize vitamin K (menaquinones) (LeBlanc et al. 2013). Such theory adds further complication to our understanding of vitamin K homeostasis.

Chronic Kidney Disease

It is widely recognized that cardiovascular diseases are the leading cause of the mortality, morbidity, and hospitalization in end-stage renal failure (ESRF). Coronary artery calcification, a risk factor of cardiovascular disease, is commonly prevalent in ESRF patients compared to population without kidney disease (Chen et al. 2017). The link between vascular calcification, vitamin K status, vitamin K-dependent proteins, and the negative effects of commonly used medications in this cohort (i.e., vitamin K inhibitory action of warfarin) has received attention (Gallieni and Fusaro 2014).

The compromised vitamin K status of this cohort could be due to therapeutic dietary restrictions such as limiting intake of potassium and phosphorous. Commonly restricted dietary components including dairy products, legumes, fruits, and vegetables. Many of these foods contain high concentration of vitamin K as discussed previously (see also Table 1).

Wyskida et al. (2016) investigated the level of functional vitamin K deficiency and its relation to vitamin K1 (phylloquinones) intake in 153 Polish ESRF patients on hemodialysis. In their study, vitamin K status was measured using two surrogate markers, namely, plasma concentration of protein induced by vitamin K absence-II (PIVKA-II) and undercarboxylated matrix Gla protein (ucMGP). The 95% confidence interval around the mean in 20 healthy adult subjects (similar ages to ESRF patients with normal kidney function) were established as a normal, 0.37–0.66 ng/mL and 5.1–9.2 mg/mL, PIVKA-II and ucMGP, respectively. The values in ESRF patients were compared with normal ranges. ESRF patients which had surrogate markers below normal ranges were defined as vitamin K deficient. Dietary vitamin K1 (phylloquinones) intake was assessed for the past year, using a food frequency questionnaire.

The results showed increased plasma concentration of PIVKA-II (>0.66 ng/mL) in 27.5% of ESRF patients. However, the mean plasma concentration of PIVKA-II was not significantly different between ESRF patients and healthy subjects (0.59 ng/mL and 0.51 ng/mL, respectively). The results also found significantly higher mean plasma concentration of ucMGP (17.9 mg/mL) in ESRF patients compared to healthy subjects (7.1 mg/mL, p < 0.001). Increased ucMGP level (>9.2 mg/mL) was found in 77% of ESRF patients (Wyskida et al. 2016).

Median vitamin K1 intake was 103 μg/day in ESRF patients. There were no significant differences between men and women. Of these109 ESRF patients, 34% subjects found to have less than the recommended values for the Polish population (at least 65 μg and 55 μg/day for adult men and adult women, respectively; (Wyskida et al. 2016).

Forty five percent of ESRF patients who showed increased plasma concentration of PIVKA-II (>0.66 ng/mL) had daily intake less than the amount recommended for the Polish population. Authors conducted further analysis of the subgroup of ESRF patients with increased PIVKA-II level > 0.66 ng/mL with the receiver operator curve analysis. ESRF patients with increased plasma concentration of PIVKA-II level > 0.66 ng/mL had lower daily vitamin K1 intake less than 40.2 μg/day, which is below aforementioned Polish daily recommendation. However, for the level of ucMGP, there was no significant difference between patient group whose vitamin K1 intake was greater than the recommendation for the Polish population and the group whose vitamin K intake was below the recommended value.

There was no correlation between plasma concentration of ucMGP and PIVKA-II and between ucMGP and daily vitamin K1 intake. The study demonstrated a correlation between plasma PIVKA-II level and dietary vitamin K intake in ESRF patients. The authors indicated PIVKA-II is superior as a surrogate marker for vitamin K deficiency compared to ucMGP.

Possible factors other than vitamin K dietary intake which could have influenced negatively in vitamin K status of ESRF patients include gut microflora composition, in vivo synthesis of vitamin K2 (menaquinones), impaired vitamin K absorption, or disturbed vitamin K metabolism (Wyskida et al. 2016).

Policies and Protocols

Readers are reminded that to ensure adequate vitamin K intake, one must have a balanced diet. However, one needs to take into account the fact that intake of vitamin K1 or K2 will depend on dietary variations. For example, vitamin K2 intake in the Japanese population is higher than that of the UK population. This is because in Japan fermented foods are an important source of vitamin K2. In the UK the majority of vitamin K comes in the form of K1 from vegetables. One also needs to consider compositional tables in context of portion size, frequency, and also concentrations within foods. For example, natto has a vitamin K concentration of approximately 1 mg per 100 g. It is rarely consumed in the UK. So it is erroneous to say that natto is an important source of vitamin K unless the country (hence the dietary profile of that country) is specified.

In examining reference intakes, one needs to emphasize that we have only discussed values for the UK, USA, and Japan. However, other countries or bodies have different reference intakes. For example, the World Health Organization suggests 55 and 65 micrograms per day for adult women and men, respectably.

Dictionary of Terms

  • Anorexia nervosa – A major form of eating disorders in which the patients starve themselves to induce weight loss. It is a primary psychological illness which can cause significant acute and chronic medical complications. It is not unknown for patients with anorexia nervosa to starve themselves to death.

  • Bioavailability – The proportion of a nutrient or other substance such as a drug that enters the circulation or body system when compared with the amount ingested. A variety of processes can impact on bioavailability, such as the nature of the food matrix, transport processes in the intestine, degradation or metabolism upon entering the gastrointestinal tract, and so on.

  • Bulimia nervosa – A major form of eating disorders. It is a psychological disorder characterized by the binge eating and purging behaviors. It is associated with a numbers of adverse health consequences including increasing suicide risk.

  • Chronic kidney disease – A long-term condition where the functions of the kidneys are gradually impaired. The degree of impairments separates stages of diseases.

  • Crohn’s disease – A condition in which segments of the digestive system become inflamed. Unlike ulcerative colitis, it can affect any part of the gastrointestinal tract. However, most commonly Crohn’s disease affects the terminal part of the ileum or the colon.

  • End-stage renal failure – The final stage of chronic kidney disease where the kidneys are hardly functioning or not functioning at all. The patients can be treated with dialysis or kidney transplant.

  • Fat-soluble vitamins – Fat-soluble vitamins are absorbed and transported with fats in the diet. Fat-soluble vitamins include vitamins A, E, D, and K.

    They have predominantly aromatic and aliphatic characteristics and are soluble in nonpolar solvents. They are stored in the liver and adipose tissue. The term “fat soluble” is used in contrast to “water-soluble vitamins” (such as the B vitamins, folate and vitamin C).

  • Gut microflora – The term is often used interchangeably with gut microbiota. It is the complex communities of microorganisms (e.g., bacteria, fungi and viruses) that inhabit in the digestive tracts of all mammals. In humans, the composition, structure, diversity, and functional capacity of gut microflora are thought to be influenced by various factors. These factors include heredity influences, diet, and medical interventions (the latter, e.g., may be the effects of antibiotics).

  • Hemostasis – The arrest or cessation of bleeding. This involves the physiological process of blood coagulation and constriction of damaged blood vessels. The role of vitamin K within blood coagulation is the most recognized biological role of vitamin K.

  • Natto – A fermented soybeans dish which has high concentrations of vitamin K2.

  • Ulcerative colitis – A condition where varying amounts of the colon and almost always the rectum become inflamed. The most common symptoms include frequent diarrhea (sometime with blood and mucus) and abdominal pain.

  • Vitamin K – Vitamin K is a fat-soluble vitamin, which has two major forms. They are the plant-derived phylloquinones (vitamin K1) and the bacterial-derived menaquinones (vitamin K2). They are abundant in nature and widely distributed in a variety of foods. Phylloquinones are commonly found in green leafy vegetables, pulses, and plant oils. Menaquinones are primarily found in animal sources such as dairy products and meats. Menaquinones are also produced by bacteria. As a consequence relatively high concentrations of menaquinones are found in fermented foods such as natto.

Summary Points

  • Vitamin K is categorized into two major forms. They are plant-derived phylloquinones (vitamin K1) and bacterial-derived menaquinones (vitamin K2). There are many vitamers within each form.

  • Dietary sources of vitamin K are widely distributed. The contributions of different foods will depend on the cultural significance (common or uncommon foods), portion size, and frequency.

  • Phylloquinones (vitamin K1) are commonly found in leafy green vegetables. Menaquinones (vitamin K2) are primarily found in animal sources (e.g., dairy products and meat) and bacterially fermented foods and synthesized by the gut microflora in the large intestine in humans.

  • The exact dietary requirements of vitamin K in numerical terms have not been fully established due to various reasons including difficulties in determining a causal link between plausible biomarkers of vitamin K deficiency and reproducible health outcome measures.

  • Clinically significant vitamin K deficiency is almost nonexistence in healthy populations except for neonatal populations. However, some other population cohort may also be vulnerable. This includes undernourished children, patients with eating disorders, those with inflammatory bowel disease, and patients with chronic kidney disease.

  • Compromised vitamin K deficiency status is multifactorial. These include reduced vitamin K intake, perturbations in absorption, altered de novo synthesis, and interaction with medications.

References

  1. Altomare R, Damiano G, Abruzzo A, Palumbo VD, Tomasello G, Buscemi S, Lo Monte AI (2015) Enteral nutrition support to treat malnutrition in inflammatory bowel disease. Nutrients 7(4):2125–2133.  https://doi.org/10.3390/nu7042125CrossRefPubMedPubMedCentralGoogle Scholar
  2. Berkner KL, Runge KW (2004) The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost 2(12):2118–2132.  https://doi.org/10.1111/j.1538-7836.2004.00968.xCrossRefPubMedGoogle Scholar
  3. Booth SL (2009) Roles for vitamin K beyond coagulation. Annu Rev Nutr 29:89–110.  https://doi.org/10.1146/annurev-nutr-080508-141217CrossRefPubMedGoogle Scholar
  4. Cashman KD (2005) Vitamin K status may be an important determinant of childhood bone health. Nutr Rev 63(8):284–289CrossRefPubMedGoogle Scholar
  5. Chen NC, Hsu CY, Chen CL (2017) The strategy to prevent and regress the vascular calcification in Dialysis patients. Biomed Res Int 2017:9035193.  https://doi.org/10.1155/2017/9035193CrossRefPubMedPubMedCentralGoogle Scholar
  6. Coombs GF, McClung JP (2017) The Vitamins: Fundamental Aspects in Nutrition and Health 5th Edition. Elsevier ScienceGoogle Scholar
  7. Deparment of Health (DH) (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Norwich: The Stationary Office (TSO)Google Scholar
  8. Gallieni M, Fusaro M (2014) Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon? Kidney Int 86(2):232–234.  https://doi.org/10.1038/ki.2014.24CrossRefPubMedGoogle Scholar
  9. Hayes A, Hennessy A, Walton J, McNulty BA, Lucey AJ, Kiely M, Flynn A, Cashman KD (2016) Phylloquinone intakes and food sources and vitamin K status in a nationally representative sample of Irish adults. J Nutr 146(11):2274–2280.  https://doi.org/10.3945/jn.116.239137CrossRefPubMedGoogle Scholar
  10. Howgate DJ, Graham SM, Leonidou A, Korres N, Tsiridis E, Tsapakis E (2013) Bone metabolism in anorexia nervosa: molecular pathways and current treatment modalities. Osteoporos Int 24(2):407–421.  https://doi.org/10.1007/s00198-012-2095-6CrossRefPubMedGoogle Scholar
  11. Kuwabara A, Tanaka K, Tsugawa N, Nakase H, Tsuji H, Shide K, Kamao M, Chiba T, Inagaki N, Okano T, Kido S (2009) High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int 20(6):935–942.  https://doi.org/10.1007/s00198-008-0764-2CrossRefPubMedGoogle Scholar
  12. LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M (2013) Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol 24(2):160–168.  https://doi.org/10.1016/j.copbio.2012.08.005CrossRefPubMedGoogle Scholar
  13. Lee SE, Schulze KJ, Cole RN, Wu LS, Yager JD, Groopman J, Christian P, West KP Jr (2016) Biological Systems of Vitamin K: a plasma Nutriproteomics study of subclinical vitamin K deficiency in 500 Nepalese children. OMICS 20(4):214–223.  https://doi.org/10.1089/omi.2015.0178CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lippi G, Franchini M (2011) Vitamin K in neonates: facts and myths. Blood Transfus 9(1):4–9.  https://doi.org/10.2450/2010.0034-10CrossRefPubMedPubMedCentralGoogle Scholar
  15. Mihatsch WA, Braegger C, Bronsky J, Campoy C, Domellof M, Fewtrell M, Mis NF, Hojsak I, Hulst J, Indrio F, Lapillonne A, Mlgaard C, Embleton N, van Goudoever J (2016) Prevention of vitamin K deficiency bleeding in newborn infants: a position paper by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr 63(1):123–129.  https://doi.org/10.1097/mpg.0000000000001232CrossRefPubMedGoogle Scholar
  16. Ministry of Health, Labour and Welfare (MHLW) (2004) Dietary Reference Intakes for Japanese (2005). Available at http://www.nibiohn.go.jp/en/files/Section_of_the_Dietary_Reference_Intakes/dris2005_eng.pdf. Accessed 21 Aug 2017
  17. Ministry of Health, Labour and Welfare (MHLW) (2015) Overview of Dietary Reference Intakes for Japanese. Available at http://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/Overview.pdf. Accessed 27 July 2017
  18. Nakajima S, Iijima H, Egawa S, Shinzaki S, Kondo J, Inoue T, Hayashi Y, Ying J, Mukai A, Akasaka T, Nishida T, Kanto T, Tsujii M, Hayashi N (2011) Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition 27(10):1023–1028.  https://doi.org/10.1016/j.nut.2010.10.021CrossRefPubMedGoogle Scholar
  19. Price M, Preedy V (2015) Urinary Markers in Nutritional Studies, General Methods in Biomarker Research and their Applications. London: Springer Reference, pp. 547–566Google Scholar
  20. Rishavy MA, Berkner KL (2012) Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Adv Nutr 3(2):135–148.  https://doi.org/10.3945/an.111.001719CrossRefPubMedPubMedCentralGoogle Scholar
  21. Schurgers LJ, Vermeer C (2000) Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis 30(6):298–307.  https://doi.org/10.1159/000054147CrossRefPubMedGoogle Scholar
  22. Scienctific Advisory Committee on Nutrition (SACN) (2011) Dietary Reference Values for Energy. Available at https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/339317/SACN_Dietary_Reference_Values_for_Energy.pdf. Accessed 11 June 2018
  23. Scienctific Advisory Committee on Nutrition (SACN) (2015) Carbohydrates and Health. Available at https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/445503/SACN_Carbohydrates_and_Health.pdf. Accessed 11 June 2018
  24. Shearer MJ, Fu X, Booth SL (2012) Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr 3(2):182–195.  https://doi.org/10.3945/an.111.001800CrossRefPubMedPubMedCentralGoogle Scholar
  25. The National Academies of Sciences Engineering Medicine (NASEM) (2016) Dietary Reference Intakes Tables and Application. Available at http://www.nationalacademies.org/hmd/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx. Accessed 27 July 2017
  26. Urano A, Hotta M, Ohwada R, Araki M (2015) Vitamin K deficiency evaluated by serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa with bone loss. Clin Nutr 34(3):443–448.  https://doi.org/10.1016/j.clnu.2014.04.016CrossRefPubMedGoogle Scholar
  27. van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, Kuis W, Vermeer C (2008) Vitamin K status is associated with childhood bone mineral content. Br J Nutr 100(4):852–858.  https://doi.org/10.1017/s0007114508921760CrossRefPubMedGoogle Scholar
  28. Weisshof R, Chermesh I (2015) Micronutrient deficiencies in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care 18(6):576–581.  https://doi.org/10.1097/mco.0000000000000226CrossRefPubMedGoogle Scholar
  29. World Health Organization (2016) BMI classification. Available at http://apps.who.int/bmi/index.jsp?introPage=intro_3.html. Accessed 11 Dec 16
  30. Wyskida K, Zak-Golab A, Wajda J, Klein D, Witkowicz J, Ficek R, Rotkegel S, Spiechowicz U, Kocemba Dyczek J, Ciepal J, Olszanecka-Glinianowicz M, Wiecek A, Chudek J (2016) Functional deficiency of vitamin K in hemodialysis patients in upper Silesia in Poland. Int Urol Nephrol 48(5):765–771.  https://doi.org/10.1007/s11255-016-1255-6CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Critical Care, Medicine and Surgery, Department of TherapiesRoyal Free Hospital, Royal Free London NHS Foundation TrustLondonUK
  2. 2.Diabetes & Nutritional Sciences DivisionSchool of Medicine, King’s College LondonLondonUK

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