Vitamin K Deficiencies

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Vitamin K status can be estimated using prothrombin time (PT). PT is used to evaluate the common pathway of blood clotting. The synthesis of clotting factors II, VII, IX, and X are vitamin K dependent. Osteocalcin or bone G1a protein (BGP), a bone turnover marker, may also be used to assess vitamin K status. The production of BGP is stimulated by dihydroxy vitamin D and depends on vitamin K. 

Vitamin K increases the carboxylation of osteocalcin or BGP, but it does not increase its overall rate of synthesis. A reduced vitamin K status is associated with reduced BGP or serum osteocalcin levels. This relationship may explain the pathophysiologic findings of vitamin K- deficiency osteoporosis. The function of osteocalcin is unclear; however, it may exist as a deposition site for hydroxyapatite crystals, or it also may affect energy metabolism via the production and act as insulin.

Vitamin K is a fat-soluble vitamin that comes in two forms. The main type is called phylloquinone, found in green leafy vegetables like collard greens, kale, and spinach. The other type, menaquinones, are found in some animal foods and fermented foods. Menaquinones can also be produced by bacteria in the human body.

Vitamin K helps to make various proteins that are needed for blood clotting and the building of bones. Prothrombin is a vitamin K-dependent protein directly involved with blood clotting. Osteocalcin is another protein that requires vitamin K to produce healthy bone tissue.

Vitamin K is found throughout the body including the liver, brain, heart, pancreas, and bone. It is broken down very quickly and excreted in urine or stool. Because of this, it rarely reaches toxic levels in the body even with high intakes, as may sometimes occur with other fat-soluble vitamins.

An “adequate intake” (AI) is used when there is not enough evidence to establish a Recommended Dietary Allowance (RDA). The AI amount is estimated to ensure nutritional adequacy.

For adults 19 years and older, the AI for vitamin K is 120 micrograms (mcg) daily for men and 90 mcg for women and for those who are pregnant or lactating. Some sources for the two types of vitamin K are listed below.

  • Phylloquinone
    • Green leafy vegetables including collard and turnip greens, kale, spinach, broccoli, Brussels sprouts, cabbage, lettuces
    • Soybean and canola oil or Salad dressings made with soybean or canola oil
    • Fortified meal replacement shakes
  • Menaquinones
    • Natto (fermented soybeans)
    • Smaller amounts in meat, cheese, eggs

Antibiotic medicines and herbal infusions may destroy vitamin-K-producing bacteria in the gut, thereby potentially decreasing vitamin K levels, especially if taking the treatments for more than a few weeks. People who have a poor appetite while using long-term antibiotics may be at greater risk for a deficiency and may benefit from a vitamin K supplement.

Vitamin K is a fat-soluble vitamin, important for the function of numerous proteins within the body, such as the coagulation factors (II, VII, IX, X and protein C and protein S), osteocalcin (a bone-forming protein) and matrix-Gla protein (MGP) (an anticalcification protein), to name a few. Vitamin K exists naturally as vitamin K1 (phylloquinone) and vitamin K2 (menaquinone, MK-4 through MK-10). Vitamin K1 is mainly found in green leafy vegetables as well as olive oil and soyabean oil, whereas vitamin K2 (menaquinone) is found in small amounts in chicken, butter, egg yolks, cheese and fermented soyabeans (better known as natto).

Vitamin K1 and vitamin K2 are required for the γ-glutamyl carboxylation of all vitamin K-dependent proteins. Despite the fact that mammalian bacterial intestinal flora are able to produce vitamin K2, the amount produced is thought to be negligible. The adequate intake (AI) for vitamin K has been proposed to be 90 µg/day for women and 120 µg/day for men. However, it has been speculated that the AI for vitamin K (90–120 µg/day) is not sufficient to induce complete carboxylation of all vitamin K-dependent proteins.

Osteoporosis is a leading contributor of fractures worldwide, causing more than 8.9 million fractures annually. Moreover, Osteoporosis affects an estimated 200 million women worldwide (approximately 1/10th of women aged 60, 1/5th of women aged 70, 2/5ths of women aged 80, and 2/3rds of women aged 90). One in 3 women and 1 in 5 men over 50 will experience an osteoporotic fracture. Additionally, 61% of all osteoporotic fractures occur in women. 

It has been predicted that the incidence of hip fracture is expected to increase by 310% in men and 240% in women by 2050; thus, the economic toll of osteoporosis is expected to significantly increase. Indeed, it has been estimated that there is a 40% lifetime risk for fractures affecting the hip, forearm and vertebrae (similar to the risk for cardiovascular disease), with nearly 75% of these types of fractures occurring in patients aged 65 years age and above.

Osteoporosis has been shown to account for more days spent in the hospital than diabetes, heart attacks or breast cancer. It is also a major cause of disability, which has been shown to be greater than that caused by cancer (except lung cancer) and comparable to or greater than disability from rheumatoid arthritis, asthma and high blood pressure related heart disease.

The overall mortality within the first 12 months after a hip fracture is approximately 20%, being higher in men than women. Moreover, men make up 20–25% of all hip fractures and have an estimated 30% lifetime risk of experiencing an osteoporotic fracture when over 50, similar to the lifetime risk of developing prostate cancer. 

Fragility fractures are the primary cause of hospitalization and/or death for US adults ≥age 65 and above. Furthermore, 44% of nursing home admissions are due to fractures. It is obvious that osteoporosis is extremely common and this condition leads to disability, costs and even death. Thus, preventing and treating this disease is of utmost importance.

It has been shown that vitamin D is not capable of addressing osteoporosis, thus, what else can a clinician prescribe to help to prevent osteoporosis and its consequences? A broad amount of data seems to indicate substantial potential for supplementary vitamin K. However, currently few guidelines recommend vitamin K therapy for prevention or treatment of osteoporosis.

Vitamin K1 (5 mg daily) given to 440 postmenopausal women with osteopenia for 2 years in a randomized, placebo-controlled, double-blind trial caused a greater than 50% reduction in clinical fractures (9 vs 20, p=0.04) versus placebo, despite the fact that there was no improvement in bone mineral density.

 Moreover, there was a 75% reduction in cancer incidence with vitamin K1 (3 vs 12, p=0.02). The benefit of vitamin K on bone is thought to be unrelated to increasing BMD but rather increasing bone strength. A recent meta-analysis has shown that vitamin K2 (45 mg/day) significantly reduces hip (77% reduction), vertebral (60% reduction) and all non-vertebral fractures (81% reduction). Whether the results of vitamin K2 at a dose of 45 mg can be translated to over the counter doses of vitamin K1 (such as 1–5 mg) is still a matter of debate, but vitamin K1 on its own has already been shown to reduce fractures and cancer in a clinical trial, although more data are needed to confirm these benefits.

Coronary artery calcium (CAC) has been shown to have increasing prevalence as kidney function declines. Indeed, CAC prevalence has been reported in 13% of ‘healthy’ patients without renal disease, 40% of patients with chronic kidney disease patients not on dialysis, 57% of patients starting dialysis and 83% of patients on long-term dialysis. 

Diets lacking vitamin K can precipitate the development of vitamin K deficiency in as little as 7 days. Additionally, subclinical vitamin K deficiency is not uncommon, especially in patients receiving warfarin. Cross-sectional and cohort data have shown a lower risk of coronary heart disease (CHD), CHD mortality, all-cause mortality, and severe aortic calcifications with higher vitamin K2 (menaquinone) intake.

This was not shown with vitamin K1 intake (phylloquinone, the major dietary source of vitamin K. Thus, dietary vitamin K1 intake, without vitamin K2, may not be sufficient to suppress arterial calcifications and/or reduce risk for subsequent cardiovascular events and death. The menaquinone form of vitamin K (ie, vitamin K2) has been presumed to be more effective than vitamin K1 at preventing and reversing arterial calcifications. It has been proposed that a substantial amount of apparently healthy patients are subclinical vitamin K deficient based on undercarboxylated osteocalcin and MGP, presumably increasing the risk of vascular calcifications, cancer and osteoporosis.

Vitamin K has a plethora of potential implications, including prevention and treatment of arterial calcifications, coronary heart disease and cancer, improvements in bone strength and reduced risks of fractures as well as improvements in insulin sensitivity. Additionally, vitamin K may even play a vital role in the stabilization of INR control for patients on warfarin.

On the basis of previously presented data, warfarin may increase arterial calcifications and osteoporosis through the inhibition of vitamin K. Larger trials should be performed to further elucidate the negative long-term health consequences of warfarin and if these can perhaps be prevented through the institution of supplemental vitamin K.

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