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Nutritional Sources of Vitamin K

  • JAMES J. LIPSKY
    Correspondence
    Address reprint requests to Dr. J. J. Lipsky, Clinical Pharmacology Unit, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
    Affiliations
    Clinical Pharmacology Unit, Department of Pharmacology, and Department of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
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      Objective

      To review the function of vitamin K in clotting and methods of its analysis, to present results of previous studies on the role of dietary vitamin K in humans and animals, and to reanalyze these data in light of current methods.

      Design

      A review of assumptions stated in the literature is presented, including the incorrect theory that a diet-induced deficiency of vitamin K is nonexistent and the unsubstantiated hypothesis that antibiotics can cause vitamin K deficiency by destroying intestinal bacteria.

      Conclusion

      The insistent belief that intestinal bacteria are an important source of vitamin K has led to erroneous conclusions about the sources of vitamin K for human nutrition. In the future, the importance of various sources of vitamin K, their pathways of absorption, and their susceptibility to administration of antibiotics should be evaluated without recourse to current assumptions.
      MTT (methyltetrazole-thiol), PIVKA (protein induced by vitamin K absence)
      A common belief is that the intestinal bacteria are an important nutritional source of vitamin K for humans. This belief affects both the understanding of the vitamin K supply and the understanding of the mechanism of antibiotic-associated hypoprothrombinemia. For example, one consequence is that a diet-induced deficiency of vitamin K in humans is nonexistent.
      • Ichihashi T
      • Takagishi Y
      • Uchida K
      • Yamada H
      Colonic absorption of menaquinone-4 and menaquinone-9 in rats.
      Another is that treatment with broad-spectrum antibiotics compromises bacterial sources of vitamin K and can produce vitamin K deficiency.
      • Bang NU
      • Kammer RB
      Hematologic complications associated with β-lactam antibiotics.
      Although the belief is widely held and taught, no definitive evidence shows that intestinal bacteria are an important nutritional source of vitamin K. This review critically examines evidence that has supported this belief.

      DESCRIPTION OF VITAMIN K

      In 1935, Dam
      • Dam H
      The antihaemorrhagic vitamin of the chick [letter].
      described a compound that prevented hemorrhage in chickens, which he labeled “Koagulation vitamin” or vitamin K (coagulation is spelled “koagulering” in Danish). Vitamin K is a term that currently describes many chemical entities that are categorized into three groups: vitamin K1 or phylloquinone, vitamin K2 or menaquinones, and vitamin K3 or menadione. Vitamin K1 is found in green leafy vegetables and is considered the main dietary source of vitamin K for humans.
      • Shearer MJ
      • McBurney A
      • Barkhan P
      Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man.
      Vitamin K2 is a group of compounds known as menaquinones, which are found in bacteria. They differ from phylloquinone in the structure and lengths of their side chains. They are often abbreviated as MK-n, in which n is the repeating five-carbon units in the side chain. Some investigators believe that this group of compounds are nutritionally important for humans. Finally, vitamin K3 is a synthetic compound and thus not part of the nutritional controversy.

      FUNCTION OF VITAMIN K

      The function of vitamin K is to serve as a cofactor in the γ-carboxylation of glutamic acid, a posttranslational step in the synthesis of clotting factors II, VII, IX, and × and proteins C and S.
      • Shearer MJ
      Vitamin K and vitamin K-dependent proteins.
      Many other proteins in various tissues also undergo this vitamin K-dependent carboxylation reaction including osteocalcin, a protein that is found in bone. Clotting factors that do not undergo this modification do not bind calcium and have no activity. Vitamin K deficiency results in clotting factors in the plasma that lack carboxylated glutamic acid residues. Prothrombin thus affected is referred to as descarboxyprothrombin or PIVKA (protein induced by vitamin K absence).

      DETERMINATION OF VITAMIN K DEFICIENCY

      The determination of vitamin K deficiency is not straightforward because of problems with both its direct and its functional coagulation-based assays. Traditionally, vitamin K deficiency has been determined by the presence of a pro-longed prothrombin time, which is reversed by the administration of vitamin K. As discussed subsequently, however, prolongation of prothrombin time is an insensitive measure of vitamin K deficiency.
      • Suttie JW
      • Mummah-Schendel LL
      • Shah DV
      • Lyle BJ
      • Greger JL
      Vitamin K deficiency from dietary vitamin K restriction in humans.

      Presence of PIVKA

      Sensitive functional assays of vitamin K deficiency are based on the presence of descarboxyprothrombin (PIVKA) in the plasma. Monoclonal anti-bodies to PIVKA
      • Krasinski SD
      • Russell RM
      • Furie BC
      • Kruger SF
      • Jacques PF
      • Furie B
      The prevalence of vitamin K deficiency in chronic gastrointestinal disorders.
      seem to be the most sensitive method of determination. PIVKA levels may also be determined indirectly by measuring the prothrombin time with use of a snake venom proteinase from Echis carinatus.
      • Allison PM
      • Mummah-Schendel LL
      • Kindberg CG
      • Harms CS
      • Bang NU
      • Suttie JW
      Effects of a vitamin K-deficient diet and antibiotics in normal human volunteers.
      This latter technique allows PIVKA to contribute to the overall prothrombin time reaction. A prothrombin time determined with use of E. carinatus is compared with a prothrombin time determined by standard techniques with use of thromboplastin. The ratio of these values can be correlated with the amount of PIVKA in the plasma. Of importance, the presence of PIVKA is not an exclusive finding of vitamin K deficiency. PIVKA has been found in patients who are receiving orally administered anticoagulant therapy and in those who have hepatitis and cirrhosis
      • Blanchard RA
      • Furie BC
      • Jorgensen M
      • Kruger SF
      • Furie B
      Acquired vitamin K-dependent carboxylation deficiency in liver disease.
      or hepatocellular carcinoma.
      • Liebman HA
      • Furie BC
      • Tong MJ
      • Blanchard RA
      • Lo K-J
      • Lee S-D
      • et al.
      Des-γ-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma.
      The previously mentioned assays are based on the measurement of an indirect result of vitamin K deficiency. Thus, a logical definition of vitamin K deficiency would apparently be based on a direct determination of vitamin K levels in the plasma. Unfortunately, the wide range of techniques used for its determination has caused a substantial variation in the results obtained. In a review of vitamin K1 levels,11 normal ranges varied from 0.1 to 7.8 ng/mL. Vitamin K1 levels have been shown to vary with age, sex, plasma lipids, alcohol consumption, and season of the year.
      • Sadowski JA
      • Hood SJ
      • Dallal GE
      • Garry PJ
      Phylloquinone in plasma from elderly and young adults: factors influencing its concentration.
      In addition, studies are hampered by the current lack of understanding of the meaning of vitamin K2 levels. Only recently has a method been developed to detect serum vitamin K2 (menaquinone)-levels.
      • Hodges SJ
      • Pilkington MJ
      • Shearer MJ
      • Bitensky L
      • Chayen J
      Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8.
      • Usui Y
      • Tanimura H
      • Nishimura N
      • Kobayashi N
      • Okanoue T
      • Ozawa K
      Vitamin K concentrations in the plasma and liver of surgical patients.
      The accuracy of this method, as well as the number of patients in whom it has been applied, precludes any definitive conclusions about what constitutes normal plasma menaquinones. A study in rats has demonstrated the difficulties in relating vitamin K plasma levels with dietary intake and liver levels.
      • Will BH
      • Suttie JW
      Comparative metabolism of phylloquinone and menaquinone-9 in rat liver.

      Prolongation of the Prothrombin Time

      Because the technology for determining vitamin K levels, as well as PIVKA, is relatively new and uncommon, most studies on vitamin K deficiency in the literature have used prolongation of the prothrombin time as the defining feature. Because of its low sensitivity, this method may overlook many cases of vitamin K deficiency. In contrast, if a response to administered vitamin K is not measured, cases of prolonged prothrombin time may be falsely defined as vitamin K deficiency.
      As previously mentioned, one frequently stated theory is that no diet-induced deficiency of vitamin K exists in humans.
      • Ichihashi T
      • Takagishi Y
      • Uchida K
      • Yamada H
      Colonic absorption of menaquinone-4 and menaquinone-9 in rats.
      • Barthelemy H
      • Chouvet B
      • Cambazard F
      Skin and mucosal manifestations in vitamin deficiency.
      This belief is clearly incorrect. As far back as 1939, a group of patients who had diets deficient in fruits and vegetables or who ate irregularly were described as having prolongation of the prothrombin time, which responded to oral administration of vitamin K.
      • Kark R
      • Lozner EL
      Nutritional deficiency of vitamin K in man: a study of four non-jaundiced patients with dietary deficiency.
      Thus, the investigators concluded that these patients had vitamin K deficiency because none had liver disease or biliary obstruction. In a later study of geriatric admissions to a hospital, 13 of 93 patients were thought to have vitamin K deficiency because of prolongation of the prothrombin time.
      • Niiya K
      • Kitagawa T
      • Fujishita M
      • Yoshimoto S
      • Kobayashi M
      • Kubonishi I
      • et al.
      Bulimia nervosa complicated by deficiency of vitamin K-dependent coagulation factors.

      Intestinal Flora

      In a study of 10 healthy men who received a vitamin K-deficient diet, descarboxyprothrombin was detected in their blood by using the E. carinatus method.
      • Suttie JW
      • Mummah-Schendel LL
      • Shah DV
      • Lyle BJ
      • Greger JL
      Vitamin K deficiency from dietary vitamin K restriction in humans.
      Of note, none of these subjects received antibiotics or any treatment that would affect the intestinal flora. The investigators pointed out that intestinal menaquinones were insufficient to prevent the “appearance” of vitamin K deficiency in the subjects. Therefore, for more than 50 years, reports and studies in the literature clearly indicated that a nutritional deficiency of vitamin K can appear in the presence of normal intestinal bacteria.
      A study commonly cited as evidence that the intestinal flora are important in maintaining adequate vitamin K status is that by Frick and associates.
      • Frick PG
      • Riedler G
      • Brogli H
      Dose response and minimal daily requirement for vitamin K in man.
      The purpose of this study was to determine the minimal daily requirement of vitamin K. Ten patients were maintained on intravenously administered fluids only, with no vitamin K supplementation. In 7 of the 10 patients who received antibiotics, vitamin K-dependent clotting factor activity decreased in 21 to 29 days. Three patients who received no antibiotics were monitored for 30 to 32 days, and they showed no “significant” change in clotting factors. (In two of these three patients, factor VII activity decreased to 70% and 75% of normal—not considered a pronounced decrease in clotting factors.) The study did not mention the names of the antibiotics used and did not measure their effect on intestinal bacteria. Therefore, a careful review of this study reveals that antibiotics were not necessary to produce vitamin K deficiency. Nonetheless, this study is often cited as proof for the importance of menaquinones in maintaining an adequate vitamin K status.
      In another study done before the development of modern methods for detecting descarboxyprothrombin, Udall
      • Udall JA
      Human sources and absorption of vitamin K in relation to anticoagulation stability.
      described healthy subjects in whom statistically significant increases in prothrombin time developed while they received vitamin K-deficient diets. He also addressed the issue of whether vitamin K could be absorbed by the intestine. In that study, 10 patients received warfarin therapy, and they had 500 mg of vitamin K1 administered into the cecum. This treatment produced no changes in the prothrombin time; however, oral administration of vitamin K1 caused the prothrombin time to decrease. Thus, vitamin K1 is apparently not absorbed by the cecum but rather in the small intestine.

      MENAQUINONES

      In light of the careful studies by Udall
      • Udall JA
      Human sources and absorption of vitamin K in relation to anticoagulation stability.
      with respect to vitamin K1, a review of the studies commonly quoted as evidence for the absorption of menaquinones by the intestine is worthwhile. Hollander and colleagues
      • Hollander D
      • Rim E
      • Ruble Jr, PE
      Vitamin K2 colonic and ileal in vivo absorption: bile, fatty acids, and pH effects on transport.
      examined the absorption of radioactive menaquinone in the ileum and large intestine of the rat. What was actually measured was a decrease in radioactivity in an intestinal perfusate. Because menaquinones are water-insoluble, all the experiments were performed with sodium taurocholic acid, at a concentration of at least 5 mM. This situation is not a physiologic condition and therefore extrapolation to humans may not be justified. More recent experiments
      • Ichihashi T
      • Takagishi Y
      • Uchida K
      • Yamada H
      Colonic absorption of menaquinone-4 and menaquinone-9 in rats.
      examined the absorption of menaquinone-9 in in situ rat intestinal loops and found no absorption in the absence of bile salts. Only a 2% absorption of menaquinone-4 was noted in the absence of bile. Even in this latter experiment, menaquinone-4 was suspended in a surfactant. Thus, the extrapolation to humans of the absorption of even this short-chain menaquinone is unknown.
      If menaquinones are present in the liver, they have biologic activity; however, because they are highly lipophilic, their bioavailability in the liver may be minimal. Indeed, a recent study
      • Will BH
      • Suttie JW
      Comparative metabolism of phylloquinone and menaquinone-9 in rat liver.
      on the turnover of menaquinone-9 in rat liver indicated that the turnover is 2 to 3 times slower than that of phylloquinone. When administered orally, menaquinone-9 was also found to be less potent than phylloquinone. In a study in which the potency of menaquinones was shown to be greater than that of phylloquinone, the menaquinones were injected intracardially.
      • Matschiner JT
      • Taggart WV
      Bioassay of vitamin K by intracardial injection in deficient adult male rats.
      Although this study clearly showed that these types of vitamin K are active, inferring that the menaquinones would be just as potent if they were present in the large intestine is unwarranted.
      In a study in which germfree rats were inoculated with various species of bacteria
      • Kindberg C
      • Suttie JW
      • Uchida K
      • Hirauchi K
      • Nakao H
      Menaquinone production and utilization in germ-free rats after inoculation with specific organisms.
      and menaquinones were measured in the liver, low amounts of menaquinones were found in the liver of some animals. Nonetheless, this finding was inconsistently detected and does not definitively indicate the route of absorption because prevention of coprophagy was unknown.
      Uchida and coworkers
      • Uchida K
      • Nomura Y
      • Takase H
      • Harauchi T
      • Yoshizaki T
      • Nakao H
      Effects of vitamin K-deficient diets and fasting on blood coagulation factors in conventional and germ-free rats.
      concluded that menaquinones arising from the intestine may not be an important nutritional source of vitamin K for the rat. They studied vitamin K deficiency in germfree rats and compared the levels of clotting factor VII and descarboxyprothrombin in both fasting germfree rats and conventional rats in which coprophagy was prevented; vitamin K deficiency was noted in both groups. No differences were found between the groups, and these investigators concluded that, in the rat, menaquinones produced in the large intestine were insufficient to prevent vitamin K deficiency. This important finding questions many of the studies performed in the rat that have been used to prove the importance of the effect of antibiotics on intestinal bacteria and the subsequent development of vitamin K deficiency.

      ANIMAL MODEL FOR VITAMIN K DEFICIENCY

      Since the 1940s,
      • Kornberg A
      • Daft FS
      • Sebrell WH
      Production of vitamin K deficiency in rats by various sulfonamides.
      the rat has been used as a model for the development of vitamin K deficiency in conjunction with antibiotic treatment. The experimental model was simple. Rats were fed diets supplemented with antibiotics, initially the sulfonamides. A correlation was observed between the effectiveness of the drugs in producing prolongation of the prothrombin time and their potency in killing intestinal bacteria. Therefore, the conclusion was that the intestinal bacteria were an important source of menaquinones in maintaining the adequacy of the vitamin K status. The assumption was that the menaquinones were absorbed by the large intestine, a theory that was undermined by the previously mentioned studies. An alternative explanation for the findings of the earlier studies was that the antibiotics caused a reduction in colonic bacteria and a subsequent decrease in a dietary source of vitamin K because rats eat their feces. Although the experiments were done in cages that were intended to prevent coprophagy, later studies conducted by another group
      • Barnes RH
      • Fiala G
      • McGehee B
      • Brown A
      Prevention of coprophagy in the rat.
      demonstrated that such caged rats were able to eat approximately 50 to 65% of their feces. This group subsequently showed that preventing coprophagy
      • Barnes RH
      • Fiala G
      Effects of the prevention of coprophagy in the rat. VI. Vitamin K.
      caused the development of prolongation of the prothrombin time after the rats were fitted with tail cups and received a vitamin K-deficient diet for 3 weeks. Thus, intestinal menaquinones were ineffective in preventing vitamin K deficiency.
      In a review more than 30 years ago,
      Vitamin K deficiency and coprophagy in the rat.
      the ability of the rat to absorb vitamin K from the large intestine was questioned. The article pointed out that the bacterial synthesis of vitamin K in rat intestine was insufficient to meet the demands for vitamin K when a vitamin K-deficient diet was given. Thus, this factor should be considered in studies attempting to induce vitamin K deficiency; however, it has often been ignored.

      APPLICATIONS IN HUMANS

      The studies in which antibiotics were used to induce vitamin K deficiency in rats were quickly applied to humans. Since 1946,
      • Rapoport S
      • Dodd K
      Hypoprothrombinemia in infants with diarrhea.
      numerous case reports have stated that administration of antibiotics causes vitamin K deficiency. The mechanism of this effect has always been considered the destruction of intestinal bacteria. This viewpoint is reiterated in the package insert of many antibiotics. A careful review of these case reports,
      • Lipsky JJ
      Antibiotic-associated hypoprothrombinaemia.
      however, indicated that the scientific methods were inadequate for demonstrating that antibiotics caused the vitamin K deficiency or that the mechanism was by the destruction of intestinal bacteria.
      A group of antibiotics (cefamandole, moxalactam, and cefoperazone) that contain the methyltetrazole-thiol (MTT) side chain is associated with prolonged prothrombin times. These antibiotics inhibit vitamin K metabolism and γ-carboxylation of glutamic acid.
      • Lipsky JJ
      N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia.
      • Lipsky JJ
      Mechanism of the inhibition of the γ-carboxylation of glutamic acid by N-methylthiotetrazole-containing antibiotics.
      • Mitchell MC
      • Mallat A
      • Lipsky JJ
      Cephalosporin-induced alteration in hepatic glutathione redox state: a potential mechanism for inhibition of hepatic reduction of vitamin K1,2,3-epoxide in the rat.
      • Creedon KA
      • Suttie JW
      Effect of N-methyl-thiotetrazole on vitamin K epoxide reductase.
      The MTT group has been shown to inhibit both the vitamin K-dependent carboxylase enzyme in vitro
      • Lipsky JJ
      N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia.
      • Lipsky JJ
      Mechanism of the inhibition of the γ-carboxylation of glutamic acid by N-methylthiotetrazole-containing antibiotics.
      and the vitamin K epoxide reductase.
      • Bechtold H
      • Andrassy K
      • Jähnchen E
      • Koderisch J
      • Koderisch H
      • Weilemann LS
      • et al.
      Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins.
      • Shearer MJ
      • Bechtold H
      • Andrassy K
      • Koderisch J
      • McCarthy PT
      • Trenk D
      • et al.
      Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.
      Hypoprothrombinemia does not develop in healthy persons who receive antibiotics that contain the MTT group. Risk factors associated with the development of hypoprothrombinemia with use of these antibiotics include renal failure, no oral intake of food, and cancer.
      • Lipsky JJ
      Antibiotic-associated hypoprothrombinaemia.
      A relative deficiency of vitamin K may predispose persons who receive these antibiotics to hypoprothrombinemia. In addition, the methylthiadiazole-thiol moiety found in cefazolin and cefazedone also has a similar effect on coagulation.
      • Kerremans AL
      • Lipsky JJ
      • Van Loon J
      • Gallego MO
      • Weinshilboum RM
      Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,3,4-thiadiazole-5-thiol.
      Except for the specific biochemical mechanism thought to cause this type of antibiotic-induced hypoprothrombinemia, other theories about its cause remain suspect.

      ASSUMPTIONS ABOUT SOURCE OF VITAMIN K

      The insistent belief that intestinal bacteria are an important source of vitamin K has led to erroneous conclusions about sources of vitamin K for human nutrition. For example, a recent review of nutrition in elderly persons stated that half the human requirement for vitamin K is provided by synthesis by intestinal bacteria.
      • Morley JE
      • Mooradian AD
      • Silver AJ
      • Heber D
      • Alfin-Slater RB
      Nutrition in the elderly.
      An article on recommendations for the dietary intake of vitamin K in humans also stated that 50% of the vitamin K was supplied by intestinal bacteria. This figure was based on assumptions about the proportion of menaquinones in the liver.
      • Olson JA
      Recommended dietary intakes (RDI) of vitamin K in humans.
      Nonetheless, when modern techniques have been used to measure vitamin K in the liver,
      • Shearer MJ
      • McCarthy PT
      • Crampton OE
      • Mattock MB
      The assessment of human vitamin K status from tissue measurements.
      • Usui Y
      • Tanimura H
      • Nishimura N
      • Kobayashi N
      • Okanoue T
      • Ozawa K
      Vitamin K concentrations in the plasma and liver of surgical patients.
      the proportion of menaquinones has been found to be much higher, approximately 90%. Therefore, statements in the literature have been based on extrapolation from incorrect assumptions and lack an actual biologic meaning.

      CONCLUSION

      Separating fact from erroneous assumptions about vitamin K deficiency in the literature is necessary. For the rat, the production of menaquinones in the large intestine by bacteria is an unimportant nutritional source. This fact questions many studies performed in the rat that have implicated antibiotics as the cause of vitamin K deficiency. In humans, except for those with renal failure or cancer or those in whom oral intake of food is not possible, antibiotics have been inappropriately cited as the cause of hypoprothrombinemia attributable to suspected vitamin K deficiency. Furthermore, humans can have nutritional deficiencies of vitamin K in the apparent presence of normal intestinal bacteria. Finally, dietary sources of vitamin K seem to be crucial for maintaining adequate vitamin K status. In humans, the role of menaquinones produced by intestinal bacteria is yet to be determined.
      In the future, the importance of various sources of vitamin K, their pathways of absorption, and their susceptibility to administration of antibiotics should be evaluated without recourse to current assumptions.

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