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Vitamin K

Vitamin K 1 (phylloquinone) both forms of the vitamin


contain a functional
naphthoquinone ring and an
aliphatic side chain.
Phylloquinone has a phytyl
side chain.
Vitamin K 2 (menaquinone). In
menaquinone, the side chain
is composed of a varying
number of isoprenoid
residues. The most common
number of these residues is
four, since animal enzymes
normally produce
menaquinone-4 from plant
phylloquinone.
A sample of phytomenadione
for injection, also called
phylloquinone.
Vitamin K refers to a group of structurally
similar, fat-soluble vitamins the human body
needs for complete synthesis of certain
proteins that are required for blood
coagulation , and also certain proteins that the
body uses to manipulate binding of calcium in
bone and other tissues. The vitamin K-related
modification of the proteins allows them to
bind calcium ions, which they cannot do
otherwise. Without vitamin K, blood
coagulation is seriously impaired, and
uncontrolled bleeding occurs. Low levels of
vitamin K also weaken bones and promote
calcification of arteries and other soft tissues.
Chemically, the vitamin K family comprises 2methyl -1,4-naphthoquinone (3-) derivatives .
Vitamin K includes two natural vitamers:
vitamin K 1 and vitamin K 2. [1] Vitamin K 2, in
turn, consists of a number of related chemical
subtypes, with differing lengths of carbon side
chains made of isoprenoid groups of atoms.
Vitamin K 1 , also known as phylloquinone ,
phytomenadione , or phytonadione , is
synthesized by plants, and is found in highest
amounts in green leafy vegetables because it
is directly involved in photosynthesis. It may
be thought of as the "plant" form of vitamin

K. It is active as a vitamin in animals and


performs the classic functions of vitamin K,
including its activity in the production of
blood-clotting proteins. Animals may also
convert it to vitamin K 2.
Vitamin K 2 , the main storage form in animals,
has several subtypes, which differ in
isoprenoid chain length. These vitamin K 2
homologues are called menaquinones, and are
characterized by the number of isoprenoid
residues in their side chains. Menaquinones
are abbreviated MK-n, where M stands for
menaquinone, the K stands for vitamin K, and
the n represents the number of isoprenoid
side chain residues. For example,
menaquinone-4 (abbreviated MK-4) has four
isoprene residues in its side chain.
Menaquinone-4 (also known as
menatetrenone from its four isoprene
residues) is the most common type of vitamin
K 2 in animal products since MK-4 is normally
synthesized from vitamin K 1 in certain animal
tissues (arterial walls, pancreas, and testes)
by replacement of the phytyl tail with an
unsaturated geranylgeranyl tail containing four
isoprene units, thus yielding menaquinone-4.
This homolog of vitamin K 2 may have enzyme
functions distinct from those of vitamin K 1.
Bacteria in the colon (large intestine) can
also convert K 1 into vitamin K 2. In addition,
bacteria typically lengthen the isoprenoid side
chain of vitamin K 2 to produce a range of
vitamin K 2 forms, most notably the MK-7 to
MK-11 homologues of vitamin K 2. All forms of
K 2 other than MK-4 can only be produced by
bacteria, which use these forms in anaerobic
respiration. The MK-7 and other bacterially
derived forms of vitamin K 2 exhibit vitamin K
activity in animals, but MK-7's extra utility
over MK-4, if any, is unclear and is a matter
of investigation.
Three synthetic types of vitamin K are known:
vitamins K 3, K 4, and K 5 . Although the natural
K 1 and all K 2 homologues and synthetic K 4
and K 5 have proven nontoxic, the synthetic
form K 3 ( menadione) has shown toxicity. [2]
Discovery of vitamin K 1
Vitamin K 1 was identified in 1929 by Danish
scientist Henrik Dam when he investigated the
role of cholesterol by feeding chickens a

cholesterol-depleted diet. [3] After several


weeks, the animals developed haemorrhages
and started bleeding. These defects could not
be restored by adding purified cholesterol to
the diet. A second compoundtogether with
the cholesterolapparently had been
extracted from the food, and this compound
was called the coagulation vitamin. The new
vitamin received the letter K because the
initial discoveries were reported in a German
journal, in which it was designated as
Koagulationsvitamin .
Conversion of vitamin K1 to
vitamin K 2 in animals
The MK-4 form of vitamin K 2 is produced by
conversion of vitamin K 1 in the testes,
pancreas, and arterial walls. [4] While major
questions still surround the biochemical
pathway for this transformation, the
conversion is not dependent on gut bacteria,
as it occurs in germ-free rats [5][6] and in
parenterally-administered K 1 in rats. [7][8] In
fact, tissues that accumulate high amounts of
MK-4 have a remarkable capacity to convert
up to 90% of the available K 1 into MK-4. [9]
[10] There is evidence that the conversion
proceeds by removal of the phytyl tail of K 1
to produce menadione as an intermediate,
which is then condensed with an activated
geranylgeranyl moiety (see also prenylation )
to produce vitamin K 2 in the MK-4
(menatetrione) form. [11]
Subtypes of vitamin K 2
Main article: Vitamin K2
Vitamin K 2 (menaquinone) includes several
subtypes. The two subtypes most studied are
menaquinone-4 ( menatetrenone, MK-4) and
menaquinone-7 (MK-7).
Menaquinone-7 is different from MK-4 in that
it is not produced by human tissue. MK-7
consumption has been shown to reduce the
risk of bone fractures and cardiovascular
disorders that are crucial health issues
worldwide. Leading research teams from
Australia, Japan, and Korea are broadening
the understanding of MK-7 and its production.
MK-7 may be converted from phylloquinone
(K 1) in the colon by E. coli bacteria. [12]
However, bacterially derived menaquinones
(MK-7) appear to contribute minimally to

overall vitamin K status. [13][14] MK-4 and


MK-7 are both found in the United States in
dietary supplements for bone health.
The U.S. Food and Drug Administration (FDA)
has not approved any form of vitamin K for
the prevention or treatment of osteoporosis;
however, MK-4 has been shown to decrease
the incidence of fractures up to 87%. [15]
MK-4 (45 mg daily) has been approved by the
Ministry of Health in Japan since 1995 for the
prevention and treatment of osteoporosis. [16]
Vitamin K 2 as MK-4, but not as MK-7 (and
also not vitamin K 1) has also been shown to
prevent bone loss and/or fractures in these
circumstances:
caused by corticosteroids (e.g., prednisone,
dexamethasone, prednisolone), [17][18][19][20]
anorexia nervosa, [21]
cirrhosis of the liver, [22]
postmenopausal osteoporosis, [16][23][24]
[25][26][27]
disuse from stroke, [28]
Alzheimer's disease ,[29]
Parkinson disease , [30]
primary biliary cirrhosis [31]
Chemical structure
The three synthetic forms of vitamin K are
vitamins K 3, K 4, and K 5 , which are used in
many areas, including the pet food industry
(vitamin K 3) and to inhibit fungal growth
(vitamin K 5). [32]
Physiology
Vitamin K 1 , the precursor of most vitamin K
in nature, is a steroisomer of phylloquinone ,
an important chemical in green plants, where
it functions as an electron acceptor in
photosystem I during photosynthesis. For this
reason, vitamin K 1 is found in large quantities
in the photosynthetic tissues of plants (green
leaves, and dark green leafy vegetables such
as romaine lettuce , kale and spinach), but it
occurs in far smaller quantities in other plant
tissues (roots, fruits, etc.). Iceberg lettuce
contains relatively little. The function of
phylloquinone in plants appears to have no
resemblance to its later metabolic and
biochemical function (as "vitamin K") in
animals, where it performs a completely
different biochemical reaction.
Vitamin K (in animals) is involved in the

carboxylation of certain glutamate residues in


proteins to form gamma-carboxyglutamate
(Gla) residues. The modified residues are
often (but not always) situated within specific
protein domains called Gla domains . Gla
residues are usually involved in binding
calcium , and are essential for the biological
activity of all known Gla proteins. [33]
At this time, 16 human proteins with Gla
domains have been discovered, and they play
key roles in the regulation of three
physiological processes:
Blood coagulation : prothrombin (factor II) ,
factors VII, IX , and X , and proteins C , S , and Z
[34]
Bone metabolism: osteocalcin, also called
bone Gla protein (BGP), matrix Gla protein
(MGP), [35] periostin , [36] and the recently
discovered Gla-rich protein (GRP). [37][38]
Vascular biology: growth arrest-specific
protein 6 (Gas6) [39]
Unknown function: proline-rich g-carboxy
glutamyl proteins (PRGPs) 1 and 2, and
transmembrane g-carboxy glutamyl proteins
(TMGs) 3 and 4. [40]
Like other lipid-soluble vitamins (A, D, E),
vitamin K is stored in the fat tissue of the
human body.
Absorption and dietary need
Previous theory held that dietary deficiency is
extremely rare unless the intestine (small
bowel) was heavily damaged, resulting in
malabsorption of the molecule. Another at-risk
group for deficiency were those subject to
decreased production of K 2 by normal
intestinal microbiota, as seen in broad
spectrum antibiotic use. [41] Taking broadspectrum antibiotics can reduce vitamin K
production in the gut by nearly 74% in people
compared with those not taking these
antibiotics. [42] Diets low in vitamin K also
decrease the body's vitamin K concentration.
[43] Those with chronic kidney disease are at
risk for vitamin K deficiency, as well as
vitamin D deficiency , and particularly those
with the apoE4 genotype. [44] Additionally, in
the elderly there is a reduction in vitamin K 2
production. [45]
Recent research results also demonstrate that
the small intestine and large intestine (colon)

seem to be inefficient at absorbing vitamin K


supplements in rat populations low in Vitamin
K. [46][47] These results are reinforced by
human cohort studies, where a majority of the
subjects showed inadequate vitamin K
amounts in the body. This was revealed by
the presence of large amounts of incomplete
gamma-carboxylated proteins in the blood, an
indirect test for vitamin K deficiency. [48][49]
[50] And in an animal model MK-4 was shown
to prevent arterial calcifications, pointing to
its potential role in prevention of such
calcification. [51] In this study vitamin K 1 was
also tested, in an attempt to make
connections between vitamin K 1 intake and
calcification reduction. Only vitamin K 2 (as
MK-4) was found to influence warfarininduced calcification in this study.
Recommended amounts
The U.S. Dietary Reference Intake (DRI) for
an Adequate Intake (AI) of vitamin K for a 25year old male is 120 micrograms (g) per day.
The AI for adult women is 90 g/day, for
infants is 1020 g/day, and for children and
adolescents 15100 g/day. To get maximum
carboxylation of osteocalcin, one may have to
take up to 1000 g of vitamin K 1. [52]
Anticoagulant drug
interactions
Phylloquinone (K 1 ) [53][54] or menaquinone
(K 2) are capable of reversing the
anticoagulant activity of the anticoagulant
warfarin (tradename Coumadin ). Warfarin
works by blocking recycling of vitamin K, so
that the body and tissues have lower levels of
active vitamin K, and thus a deficiency of
vitamin K.
Supplemental vitamin K (for which oral dosing
is often more active than injectable dosing in
human adults) reverses the vitamin K
deficiency caused by warfarin, and therefore
reduces the intended anticoagulant action of
warfarin and related drugs. [55] Sometimes
small amounts of vitamin K (one milligram per
day) are given orally to patients taking
Coumadin so that the action of the drug is
more predictable. [56] The proper
anticoagulant action of the drug is a function
of vitamin K intake and drug dose, and due to
differing absorption must be individualized for

each patient. [citation needed ] The action of


warfarin and vitamin K both require two to
five days after dosing to have maximum
effect, and neither Coumadin or vitamin K
shows much effect in the first 24 hours after
they are given. [57]
In two separate studies in the rat model, after
long term administration of Coumadin to
induce calcification of arteries in the rodents,
supplemental vitamin K was found to reverse
or prevent some of the arterial calcification
attendant on the long-term blockade of
vitamin K. [58] A second study found that only
vitamin K 2 as MK-4, and not vitamin K 1 was
effective at preventing warfarin-induced
arterial calcification in rats, suggesting
differing roles for the two forms of the
vitamin in some calcium-dependent
processes. [59]
The newer anticoagulants dabigatran and
rivaroxaban have different mechanisms of
action that do not interact with vitamin K, and
may be taken with supplemental vitamin K.
[60][61]
Vitamin K 1 is found chiefly in leafy green
vegetables such as dandelion greens (which
contain 778.4 g per 100 g, or 741% of the
recommended daily amount), spinach, swiss
chard, lettuce and Brassica ( e.g. cabbage ,
kale , cauliflower, broccoli, and brussels
sprouts) and often the absorption is greater
when accompanied by fats such as butter or
oils; some fruits , such as avocado, kiwifruit
and grapes , are also high in vitamin K. By
way of reference, two tablespoons of parsley
contain 153% of the recommended daily
amount of vitamin K. [64] Some vegetable oils,
notably soybean, contain vitamin K, but at
levels that would require relatively large
calorific consumption to meet the USDArecommended levels. [65] Colonic bacteria
synthesize a significant portion of humans'
vitamin K needs; newborns often receive a
vitamin K shot at birth to tide them over until
their colons become colonized at five to
seven days of age from the consumption of
their mother's milk.
Phylloquinone's tight binding to thylakoid
membranes in chloroplasts makes it less
bioavailable. For example, cooked spinach has

a 5% bioavailability of phylloquinone, however,


fat added to it increases bioavailability to 13%
due to the increased solubility of vitamin K in
fat. [66]
Vitamin K 2
Food sources of vitamin K 2 include fermented
or aged cheeses, eggs, meats such as chicken
and beef and their fat, livers, and organs, and
in fermented vegetables, especially natto , as
well as sauerkraut and kefir.
Vitamin K 2 (menaquinone-4) is synthesized by
animal tissues and is found in meat, eggs, and
dairy products. [68] Menaquinone-7 is
synthesized by bacteria during fermentation
and is found in fermented soybeans ( natto ),
and in most fermented cheeses. [69] In natto ,
none of the vitamin K is from menaquinone-4,
and in cheese only 27% is. [70]
Deficiency
Main article: Vitamin K deficiency
Average diets are usually not lacking in
vitamin K, and primary deficiency is rare in
healthy adults. Newborn infants are at an
increased risk of deficiency. Other populations
with an increased prevalence of vitamin K
deficiency include those who suffer from liver
damage or disease (e.g., alcoholics), cystic
fibrosis, or inflammatory bowel diseases, or
have recently had abdominal surgeries.
Secondary vitamin K deficiency can occur in
bulimics, those on stringent diets, and those
taking anticoagulants. Other drugs associated
with vitamin K deficiency include salicylates,
barbiturates, and cefamandole, although the
mechanisms are still unknown. Vitamin K 1
deficiency can result in coagulopathy , a
bleeding disorder. [71] Symptoms of K 1
deficiency include anemia, bruising, and
bleeding of the gums or nose in both sexes,
and heavy menstrual bleeding in women.
Osteoporosis [72][73] and coronary heart
disease [74][75] are strongly associated with
lower levels of K 2 (menaquinone). Vitamin K 2
(MK-7) deficiency is also related to severe
aortic calcification and all-cause mortality. [76]
Menaquinone is not inhibited by salicylates as
happens with K 1, so menaquinone
supplementation can alleviate the chronic
vitamin K deficiency caused by long-term

aspirin use. [citation needed ]


Toxicity
Although allergic reaction from
supplementation is possible, no known toxicity
is associated with high doses of the
phylloquinone (vitamin K 1 ) or menaquinone
(vitamin K 2) forms of vitamin K, so no
tolerable upper intake level (UL) has been set.
[77]
Blood clotting ( coagulation ) studies in humans
using 45 mg per day of vitamin K 2 (as MK-4)
[27] and even up to 135 mg/day (45 mg three
times daily) of K 2 (as MK-4), [78] showed no
increase in blood clot risk. Even doses in rats
as high as 250 mg/kg body weight did not
alter the tendency for blood-clot formation to
occur. [79]
Unlike the safe natural forms of vitamin K 1
and vitamin K 2 and their various isomers , a
synthetic form of vitamin K, vitamin K 3
( menadione), is demonstrably toxic. The U.S.
FDA has banned this form from over-thecounter sale in the United States because
large doses have been shown to cause
allergic reactions, hemolytic anemia , and
cytotoxicity in liver cells. [2]
Biochemistry
Vitamin K structures. MK-4 and MK-7 are both
subtypes of K 2.
The function of vitamin K 2 in the animal cell
is to add a carboxylic acid functional group to
a glutamate amino acid residue in a protein,
to form a gamma-carboxyglutamate (Gla)
residue. This is a somewhat uncommon
posttranslational modification of the protein,
which is then known as a "Gla protein." The
presence of two -COOH (carboxylate) groups
on the same carbon in the gammacarboxyglutamate residue allows it to chelate
calcium ion. The binding of calcium ion in this
way very often triggers the function or binding
of Gla-protein enzymes, such as the so-called
vitamin K dependent clotting factors
discussed below.
Within the cell, vitamin K undergoes electron
reduction to a reduced form called vitamin K
hydroquinone by the enzyme vitamin K
epoxide reductase (VKOR). [80] Another
enzyme then oxidizes vitamin K hydroquinone
to allow carboxylation of Glu to Gla; this

enzyme is called the gamma-glutamyl


carboxylase [81][82] or the vitamin Kdependent carboxylase. The carboxylation
reaction only proceeds if the carboxylase
enzyme is able to oxidize vitamin K
hydroquinone to vitamin K epoxide at the
same time. The carboxylation and epoxidation
reactions are said to be coupled. Vitamin K
epoxide is then reconverted to vitamin K by
VKOR. The reduction and subsequent
reoxidation of vitamin K coupled with
carboxylation of Glu is called the vitamin K
cycle. [83] Humans are rarely deficient in
vitamin K 1 because, in part, vitamin K 1 is
continuously recycled in cells. [84]
Warfarin and other 4-hydroxycoumarins block
the action of the VKOR. [85] This results in
decreased concentrations of vitamin K and
vitamin K hydroquinone in the tissues, such
that the carboxylation reaction catalyzed by
the glutamyl carboxylase is inefficient. This
results in the production of clotting factors
with inadequate Gla. Without Gla on the
amino termini of these factors, they no longer
bind stably to the blood vessel endothelium
and cannot activate clotting to allow
formation of a clot during tissue injury. As it
is impossible to predict what dose of warfarin
will give the desired degree of clotting
suppression, warfarin treatment must be
carefully monitored to avoid overdose.
Main article: gla domain
The following human Gla-containing proteins
("gla proteins") have been characterized to
the level of primary structure: the blood
coagulation factors II (prothrombin), VII, IX,
and X, the anticoagulant proteins C and S, and
the factor X-targeting protein Z . The bone Gla
protein osteocalcin, the calcification-inhibiting
matrix Gla protein (MGP), the cell growth
regulating growth arrest specific gene 6
protein (Gas6), and the four transmembrane
Gla proteins (TMGPs), the function of which
is at present unknown. Gas6 can function as
a growth factor to activate the Axl receptor
tyrosine kinase and stimulate cell proliferation
or prevent apoptosis in some cells. In all
cases in which their function was known, the
presence of the Gla residues in these proteins
turned out to be essential for functional

activity.
Gla proteins are known to occur in a wide
variety of vertebrates: mammals, birds,
reptiles, and fish. The venom of a number of
Australian snakes acts by activating the
human blood-clotting system. In some cases,
activation is accomplished by snake Glacontaining enzymes that bind to the
endothelium of human blood vessels and
catalyze the conversion of procoagulant
clotting factors into activated ones, leading to
unwanted and potentially deadly clotting.
Another interesting class of invertebrate Glacontaining proteins is synthesized by the fishhunting snail Conus geographus . [86] These
snails produce a venom containing hundreds
of neuroactive peptides, or conotoxins, which
is sufficiently toxic to kill an adult human.
Several of the conotoxins contain two to five
Gla residues. [87]
Vitamin K status can be assessed by:
The prothrombin time (PT) test measures
the time required for blood to clot. A blood
sample is mixed with citric acid and put in a
fibrometer; delayed clot formation indicates a
deficiency. This test is insensitive to mild
deficiency, as the values do not change until
the concentration of prothrombin in the blood
has declined by at least 50%. [88]
Undercarboxylated prothrombin (PIVKA-II),
in a study of 53 newborns, found "PT
(prothrombin time) is a less sensitive marker
than PIVKA II", [89] and as indicated above, PT
is unable to detect subclinical deficiencies
that can be detected with PIVKA-II testing.
Plasma phylloquinone was found to be
positively correlated with phylloquinone intake
in elderly British women, but not men, [90]
but an article by Schurgers et al. reported no
correlation between FFQ and plasma
phylloquinone. [91]
Urinary -carboxyglutamic acid responds to
changes in dietary vitamin K intake. Several
days are required before any change can be
observed. In a study by Booth et al. , increases
of phylloquinone intakes from 100 g to
between 377 and 417 g for five days did not
induce a significant change. Response may be
age-specific. [92]
Undercarboxylated osteocalcin (UcOc)

levels have been inversely correlated with


stores of vitamin K [93] and bone strength in
developing rat tibiae. Another study following
78 postmenopausal Korean women found a
supplement regimen of vitamins K and D, and
calcium, but not a regimen of vitamin D and
calcium, was inversely correlated with
reduced UcOc levels. [94]
Many bacteria, such as Escherichia coli found
in the large intestine , can synthesize vitamin
K 2 (menaquinone-7 or MK-7, up to MK-11),
[95] but not vitamin K 1 (phylloquinone). In
these bacteria, menaquinone transfers two
electrons between two different small
molecules, during oxygen-independent
metabolic energy production processes
( anaerobic respiration). [96] For example, a
small molecule with an excess of electrons
(also called an electron donor) such as
lactate , formate , or NADH , with the help of an
enzyme, passes two electrons to a
menaquinone. The menaquinone, with the help
of another enzyme, then transfers these two
electrons to a suitable oxidant, such fumarate
or nitrate (also called an electron acceptor).
Adding two electrons to fumarate or nitrate
converts the molecule to succinate or nitrite +
water, respectively.
Some of these reactions generate a cellular
energy source, ATP, in a manner similar to
eukaryotic cell aerobic respiration, except the
final electron acceptor is not molecular
oxygen, but fumarate or nitrate . In aerobic
respiration, the final oxidant is molecular
oxygen (O 2), which accepts four electrons
from an electron donor such as NADH to be
converted to water . E. coli , as facultative
anaerobes , can carry out both aerobic
respiration and menaquinone-mediated
anaerobic respiration.
Injection in newborns
The blood clotting factors of newborn babies
are roughly 30 to 60% that of adult values;
this may be due to the reduced synthesis of
precursor proteins and the sterility of their
guts. Human milk contains 14 g/L of
vitamin K 1, while formula-derived milk can
contain up to 100 g/L in supplemented
formulas. Vitamin K 2 concentrations in human
milk appear to be much lower than those of

vitamin K 1. Occurrence of vitamin K


deficiency bleeding in the first week of the
infant's life is estimated at 0.25 to 1.7%, with
a prevalence of two to 10 cases per 100,000
births. [97] Premature babies have even lower
levels of the vitamin, so they are at a higher
risk from this deficiency.
Bleeding in infants due to vitamin K
deficiency can be severe, leading to
hospitalization, blood transfusions, brain
damage, and death. Supplementation can
prevent most cases of vitamin K deficiency
bleeding in the newborn. Intramuscular
administration is more effective in preventing
late vitamin K deficiency bleeding than oral
administration. [98][99]
As a result of the occurrences of vitamin K
deficiency bleeding, the Committee on
Nutrition of the American Academy of
Pediatrics has recommended 0.5 to 1.0 mg
vitamin K 1 be administered to all newborns
shortly after birth. [99]
In the UK vitamin K supplementation is
recommended for all newborns within the first
24 hours. [100] This is usually given as a
single intramuscular injection of 1 mg shortly
after birth but as a second-line option can be
given by three oral doses over the first
month. [101]
Controversy arose in the early 1990s
regarding this practice, when two studies
suggested a relationship between parenteral
administration of vitamin K and childhood
cancer, [102] however, poor methods and small
sample sizes led to the discrediting of these
studies, and a review of the evidence
published in 2000 by Ross and Davies found
no link between the two. [103] Doctors
reported emerging concerns in 2013, [104]
after treating children for serious bleeding
problems. They cited lack-of newborn Vitamin
K administration, as the reason that the
problems occurred, and recommended that
breast-fed babies could have an increased risk
unless they receive a preventative dose.
Health effects
There is no good evidence that vitamin K
supplementation helps prevent osteoporosis or
fractures in postmenopausal women. [105]
45 mg daily MK-4 has been approved by the

Ministry of Health in Japan since 1995 for the


prevention and treatment of osteoporosis. [16]
MK-4 (but not MK-7 or vitamin K 1) prevented
bone loss and/or fractures in the following
circumstances:
caused by corticosteroids (e.g., prednisone,
dexamethasone , prednisolone ) [17][18][19][20]
anorexia nervosa [21]
cirrhosis of the liver[22]
postmenopausal osteoporosis[16][23][24]
[25][26][27]
disuse from stroke[28]
Alzheimer's disease [29]
Parkinson disease [30]
primary biliary cirrhosis [31]
leuprolide treatment (for prostate cancer).
[106]
Menaquinone-7 (MK-7), which is abundant in
fermented soybeans (natto), has been
demonstrated to stimulate osteoblastic bone
formation and to inhibit osteoclastic bone
resorption. [107] In another study, use of MK-7
caused significant elevations of serum Ycarboxylated osteocalcin concentration, a
biomarker of bone formation. MK-7 also
completely inhibited a decrease in the calcium
content of bone tissue by inhibiting the boneresorbing factors parathyroid hormone and
prostaglandin E 2. [108] On 19 February 2011,
HSA (Singapore) approved a health
supplement that contains vitamin K 2 (MK-7)
and vitamin D 3 for increasing bone mineral
density. [ citation needed ]
The potential benefit of vitamin k in reducing
cardiovascular disease (CVD) risk is due to its
function as a cofactor in the post-translational
modification of matrix gla protein (MGP) in
vascular smooth muscle cells (VSMC).
Increased calcification of blood vessels is a
risk factor for CVD as it lends to the
hardening of arteries and/or to the
development of hard atherosclerotic plaque.
MGP may play a role in preventing ectopic
calcification in the arteries. Although the
mechanism of MGP on arterial calcification is
not fully understood, it is known that MGP
must be in its active form to have a beneficial
effect in the blood vessel. MGP becomes
activated by carboxylation, which requires
vitamin k as a cofactor. Because it is thought

that phylloquinones exerts its actions mainly


in the liver, it is speculated that
menaquinones may have a more significant
influence in the extra-hepatic regions of the
body, such as VSMCs, where they are known
to travel to by LDL. [109] In addition,
menaquinones have been demonstrated to
have a longer half-life in circulation compared
to phylloquinone. [109] Menaquinones may
therefore be important for preventing vascular
calcification (VC) and thus reducing risk for
CVD.
Previous research conducted on MGP
knockout mice demonstrated the importance
of MGP on inhibiting VC. Luo, Ducy, McKee,
Pinero, Loyer, Behringer, and Karsenty (1997)
found that the aorta of MGP knockout mice
became severely calcified within the first two
months of life, leading to rupture of the artery
and finally death of the mice due to internal
hemorrhaging. [110] This study became a basis
for many future studies to further explore the
influence of MGP on VC since it was
hypothesized that if a human had low levels
of MGP they could develop VC more quickly
than those with optimal levels of MGP. It
became a question as to whether MGP could
help to reduce the risk of CVD development.
However, because MGP undergoes different
post-translational modifications, several forms
of MGP can exist in the human body, so
which form of MGP is most effective at
preventing VC? Schurgers, Spronk, Soute,
Schiffers, DeMay, andVermeer (2007) found
that the carboxylated form of MGP was
responsible for reducing VC in rats. [111] In
the study, rats were subjected to a dose of
warfarin to induce VC. Warfarin is a
commonly prescribed drug given to humans to
help prevent heart disease and stroke by
reducing the development of blood clots in
the blood vessels. Warfarin acts to inhibit the
vitamin k cycle; thereby preventing activation
of essential blood clotting factors. In the
aforementioned study, VC was significantly
decreased in the rats inflicted with VC via
warfarin, when supplemented for 6 weeks with
a high dose of either menaquinone or
phylloquinone. [111] Both menaquinone and
phylloquinone supplementation in

concentrations of 100 g/g (supplied in the


rat food), were able to inflict a significant
reduction in VC in the rats. [111] When
examining the different MGP forms in the
rats, it was found that the high menaquinone
and phylloquinone supplement groups had
greater levels of carboxylated MGP compared
to the control, rats receiving warfarin, and
rats receiving a normal phylloquinone dose.
[111] Furthermore, levels of uncarboxylated
MGP were higher in the rats receiving
warfarin and in the rats receiving a normal
phylloquinone dose. [111] This study
demonstrated a benefit of both menaquinone
and phylloquinone on VC but did not
determine the mechanism by which
carboxylated MGP was able to reduce VC. In
2008, Wallin, Schurgers, and Wajih set out to
help establish this mechanism. The
researchers evaluated uncarboxylated MGP
and carboxylated MGP by experimenting with
the glutamic acid and gammacarboxyglutamic acid residues of MGP. [112] It
was found that the gamma-carboxyglutamic
acid residues were capable of inhibiting a
protein called bone morphogenic protein-2
(BMP-2), that may play a role in
differentiation of vascular smooth muscle
cells (VSMCs) into bone-like cells. [112] On
the other hand, the glutamic acid residues
were unable to inhibit BMP-2, which
confirmed that MGP must be carboxylated to
be active in VC inhibition. [112]
Intervention studies with menaquinones in
humans have become more frequently
published in recent years. In a randomized,
double blind, placebo controlled human trial,
menaquinone-7 supplementation was studied
in healthy adults for its influence on
circulating forms of MGP. In the twelve-week
study, sixty adults were divided into three
supplement groups: placebo, 180 g
menaquinone-7/day, and 360 g
menaquinone-7/day and circulating forms of
MGP were analyzed from blood and urine
samples that were collected at weeks 1, 4,
and 12. [113] The researchers found that after
only 4 weeks of menaquinone-7
supplementation, the total level of
dephosphorylated-uncarboxylated MGP was

decreased compared to baseline and that the


effect was dose dependent with 360 g
menaquinone-7/day having a greater effect
than 180 g menaquinone-7/day. [113]
Furthermore, no change in dephosphorylateduncarboxylated MGP was evident in the
placebo group. [113] In another study
examining the relationship between
menaquinone-7 supplementation and
circulating dephosphorylated-uncarboxylated
MGP levels, 165 patients undergoing chronic
hemodialysis were divided into three
menaquinone-7 supplementation groups: 360
g/day, 720 g/day, or 1080 g/day for a total
of 8 weeks. [114] At baseline, it was
determined through 3-day food diaries that
there was a significant inverse relationship
between menaquinone intake and
dephosphorylated-uncarboxylated MGP levels,
whereas phylloquinone intake had no
association. [114] After 8 weeks of
menaquinone-7 supplementation, the
researchers found that circulating
dephosphorylated-uncarboxylated MGP levels
had significantly decreased, and that the
effect was dose dependent. [114]
Unfortunately, other forms of MGP were not
measured. In both of these aforementioned
studies, neither examined the relationship of
dephosphorylated-uncarboxylated MGP levels
to VC or CVD. However, a recent cohort study
investigating vitamin k insufficiency and CVD
found that low circulating dephosphorylateduncarboxylated MGP levels (less than 400
pmol/L) were significantly associated with
increased risk of fatal and non-fatal CVD in
577 healthy men and women aged 55 65
years. [115]
If VC can be prevented or reduced by
menaquinones then the risk for CVD may also
be reduced. Future strategies to reduce the
risk of CVD may one day encourage
increasing ones intake of dietary
menaquinone.
A study by Gast et al. (2009), [75] reports "an
inverse association between vitamin K 2 and
risk of CHD with a Hazard Ratio (HR) of 0.91
[95% CI 0.851.00] per 10 g/d vitamin K 2
intake. This association was mainly due to
vitamin K 2 subtypes MK-7, MK-8 and MK-9.

Vitamin K 1 intake was not significantly


related to CHD. The authors conclude that "a
high intake of menoquinones, especially MK-7,
MK-8 and MK-9, could protect against CHD.
However, more research is necessary to
define optimal intake levels of vitamin K
intake for the prevention of CHD."
Research into the antioxidant properties of
vitamin K indicates that the concentration of
vitamin K is lower in the circulation of
carriers of the APOE4 gene, and recent
studies have shown its ability to inhibit nerve
cell death due to oxidative stress . It has been
hypothesized that vitamin K may reduce
neuronal damage and that supplementation
may hold benefits to treating Alzheimer's
disease , although more research is necessary
in this area. [116]
While researchers in Japan were studying the
role of vitamin K 2 as the menaquinone-4
(MK-4) form in the prevention of bone loss in
females with liver disease, they discovered
another possible effect. This two-year study
that involved 21 women with viral liver
cirrhosis found that women in the supplement
group were 90% less likely to develop liver
cancer . [117][118] A prospective (i.e.,
longitudinal) study performed in healthy men
reported a significant inverse association
between vitamin K 2 consumption and the risk
of advanced prostate cancer. [119]
In 2006, a clinical trial showed that K 2 as the
menaquinone-4 (MK-4) (called menatetrenone
in the study) might be able to reduce
recurrence of liver cancer after surgery. It
should be noted that this was a small pilot
study and other similar studies did not show
much effect. MK-4 is now being tested along
with other drugs to reduce liver cancer and
has shown promising early results. [120]
A research shows that total diabetes risk of
individual who have highest circulating levels
of vitamin K 1 were 51% lower than those with
the lowest levels. The researchers conclude
that dietary phylloquinone intake is associated
with reduced risk of type 2 diabetes. [121]
A research shows that the risk of developing
non-Hodgkin lymphoma was decreased by 45
percent for the study participants who had
the highest vitamin K levels compared to

participants with the lowest levels of the


vitamin. [122]
Vitamin K is part of the suggested treatment
regime for poisoning by rodenticide . [123]
Vitamin K antagonists are substances that
reduce blood clotting by reducing the active
form of vitamin K. They are used as rat
poisons and as medications to prevent
thrombosis . Examples include 4hydroxycoumarins such as the pharmaceutical
warfarin , and also anticoagulant-mechanism
poisons such as bromadiolone , which are
commonly found in
rodenticides . [citation needed ]
4-Hydroxycoumarin drugs possess
anticoagulatory and rodenticidal properties
because they inhibit recycling of vitamin K
and thus cause simple deficiency of active
vitamin K. This deficiency results in
decreased vitamin K-dependent synthesis of
some clotting factors by the liver. Death is
usually a result of internal hemorrhage.
Treatment for rodenticide poisoning usually
consists of repeated intravenous doses of
vitamin K, followed by doses in pill form for a
period of at least two weeks, though possibly
up to 2 months, after poisoning (this is
necessary for the more potent 4hydoxycoumarins used as rodenticides, which
act by being fat-soluble and thus having a
longer residence time in the body). If caught
early, prognosis is good even when great
amounts of the drug or poison are ingested,
as these drugs are not true vitamin K
antagonists, so the same amount of fresh
vitamin K administered each day is sufficient
for any dose of poison (although as noted, this
must be continued for a longer time with more
potent poisons). No matter how large the
dose of these agents, they can do no more
than prevent vitamin K from being recycled,
and this metabolic problem may always be
simply reversed by giving sufficient vitamin K
(often 5 mg per day) to ensure that enough
fresh vitamin K resides in the tissues to carry
out its normal functions, even when efficient
use of it by the body is prevented by the
poison. [medical citation needed ]
A recent study has shown that rats who are
fed excess amounts of vitamin K had greater

amounts of brain sulfatide concentrations.


[124] This study indicates that vitamin K has
more uses than originally thought, thus
furthering the importance of daily vitamin K
intake. The same study showed that a diet
with insufficient vitamin K levels decreased
the brain sulfatide concentrations in rats at
the (p < 0.01) significance level. Another
study involving rats has indicated that
different species, strains and genders of rats
required different amounts of vitamin K
intake, depending on how much was stored in
their livers. [125] This may indicate that
different humans should have different needs
for their vitamin K intake. A third study looked
at the way rats and chicks are able to recycle
parts of vitamin K. The study found that
chicks are about 10% less efficient in
recycling the vitamin K than their rat
counterparts. [126] This evidences also helps
to confirm that vitamin K levels are unique to
each species, and the previous study shows
that required vitamin K intake also varies
within species.
Vitamin K may be applied topically, typically
as a 5% cream, to diminish postoperative
bruising from cosmetic surgery and injections,
to treat broken capillaries (spider veins), to
treat rosacea, and to aid in the fading of
hyperpigmentation and dark under-eye circles.
[127][128]
History of discovery
In 1929, Danish scientist Henrik Dam
investigated the role of cholesterol by feeding
chickens a cholesterol-depleted diet. [3] After
several weeks, the animals developed
hemorrhages and started bleeding. These
defects could not be restored by adding
purified cholesterol to the diet. It appeared
thattogether with the cholesterola second
compound had been extracted from the food,
and this compound was called the coagulation
vitamin. The new vitamin received the letter
K because the initial discoveries were
reported in a German journal, in which it was
designated as Koagulationsvitamin. Edward
Adelbert Doisy of Saint Louis University did
much of the research that led to the
discovery of the structure and chemical
nature of vitamin K. [129] Dam and Doisy

shared the 1943 Nobel Prize for medicine for


their work on vitamin K (K 1 and K 2 ) published
in 1939. Several laboratories synthesized the
compound(s) in 1939. [130]
For several decades, the vitamin K-deficient
chick model was the only method of
quantifying vitamin K in various foods: the
chicks were made vitamin K-deficient and
subsequently fed with known amounts of
vitamin K-containing food. The extent to
which blood coagulation was restored by the
diet was taken as a measure for its vitamin K
content. Three groups of physicians
independently found this: Biochemical
Institute, University of Copenhagen (Dam and
Johannes Glavind), University of Iowa
Department of Pathology ( Emory Warner,
Kenneth Brinkhous, and Harry Pratt Smith ),
and the Mayo Clinic ( Hugh Butt, Albert Snell ,
and Arnold Osterberg). [131]
The first published report of successful
treatment with vitamin K of life-threatening
hemorrhage in a jaundiced patient with
prothrombin deficiency was made in 1938 by
Smith, Warner, and Brinkhous. [132]
The precise function of vitamin K was not
discovered until 1974, when three laboratories
(Stenflo et al. , [133] Nelsestuen et al. ,[134] and
Magnusson et al. [135] ) isolated the vitamin Kdependent coagulation factor prothrombin
(Factor II) from cows that received a high
dose of a vitamin K antagonist, warfarin . It
was shown that, while warfarin -treated cows
had a form of prothrombin that contained 10
glutamate amino acid residues near the amino
terminus of this protein, the normal
(untreated) cows contained 10 unusual
residues that were chemically identified as
gamma-carboxyglutamate, or Gla. The extra
carboxyl group in Gla made clear that vitamin
K plays a role in a carboxylation reaction
during which Glu is converted into Gla.
The biochemistry of how vitamin K is used to
convert Glu to Gla has been elucidated over
the past thirty years in academic laboratories
throughout the world.