Because of the minimal extent of transfer of vitamin K across the placenta, the fetus and newborn infant have much lower circulating vitamin K than adults (typically 30-fold lower). In addition, human milk has a lower concentration of the vitamin than that of most other mammalian species. Although low vitamin K levels have not been found to affect the developing fetus in a functionally deleterious way, it is clear that the newborn, and especially the solely breast-fed infant, is at higher risk of functional deficiency than older infants and adults. In a minority of cases, this can lead to life-threatening or long-term damage associated with intracranial bleeding. Hemorrhagic disease of the newborn (HDN) is classified as early (first 24 h of life), classic (days 1-7), or late (2-12 weeks). Of these, the third category is most likely to involve dangerous intracranial bleeding. Risk factors for HDN include intestinal fat malabsorption and hepatic disease. In Western countries, since the 1950s, it has been routine practice to give prophylactic phylloquinone in a 1 or 2 mg dose at birth, and this has been found to considerably reduce the risk of HDN. An intramuscular depot dose was found to be highly effective; however, a study in the United Kingdom in the 1990s suggested a possible link with childhood cancer. Despite little subsequent support for this contraindication, the adverse publicity led to a shift in practice toward oral dosing. An oral micel-lar preparation containing glycholate and lecithin has been developed that has improved absorption characteristics. Another approach toward the avoidance of late HDN is vitamin K supplementation of breastfeeding mothers since breast milk vitamin K levels can be increased substantially by dosage to the mother. Modern commercial formula feeds typically contain 50-125 mg phylloquinone/l.
Antibiotic-treated patients may be at increased risk of developing vitamin K deficiency. Some antibiotics may reduce the production of usable menaquinones by gut bacteria; others, such as cephalosporin, may exert vitamin K epoxide reductase inhibitory effects. Vitamins A and E in large doses may increase the risk of vitamin K deficiency and/or its sequelae in susceptible people. Thus, in one study, patients receiving anticoagulant drugs exhibited a further reduction of pro-thrombin levels if they were given 400IU a-tocopherol per day for 4 weeks. The microsomal vitamin K-depen-dent carboxylase enzyme was found to be inhibited by a-tocopheryl quinone and, to a lesser extent, by a-tocopherol. It is also inhibited by other oxygen free radical antagonists. Control of blood clotting with warfarin-type drugs thus requires control of intakes of vitamins A and E as well as vitamin K so as to achieve consistent results.
As noted previously, some older people, especially postmenopausal women, seem to be at increased risk of developing marginal vitamin K deficiency, which manifests itself, for instance, by an increased percentage of undercarboxylated osteocalcin (ucOC) in the circulation. The sequelae of such marginal deficiency, and in particular its implications for bone health, are currently the subject of considerable research effort (Table 2). Several epidemiological cross-sectional studies have noted an association between higher vitamin K intakes and higher bone mineral density or lower fracture risk. One study reported that a subgroup of postmenopausal women who were 'fast losers' of calcium responded to vitamin K supplements by reduced calcium and hydroxyproline excretion. Although vitamins D and K have distinct functions in calcium absorption, and its distribution, deposition, and excretion, there is evidence that synergistic interactions can occur between them, and that both can affect the same cell-signalling pathways. Osteocalcin and MGP synthesis is stimulated by 1,25-dihydroxy vitamin D in cell culture.
MK-4 in large doses has been used for prophylaxis and treatment of osteoporosis, especially in
Table 2 Studies (1985-2001) linking vitamin K intake, status, or effects of supplementation with bone health in humans
Nature of evidence No. of studies
Serum vitamin K positively correlated with BMD 4 Serum vitamin K lower in people with hip or 3
vertebral fractures Vitamin K intake directly correlated with BMD 2
ucOC directly correlated with risk of hip fracture 5 ucOC inversely correlated with velocity of 1
ultrasound (a measure of bone quality) ucOC inversely correlated with BMD 2
Supplementation with phylloquinone increased 7
carboxylation of osteocalcin Supplementation with phylloquinone or 3
menaquinone reduced calcium loss Supplementation with phylloquinone increased 1 markers of bone formation and reduced markers of bone resorption Supplementation with phylloquinone 1
(+vitamin D) increased BMD Supplementation with menaquinone 2
(+vitamin D) increased BMD Supplementation with menaquinone alone 6
increased BMD and/or decreased bone loss Supplementation with menaquinone reduced 2
BMD, bone mineral density; ucOC, undercarboxylated osteocalcin. Data from Weber P (2001) Vitamin K and bone health. Nutrition 17: 880-887, and S. Karger AG, Basel.
Japan. A study in The Netherlands reported reduced bone loss after 2 years of treatment of postmenopausal women with amounts of phylloquinone that are achievable from dietary sources. More long-term intervention trials are needed.
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