**2. Avian vitamin K requirements**

Given that the original identification of vitamin K was made in the chicken by Henrik Dam [19, 20], it is appropriate to begin this overview by considering avian species. The early work of Dam demonstrated that chicks fed a diet designed to be deficient in sterols, following the non‐ polar solvent extraction of their feed, developed subdural or muscular hemorrhage and presented with a retardation in their blood clotting time. Subsequent experiments demon‐ strated that Inclusion of other essential nutrients, which were known at that time, did not prevent hemorrhage, suggesting the existence of a new vitamin.

Extending his investigations, Dam determined that geese and ducks were also susceptible to the development of clotting problems, but pigeons and canaries appeared to be much less prone to develop hemorrhagic problems [21].

Due to the enormous value of avian species in human nutrition, vitamin K sufficiency is an important subject. Furthermore, the more recent suggestion of a role for vitamin K in skeletal biology also promotes the understanding of adequate vitamin K nutrition in avian species, such as the turkey, which is prone to suffer from skeletal health problems [22] and which has considerable economic consequences [23]. Similarly, broiler chickens, with their rapid growth requirements, also have skeletal health problems [24]. The vitamin K in the feed for hens to offset skeletal health problems has been investigated, and there is some benefit from 8 to 10  mg/Kg feed of vitamin K3 [25, 26]. A more recent study [27] has suggested that in the chicken, the liver and the pancreas process vitamin K, and in particular menaquinone‐4, in different ways. The observation of a 10‐fold greater proportion of menaquinone‐4 epoxide in the chicken pancreas as compared to the liver suggested that the vitamin K 2,3‐epoxide reductase complex (VKOR) may not be as efficient in the avian pancreas as it is in the liver.

The production demands on laying hens also puts considerable strains on the bird's skeleton, which has also been shown to benefit from additional vitamin K3 in the diet [28]. From the discussion on the need to modify vitamin K3 into an active form of vitamin K, there is a strong likelihood of commercial avian health needs being met by the conversion of vitamin K3 into vitamin K2, as either menaquinone‐4 or, with the potential for coprophagy, longer chain menaquinones from fecal bacteria.

Non‐commercial avian species have received little attention for their vitamin K requirements. However, it should be noted that wild birds can often be the casualties of deliberate or accidental poisoning from anticoagulant agents that inhibit the vitamin K cycle [29, 30].

#### **2.1. Rodentia and Lagomorpha**

#### *2.1.1. The rat*

possible for the specific form of vitamer, menaquinone‐4, to be synthesized in animal tissues from vitamin K3 [5–7]. It is also worth noting that, in the rat, vitamin K1 can be converted to

The general understanding of vitamin K in the physiology and pathophysiology of animal health and well‐being is less well developed than it is for man. As with man, overt vitamin K deficiency is rare in animals and several examples will be identified. It is clearly not possible to cover all animal species in this overview, and we have selected a reasonably broad range of

With respect to captive collection species, although not discussed here as there is very limited information available, the general concepts of vitamin K in the health and well‐being of these animals are open to review. This is particularly pertinent to the conservation programmes to support endangered animal breeding projects, as vitamin K2 is beginning to be highlighted as

For the purposes of this overview, animals can be broadly divided into herbivores and omnivore/carnivores. Common sense would suggest that the former group would be consid‐ ered to derive most of their vitamin K from the plant vitamer, vitamin K1. We will demonstrate that this is not a simple extrapolation to food source and that vitamin K2 congeners can, in some cases, be at least as dominant a source of vitamin K. The latter grouping of animals is diverse, and we will develop the hypothesis that the vitamin K2 congeners are a dominant form of vitamin K that makes a significant contribution to maintaining the vitamin K status of

Investigation into the feeding practices for domesticated animals, both companion and agricultural animals, demonstrates that there are several examples where nutritional devel‐ opments of animal feeds have defaulted into the use of vitamin K3, even though this naph‐ thoquinone compound is unable to participate directly in the gamma‐carboxylation of vitamin K‐dependent proteins [11]. The value of vitamin K3 in animal nutrition may be derived, in part, from its role as a bacterial growth factor [12–14], where it is converted into vitamin K2 [15]. Many bacteria, particularly the gram‐positive bacteria, contain vitamin K2 as their major quinone [16–18]. There are indications that vitamin K2 derived from intestinal bacteria contribute to the vitamin K status of some animals, such as ruminants, more than other animals,

The following sections will discuss where animals derive their source, or sources, of vitamin K and, where known, what vitamin K‐related health pathologies have been described in

Given that the original identification of vitamin K was made in the chicken by Henrik Dam [19, 20], it is appropriate to begin this overview by considering avian species. The early work of Dam demonstrated that chicks fed a diet designed to be deficient in sterols, following the non‐

menaquinone‐4 without the need for bacterial mediators [8–10].

and this will be discussed in more detail in the relevant sections.

**2. Avian vitamin K requirements**

important agricultural and companion animals.

an essential factor in embryogenesis.

216 Vitamin K2 - Vital for Health and Wellbeing

these animals.

animals.

The wild the rat, as an omnivore, will derive their vitamin K from a variety of sources such as plant material and dead animal tissues and also from bacteria in decaying plant and animal materials. In the laboratory, the rat has been the most extensively investigated animal for vitamin K physiological and pathophysiological requirements. It has provided the standard, from which much human investigation has been initiated.

One of the fundamental elements of undertaking a rodent experiment on vitamin K has been the need to derive an animal with a vitamin K deficiency that survives long enough for investi‐ gation. Outside the use of a vitamin K‐specific anticoagulants, such as warfarin and brodifa‐ coum, this has been difficult to achieve nutritionally derived vitamin K deficiency [31,32]; Dr Cees Vermeer, personal communication. With fastidious experimentation, it is possible to reduce vitamin K tissue levels in rats, and with certain diets, this can affect the intestinal vitamin K2‐producing flora [33].

agy is also normal for the wild rabbit [42]. The caecum of the rabbit is a perfect environment for the incubation of numerous species of bacteria [43] and that the nursing doe probably carries the responsibility for ensuring her kittens have the appropriate intestinal/caecal microbial flora established early in life [44]. Indeed, an incorrect microbiota platform may lead

Vitamin K2 in Animal Health: An Overview http://dx.doi.org/10.5772/63901 219

The sequelae from the discussion on coprophagy in the rabbit are that the recycling of bacterial contents from feces and maybe, importantly, the caecal content microbiota could contribute significantly to the animal's vitamin K status, in addition to their nutritional vitamin K1 intake. This has not been directly measured in the rabbit, but while there is ongoing debate about the vitamin K2 nutritional benefits from large bowel absorption of these fat‐soluble vitamins, the

There is no information on the hare that describes how it meets its full requirements for vitamin K, and presumably, the rabbit serves as an appropriate example to draw similar conclusions.

Agricultural species are important for essential food and other product production, and the health and well‐being of livestock is important for their growth and reproduction. We will consider several major animal species, but with centuries of breeding and a wide diversity in breeds, we take a generic position in descriptions, except where specific health problems have been identified. The horse is included in this discussion as, while there is a substantial element of meat production from the horse and related species, it also has value in equine sport activities

With over 200 sheep breeds that have been reared over thousands of years for different features, such as wool, milk, skins, meat and even the ability to clear vegetation, a great deal of genetic diversity has been engineered into the different flocks. As committed grazing herbivores, most of their vitamin K needs will be met by vitamin K1. However as a ruminant, there will be an added contribution through vitamin K2 from the microflora that undertake additional fermentation in their rumen. There is more direct published literature on vitamin K in the cow

Grazing can bring sheep into contact with toxic plants, such as giant fennel (*Ferula communis*) which contains a 4‐hydroxycoumarin compound, a relative of the widely used human anticoagulant pharmaceutical and rodenticide warfarin. The giant fennel is widely distributed around the Mediterranean basin and has been associated with a hemorrhagic syndrome in several species of livestock, including sheep and goats [47]. In vivo experiments in sheep show that extracts from the plant can cause a range of symptoms, including hemorrhage [48, 49]. The active coumarol agents inhibit the VKOR enzyme in much the same way as warfarin, and there is a report of species susceptibility differences [50]. This syndrome can be successfully

and a rapid growth rate is a selected feature for many of these activities.

and the relationship to rumination, this is considered in Section 2.3.4.

to pathological conditions in the rabbit [45].

small intestine absorption of vitamin is known [46].

**2.2. Agricultural animals**

*2.2.1. Ovine vitamin K requirements*

treated with vitamin K [51].

The reported high fecal coprophagy in the rat demonstrates that inducing vitamin K deficiency is difficult, even when animals are contained in elevated, wire‐bottom metabolic cages with additional tail‐cups on the rats to collect feces [34].

There is also tissue variation in the activity of VKOR in the rat [35], which can have implications, in some circumstances, on the functional efficacy of carboxylation of vitamin K‐dependent proteins in extrahepatic tissues.

Polymorphism within the gene for VKOR has been associated with increased rodent resistance to anticoagulant rodenticides. This has profound potential commercial implications as the initial shift to more potent agents from the original warfarin used to control rodents has shown potential problems, due to environmental persistence, while the need to control rodents remains necessary [36].

#### *2.1.2. The mouse*

In the wild, the mouse has the same exposure to sources of vitamin K as described for the rat, and, like the rat, mice in the wild are also showing increasing vitamin K anticoagulant resistance.

The mouse has been widely used as a laboratory model for many diseases due to a fast breeding rate and the potential for genetic homogeneity. The additional development of creating transgenic mice that over‐ or under‐express a specific gene (or genes) together with site‐ directed, or conditional, gene manipulation has increased their importance in medical and scientific research enormously. These technologies have been exploited to demonstrate the essential nature of the VKOR enzyme [37].

The enzyme UbiA prenyltransferase domain‐containing protein 1 (UBIAD1) is expressed across vertebrates and has been shown to synthesize the vitamin K2 congener menaquinone‐ 4 [38]. Deletion of this gene in mice has been found to be lethal, preventing development beyond embryonic day 7.5 [39], suggesting a fundamentally important role for vitamin K2 in embryonic development.

Mice have the same limitations for vitamin K research as described for the rat. Inducing nutritional deficiency and preventing coprophagy is difficult, but can be achieved with some success using strict practices.

#### *2.1.3. The rabbit*

Rabbits and hares are prolific herbivores, and therefore, a large amount of their vitamin K requirement is derived from vitamin K1. Although, as with rodents, rabbits consume sub‐ stantial fecal matter; as long ago as 1882 it was reported that rabbits produce two types of fecal matter, one more liquid than the other [40]. Subsequently, the 'soft' feces were found to have a similar protein, fiber and nutrient composition to the caecal contents [41] and that coproph‐ agy is also normal for the wild rabbit [42]. The caecum of the rabbit is a perfect environment for the incubation of numerous species of bacteria [43] and that the nursing doe probably carries the responsibility for ensuring her kittens have the appropriate intestinal/caecal microbial flora established early in life [44]. Indeed, an incorrect microbiota platform may lead to pathological conditions in the rabbit [45].

The sequelae from the discussion on coprophagy in the rabbit are that the recycling of bacterial contents from feces and maybe, importantly, the caecal content microbiota could contribute significantly to the animal's vitamin K status, in addition to their nutritional vitamin K1 intake. This has not been directly measured in the rabbit, but while there is ongoing debate about the vitamin K2 nutritional benefits from large bowel absorption of these fat‐soluble vitamins, the small intestine absorption of vitamin is known [46].

There is no information on the hare that describes how it meets its full requirements for vitamin K, and presumably, the rabbit serves as an appropriate example to draw similar conclusions.

#### **2.2. Agricultural animals**

Cees Vermeer, personal communication. With fastidious experimentation, it is possible to reduce vitamin K tissue levels in rats, and with certain diets, this can affect the intestinal vitamin

The reported high fecal coprophagy in the rat demonstrates that inducing vitamin K deficiency is difficult, even when animals are contained in elevated, wire‐bottom metabolic cages with

There is also tissue variation in the activity of VKOR in the rat [35], which can have implications, in some circumstances, on the functional efficacy of carboxylation of vitamin K‐dependent

Polymorphism within the gene for VKOR has been associated with increased rodent resistance to anticoagulant rodenticides. This has profound potential commercial implications as the initial shift to more potent agents from the original warfarin used to control rodents has shown potential problems, due to environmental persistence, while the need to control rodents

In the wild, the mouse has the same exposure to sources of vitamin K as described for the rat, and, like the rat, mice in the wild are also showing increasing vitamin K anticoagulant

The mouse has been widely used as a laboratory model for many diseases due to a fast breeding rate and the potential for genetic homogeneity. The additional development of creating transgenic mice that over‐ or under‐express a specific gene (or genes) together with site‐ directed, or conditional, gene manipulation has increased their importance in medical and scientific research enormously. These technologies have been exploited to demonstrate the

The enzyme UbiA prenyltransferase domain‐containing protein 1 (UBIAD1) is expressed across vertebrates and has been shown to synthesize the vitamin K2 congener menaquinone‐ 4 [38]. Deletion of this gene in mice has been found to be lethal, preventing development beyond embryonic day 7.5 [39], suggesting a fundamentally important role for vitamin K2 in

Mice have the same limitations for vitamin K research as described for the rat. Inducing nutritional deficiency and preventing coprophagy is difficult, but can be achieved with some

Rabbits and hares are prolific herbivores, and therefore, a large amount of their vitamin K requirement is derived from vitamin K1. Although, as with rodents, rabbits consume sub‐ stantial fecal matter; as long ago as 1882 it was reported that rabbits produce two types of fecal matter, one more liquid than the other [40]. Subsequently, the 'soft' feces were found to have a similar protein, fiber and nutrient composition to the caecal contents [41] and that coproph‐

K2‐producing flora [33].

218 Vitamin K2 - Vital for Health and Wellbeing

proteins in extrahepatic tissues.

essential nature of the VKOR enzyme [37].

remains necessary [36].

embryonic development.

success using strict practices.

*2.1.3. The rabbit*

*2.1.2. The mouse*

resistance.

additional tail‐cups on the rats to collect feces [34].

Agricultural species are important for essential food and other product production, and the health and well‐being of livestock is important for their growth and reproduction. We will consider several major animal species, but with centuries of breeding and a wide diversity in breeds, we take a generic position in descriptions, except where specific health problems have been identified. The horse is included in this discussion as, while there is a substantial element of meat production from the horse and related species, it also has value in equine sport activities and a rapid growth rate is a selected feature for many of these activities.

#### *2.2.1. Ovine vitamin K requirements*

With over 200 sheep breeds that have been reared over thousands of years for different features, such as wool, milk, skins, meat and even the ability to clear vegetation, a great deal of genetic diversity has been engineered into the different flocks. As committed grazing herbivores, most of their vitamin K needs will be met by vitamin K1. However as a ruminant, there will be an added contribution through vitamin K2 from the microflora that undertake additional fermentation in their rumen. There is more direct published literature on vitamin K in the cow and the relationship to rumination, this is considered in Section 2.3.4.

Grazing can bring sheep into contact with toxic plants, such as giant fennel (*Ferula communis*) which contains a 4‐hydroxycoumarin compound, a relative of the widely used human anticoagulant pharmaceutical and rodenticide warfarin. The giant fennel is widely distributed around the Mediterranean basin and has been associated with a hemorrhagic syndrome in several species of livestock, including sheep and goats [47]. In vivo experiments in sheep show that extracts from the plant can cause a range of symptoms, including hemorrhage [48, 49]. The active coumarol agents inhibit the VKOR enzyme in much the same way as warfarin, and there is a report of species susceptibility differences [50]. This syndrome can be successfully treated with vitamin K [51].

The new‐born lamb, such as human neonates, can to some extent experience postpartum hemorrhage. In the case of the Rambouillet breed of sheep, there is a potentiation of this problem [52]. This problem has been causally linked to a genetic defect in the vitamin K‐ dependent carboxylase enzyme [53, 54].

probably a major predator of these animals. Domestication from the auroch has been suggested to date back to around 10,000 years in Asia and in the Near East. The modern‐day descendents are the Zebu cattle in Asia and the common taurine cattle breeds in Europe. Genetic diversity from the DNA of skeletal remains of the European ancestors suggests that their diversity is so limited as to indicate that the modern taurine bovid has been derived from as few as 80 original

Vitamin K2 in Animal Health: An Overview http://dx.doi.org/10.5772/63901 221

The bovids, as ruminants, are as likely to derive their vitamin K requirements from rumen microflora as they are from plant sources. This has support when bovine liver menaquinone stores are considered against equine liver stores. The long‐chain vitamin K2 congeners in bovine liver contain measurable menaquinones, up to menaquinone‐13, while equine liver does not and vitamin K1 from plants is the principle form of vitamin K found in the liver of

A recent study looking at muscle levels of vitamin K in two bovine breeds, the Norwegian Red and the Jersey, raised under identical conditions in one location [64], found that the tissue distribution in muscle is distinctly different to that reported for the liver and different between the two breeds. This study found that there were two dominant forms of vitamin K, vitamin K1 and menaquinone‐4. The former correlating with the muscle fat content, there being no equivalent relationship for menaquinone‐4. These findings mirror a previous food screen report [65]. Also, different muscles in the two breeds found varying levels of vitamins K. The possibility of a relationship between the enzyme UBIAD1 and menaquinone‐4 levels was not considered in the study, but this could, at least in part, explain some of the vitamin K2 findings.

Possibly, the single most relevant historical relationship between bovine species and vitamin K is the discovery of a vitamin K anticoagulant from the ingestion of spoilt sweet clover feed. This eventually led to the discovery and development of one of the world's most prescribed

The finding that horse liver contains predominantly vitamin K1 relates to the dietary source for this animal, but which also supports the contention that ruminants gain broader vitamin K support from bacterial vitamin K2 sources. In a large, rapidly growing animal like the horse, an adequate vitamin K supply may need to meet more than coagulation requirements. An indication of this may be suggested from a 4‐week‐old Standardbred colt initially presenting with vitamin K deficiency bleeding that continued to fail to thrive after normalization of the coagulation defect by the administration of vitamin K [72]. While there may have been other underlying pathologies, this observation of a vitamin K deficiency bleeding may have been the result of a genetic mutation in the breeding line as the stallion that sired the described foal had also previously sired a colt with coagulopathy health problems [72]. An inability to follow up the research prevented a definitive description of a vitamin K‐dependent deficiency disease

A study, with an interest in race horse growth, and in particular bone health [73], investigated the best form of vitamin K to administer orally to horses. Circulating vitamin K1 increased in

cows [60].

the horse [61–63].

pharmaceutical drugs, warfarin [66–71].

*2.2.5. Equine vitamin K requirements*

in these horses.

#### *2.2.2. Caprine vitamin K requirements*

As with sheep, the goat has a long history of domestication by man and there are now many breeds of goat that have been generated, as with sheep, for a diverse range of reasons. In contrast to sheep, goats are browsers and will also crop tree branches and shrubs. While the goat is credited with eating anything, this is not the case, being inquisitive animals they test many things with their lips and mouth, and may then ingest inedible objects. The goat has the same chance of eating toxic plants as sheep, such as giant fennel.

The absence of the literature on hemorrhagic disease suggests that millennia of breeding programmes have not drawn in a vitamin K‐related genetic hemorrhagic disease or, if it did, the mutation was lethal before the animal reached reproductive maturity.

#### *2.2.3. Porcine vitamin K requirements*

The history of the pig is even older than that of sheep and goats with indications that the pig was first domesticated 9–10,000 years ago in the Middle East [55]. Despite this heritage, there are many fewer breeds of pig than there are for sheep and goats. The pig, wild boar and hogs are natural scavengers and will consume anything edible, including decaying matter and fecal waste; the latter ability has been utilized by humans as part of local sewage management in the form of the 'pig‐privy' [56]. This suggests that in the wild and in free‐living domestic pig populations, long‐chain vitamin K2 will be at least as important, if not more important, as vitamin K1 in maintaining the vitamin K status of the pig.

The vitamin K status of boar and hogs has not been the subject of investigation. However, husbandry of the domestic pig, due to its economic importance, has been considered exten‐ sively.

A comparative investigation into the coagulation status of several animal species found that the pig most closely mirrored the human neonate [57]. Therefore, the description of postpar‐ tum hemorrhage in the piglet due to vitamin K deficiency [58] is not too surprising as it is seen in the new‐born human infant, where the recommendation is for vitamin K prophylaxis at birth. Increased hygienic conditions for farrowing sows housed in elevated sties preventing coprophagy and antibiotic usage were identified as potential factors in vitamin K deficiency in the pig. Around this time, supplementation with 2.2 mg/Kg feed with vitamin K3 was suggested for pigs if a vitamin K deficiency was suspected [59].

#### *2.2.4. Bovine vitamin K requirements*

Bovine species have as long an association with man as other domesticated animals. Cave paintings demonstrate that ancient man was aware of the auroch in his environment and was probably a major predator of these animals. Domestication from the auroch has been suggested to date back to around 10,000 years in Asia and in the Near East. The modern‐day descendents are the Zebu cattle in Asia and the common taurine cattle breeds in Europe. Genetic diversity from the DNA of skeletal remains of the European ancestors suggests that their diversity is so limited as to indicate that the modern taurine bovid has been derived from as few as 80 original cows [60].

The bovids, as ruminants, are as likely to derive their vitamin K requirements from rumen microflora as they are from plant sources. This has support when bovine liver menaquinone stores are considered against equine liver stores. The long‐chain vitamin K2 congeners in bovine liver contain measurable menaquinones, up to menaquinone‐13, while equine liver does not and vitamin K1 from plants is the principle form of vitamin K found in the liver of the horse [61–63].

A recent study looking at muscle levels of vitamin K in two bovine breeds, the Norwegian Red and the Jersey, raised under identical conditions in one location [64], found that the tissue distribution in muscle is distinctly different to that reported for the liver and different between the two breeds. This study found that there were two dominant forms of vitamin K, vitamin K1 and menaquinone‐4. The former correlating with the muscle fat content, there being no equivalent relationship for menaquinone‐4. These findings mirror a previous food screen report [65]. Also, different muscles in the two breeds found varying levels of vitamins K. The possibility of a relationship between the enzyme UBIAD1 and menaquinone‐4 levels was not considered in the study, but this could, at least in part, explain some of the vitamin K2 findings.

Possibly, the single most relevant historical relationship between bovine species and vitamin K is the discovery of a vitamin K anticoagulant from the ingestion of spoilt sweet clover feed. This eventually led to the discovery and development of one of the world's most prescribed pharmaceutical drugs, warfarin [66–71].

#### *2.2.5. Equine vitamin K requirements*

The new‐born lamb, such as human neonates, can to some extent experience postpartum hemorrhage. In the case of the Rambouillet breed of sheep, there is a potentiation of this problem [52]. This problem has been causally linked to a genetic defect in the vitamin K‐

As with sheep, the goat has a long history of domestication by man and there are now many breeds of goat that have been generated, as with sheep, for a diverse range of reasons. In contrast to sheep, goats are browsers and will also crop tree branches and shrubs. While the goat is credited with eating anything, this is not the case, being inquisitive animals they test many things with their lips and mouth, and may then ingest inedible objects. The goat has the

The absence of the literature on hemorrhagic disease suggests that millennia of breeding programmes have not drawn in a vitamin K‐related genetic hemorrhagic disease or, if it did,

The history of the pig is even older than that of sheep and goats with indications that the pig was first domesticated 9–10,000 years ago in the Middle East [55]. Despite this heritage, there are many fewer breeds of pig than there are for sheep and goats. The pig, wild boar and hogs are natural scavengers and will consume anything edible, including decaying matter and fecal waste; the latter ability has been utilized by humans as part of local sewage management in the form of the 'pig‐privy' [56]. This suggests that in the wild and in free‐living domestic pig populations, long‐chain vitamin K2 will be at least as important, if not more important, as

The vitamin K status of boar and hogs has not been the subject of investigation. However, husbandry of the domestic pig, due to its economic importance, has been considered exten‐

A comparative investigation into the coagulation status of several animal species found that the pig most closely mirrored the human neonate [57]. Therefore, the description of postpar‐ tum hemorrhage in the piglet due to vitamin K deficiency [58] is not too surprising as it is seen in the new‐born human infant, where the recommendation is for vitamin K prophylaxis at birth. Increased hygienic conditions for farrowing sows housed in elevated sties preventing coprophagy and antibiotic usage were identified as potential factors in vitamin K deficiency in the pig. Around this time, supplementation with 2.2 mg/Kg feed with vitamin K3 was

Bovine species have as long an association with man as other domesticated animals. Cave paintings demonstrate that ancient man was aware of the auroch in his environment and was

same chance of eating toxic plants as sheep, such as giant fennel.

vitamin K1 in maintaining the vitamin K status of the pig.

suggested for pigs if a vitamin K deficiency was suspected [59].

the mutation was lethal before the animal reached reproductive maturity.

dependent carboxylase enzyme [53, 54].

*2.2.2. Caprine vitamin K requirements*

220 Vitamin K2 - Vital for Health and Wellbeing

*2.2.3. Porcine vitamin K requirements*

*2.2.4. Bovine vitamin K requirements*

sively.

The finding that horse liver contains predominantly vitamin K1 relates to the dietary source for this animal, but which also supports the contention that ruminants gain broader vitamin K support from bacterial vitamin K2 sources. In a large, rapidly growing animal like the horse, an adequate vitamin K supply may need to meet more than coagulation requirements. An indication of this may be suggested from a 4‐week‐old Standardbred colt initially presenting with vitamin K deficiency bleeding that continued to fail to thrive after normalization of the coagulation defect by the administration of vitamin K [72]. While there may have been other underlying pathologies, this observation of a vitamin K deficiency bleeding may have been the result of a genetic mutation in the breeding line as the stallion that sired the described foal had also previously sired a colt with coagulopathy health problems [72]. An inability to follow up the research prevented a definitive description of a vitamin K‐dependent deficiency disease in these horses.

A study, with an interest in race horse growth, and in particular bone health [73], investigated the best form of vitamin K to administer orally to horses. Circulating vitamin K1 increased in relation to the administered dose; however, menaquinone‐4 administration did not show corresponding plasma level increases, the suggestion being that the horses in this study did not absorb this vitamer. Interestingly, administration of vitamin K3 did cause menaquinone‐4 plasma levels to rise, which may relate to UBIAD1 synthesis of menaquinone‐4 or intestinal flora.

expressed as early as the single‐cell stage. With continued development, the *reh* zebrafish mutant presents with higher expression of UBIAD1 in the vasculature than cardiac tissues and gene expression decreases with time. Introduction of an antisense morpholino oligonucleotide targeted splice to knockdown wild‐type UBIAD1, or the administration of warfarin, produced similar vascular models to the reh mutant, with the warfarin challenge having notably less impact on cardiac tissue compared to the vascular effects. The defect in these fish could be salvage by the introduction of wild‐type zebrafish or human UBIAD1 mRNA, but not *reh* UBIAD1 mRNA. Similarly, the knockdown or warfarin‐treated larvae could be rescued by the administration of vitamin K1 or menaquinone‐4, vitamin K1 being used as the source of naphthoquinone for the UBIAD1 conversion to menaquinone‐4. The overall finding that the UBIAD1 gene and enzyme expression has an important role in vascular endothelial cell

Vitamin K2 in Animal Health: An Overview http://dx.doi.org/10.5772/63901 223

Bone and spinal deformities are a major problem in commercial fish farming. Deformities are not only an economic problem for fish farms, but also raise ethical and welfare issues for the aquaculture industry. The importance of vitamin K in fish skeletal health has increased interest in vitamin K requirement for normal bone development in fish. There are a few studies that have dealt specifically with the effect of vitamin K deficiency on fish bone health [78, 88, 90, 96, 97]. Tissue‐specific gene expression of the vitamin K‐dependent proteins, such as osteo‐ calcin and matrix Gla protein (MGP), has been shown in the vertebrae of Atlantic salmon; however, dietary vitamin K was not found to regulate the expression of MGP [90, 98]. Inter‐ estingly, neither juvenile Atlantic salmon [90] or Atlantic salmon smolts [88] showed any sign

Mummichog given feed that was not enriched with vitamin K grew thin, weak bones. Vitamin K deficiency induced bone structure abnormalities such as vertebral fusion and row irregu‐ larity, both in early development and during later growth [78, 96]. Furthermore, the offspring of vitamin K‐deprived fish had higher incidences of abnormal vertebral formation 5 days after hatching when compared to larvae from fish fed a vitamin K‐enriched diet [78]. In haddock, vitamin K appears to be necessary for bone mineralization [99]. However, vitamin K does not affect the number of osteoblast in haddock, while bone deformities coincided with an increased amount of osteoid and a decrease in bone mineral content. In the Senegalese sole given feed enriched with vitamin K, there was a notable improved larval growth performance and post‐ larval skeletal quality. Also, vitamin K modulated expression of protein involved in several biological processes including muscle contraction and development, cytoskeletal network, skin development, energy metabolism, protein chaperoning and folding, and bone develop‐

It now seems that vitamin K supply may be less than optimal for bone development, but

Fish feed is commonly enriched with vitamin K3 (menadione) in the form of water soluble salts, normally menadione sodium bisulphite (MSB) and menadione nicotinamide bisulphite

survival has implications across all tissues and in cancer.

of deformities on a diet lacking vitamin K supplementation.

sufficient to maintain normal growth and hemostasis [82, 87].

ment [97].

(MNB) [82].

Another consideration in equine health is for vitamin K3 administered parenterally; this form of intervention was been found to cause pronounced renal toxic effects [74, 75]. Reports of parenteral administration of vitamin K1 or K2 prophylaxis, or remedial coagulopathy, interventions were not obvious from screening the literature.
