Vitamin K deficiency causes

VITAMIN K IN HEALTH AND DISEASE

The best understood metabolic roles of vitamin K are those involved in its anti-hemorrhagic function, which after all led to the vitamin’s discovery. It has since become clear that vitamin K plays important metabolic roles beyond clotting.

Vitamin K deficiency


Coagulation

Coagulopathies now associated with vitamin K deficiency were reported in the nineteenth century. These include those that were called “hemorrhagic disease of the newborn, which differed from hemophilia by its earlier presentation (within a couple of days after birth) and absence of family history. Routine prophylaxis of newborns with vitamin K has made this condition rare in countries with that practice. Hereditary combined vitamin K-dependent clotting factor deficiency is a rare autosomal recessive disorder involving mutations in the genes for both vitamin K-dependent epoxide reductase and carboxylase. This involves suboptimal levels of coagulation factors II, VII, IX, and X, as well as proteins C, S, and Z. It is manifest as a range of spontaneous bleeding symptoms. High-level vitamin K supplementation is effective in managing the disorder. Low vitamin K status appears to contribute to unstable anticoagulation control in warfarin treatment, which condition affects as many as half of patients. Interventions with vitamin K have been found to improve anticoagulation control.

Bone Health

Several studies have shown individuals with low circulating vitamin K levels or vitamin K intakes to be at elevated risk of osteoporosis or fracture.35 The Nurses’ HealthStudy, a 10-year prospective study of more than 72,000 women, found the age-adjusted risk of hip fracture to be 30% less in women with vitamin K intakes 109 μg/d than in those consuming lower amounts.36 A similar relationship was observed in the Framingham Heart Study: subjects in the highest quartile of vitamin K intake (median intake 254 μg/day) have significant reductions in hip fracture risk compared to those in the lowest quartile (median intake 56 μg/day)

 Cardiovascular Health

Vitamin K-dependent proteins may play roles in atherogenesis, which involves thrombus-induced coagulation as well as intimal calcification. Gene deletion studies in mice have suggested that MGP may be a regulator of this process. Its undercarboxylation (due to warfarin treatment) results in arterial calcification in the rat.

Osteocalcin, normally expressed only in bone, is upregulated in arterial calcification. It has been suggested that Gas6 and protein S may inhibit calcification through enhancing apoptosis, which is extensive in atherosclerotic lesions. It is possible that increased dietary intakes of the vitamin may be useful in reducing atherosclerosis risk.

Anticarcinogenesis

That vitamin K status can play an anticarcinogenic role was suggested some six decades ago when MK treatment was found to increase the survival of inoperable bronchial carcinoma patients. Since then it has been observed that patients with hepatocellular carcinoma typically have abnormally high circulating levels of under-γ-carboxylated prothrombin (see “Signs of Vitamin K Deficiency,” page 228). Recently, a large (24,340 subjects) prospective study showed that the intake of MKs, but not phylloquinone, was associated with reduced cancer incidence and mortality.40 In an 8-year randomized clinical trial, MK (45 mg/day) reduced risk of hepatocellular carcinoma in 43 women with viral cirrhosis of the liver by 87% compared to controls.

Obesity

Obesity appears to impair the utilization of vitamin K. Adipose tissue stores vitamin K at relatively high levels, 42 and plasma phylloquinone levels have been found to vary inversely with percentage body fat in women who also showed increased circulating levels of undercarboxylated prothrombin. A 3-year intervention study found that phylloquinone supplementation reduced insulin resistance in men.43 However, no significant benefits were found in women in that or another trial.

Nervous Function

The vitamin is abundant in the rat brain, almost exclusively as MK-4. It is found in greatest concentrations in myelinated regions such as the pons medulla and midbrain. Still, the role of vitamin K in neural function is unclear. A function of the vitamin in sphingolipid metabolism has been shown in bacteria; such a role could have functional significance in mammalian neurons, as sphingolipids are important components of membranes and also serve as second messengers for intracellular signal transduction pathways. However, such a role has not been reported in animals, although studies have shown warfarin treatment to reduce brain sulfatides, and vitamin K depletion treatment to reduce the activity of brain glutathione S-transferase. Both Gas6 and protein S are widely expressed in the central nervous system of the rat. Gas6 has been shown to have neurotrophic activity toward hippocampal neurons, and to promote growth and survival of several types of neural cells.

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