Vitamin K

Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation and for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.
Vitamin K is used in the liver as the intermediate VKH₂ to deprotonate a glutamate residue and then is reprocessed into vitamin K through a vitamin K oxide intermediate. The presence of uncarboxylated proteins indicates a vitamin K deficiency. Carboxylation allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Research suggests that deficiency of vitamin K may also weaken bones, potentially contributing to osteoporosis, and may promote calcification of arteries and other soft tissues.
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone derivatives. Vitamin K includes two natural vitamers: vitamin K₁ and vitamin K₂. Vitamin K₂, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms. The two most studied are menaquinone-4 and menaquinone-7.
Vitamin K₁ is made by plants, and is found in highest amounts in green leafy vegetables, being directly involved in photosynthesis. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K₂, variant MK-4. Bacteria in the gut flora can also convert K₁ into K₂. All forms of K₂ other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration. Vitamin K₃, a synthetic form of vitamin K, was used to treat vitamin K deficiency, but because it interferes with the function of glutathione, it is no longer used in this manner in human nutrition.

Definition

Vitamin K refers to several structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. These are similar in structure in that they share a quinone ring, but differ in the length and degree of saturation of the carbon tail and the number of repeating isoprene units in the side chain. Plant-sourced forms are primarily vitamin K₁. Animal-sourced foods are primarily vitamin K₂. Vitamin K has several roles: an essential nutrient absorbed from food, a product synthesized and marketed as part of a multi-vitamin or as a single-vitamin dietary supplement, and a prescription medication for specific purposes.

Dietary recommendations

The US National Academy of Medicine does not distinguish between K₁ and K₂ – both are counted as vitamin K. When recommendations were last updated, in, sufficient information was not available to establish an estimated average requirement or recommended dietary allowance, terms that exist for most vitamins. In instances such as these, the academy defines adequate intakes as amounts that appear to be sufficient to maintain good health, with the understanding that at some later date, AIs will be replaced by more exact information. The current AIs for adult women and men ages 19 and older are 90 and 120 μg/day, respectively, for pregnancy is 90 μg/day, and for lactation is 90 μg/day. For infants up to 12 months, the AI is 2.0–2.5 μg/day; for children ages 1–18 years the AI increases with age from 30 to 75 μg/day. As for safety, the academy sets tolerable upper intake levels for vitamins and minerals when evidence is sufficient. Vitamin K has no upper limit, as human data for adverse effects from high doses are not sufficient.
In the European Union, adequate intake is defined the same way as in the US. For women and men over age 18 the adequate intake is set at 70 μg/day, for pregnancy 70 μg/day, and for lactation 70 μg/day. For children ages 1–17 years, adequate intake values increase with age from 12 to 65 μg/day. Japan set adequate intakes for adult women at 65 μg/day and for men at 75 μg/day. The European Union and Japan also reviewed safety and concluded – as had the United States – that there was insufficient evidence to set an upper limit for vitamin K.
For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value. For vitamin K labeling purposes, 100% of the daily value was 80 μg, but on 27 May 2016 it was revised upwards to 120 μg, to bring it into agreement with the highest value for adequate intake. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Fortification

According to the Global Fortification Data Exchange, vitamin K deficiency is so rare that no countries require that foods be fortified. The World Health Organization does not have recommendations on vitamin K fortification.

Vitamin K₁

Plant-sourced	Amount K₁
Hazelnuts chopped,	16
Grapes,	11
Tomato products,	9.2
Olive oil, 1 tablespoon	8.1
Zucchini boiled, drained, 1.	7.6
Mango pieces,	6.9
Pears, pieces,	6.2
Potato baked, including skin, one	6.0
Sweet potato baked, one	2.6
Bread whole wheat, 1 slice	2.5
Bread white, 1 slice	2.2
Nattō, 100 g	34.7

Vitamin K₂

Animal-sourced foods are a source of vitamin K₂. The MK-4 form is from conversion of plant-sourced vitamin K₁ in various tissues in the body.

Animal source	Amount K₂ MK-4 to MK-7
Goose	31
Chicken	8.9
Pork	2.1
Beef	1.1
Salmon	0.5
Egg yolk	32
Egg white	0.9

Animal source	Amount K₂ MK-4 to MK-7
Milk, whole	0.9
Milk, skim	0.0
Yogurt, whole milk	0.9
Butter	15
Cheese, hard	8–10
Cheese, soft	3.6

Fermented source	Amount K₂ MK-4 to MK-7
Nattō	1103

Vitamin K deficiency

Because vitamin K aids mechanisms for blood clotting, its deficiency may lead to reduced blood clotting, and in severe cases, can result in increased bleeding and increased prothrombin time.
Normal diets are usually not deficient in vitamin K, indicating that deficiency is uncommon in healthy children and adults. An exception may be infants who are at an increased risk of deficiency regardless of the vitamin status of the mother during pregnancy and breast feeding due to poor transfer of the vitamin to the placenta and low amounts of the vitamin in breast milk.
Secondary deficiencies can occur in people who consume adequate amounts, but have malabsorption conditions, such as cystic fibrosis or chronic pancreatitis, and in people who have liver damage or disease. Secondary vitamin K deficiency can also occur in people who have a prescription for a vitamin K antagonist drug, such as warfarin. A drug associated with increased risk of vitamin K deficiency is cefamandole, although the mechanism is unknown.

Medical uses

Treating vitamin deficiency in newborns

Vitamin K₁ is given as an injection to newborns to prevent vitamin K deficiency bleeding. The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this appears to be a consequence of poor transfer of the vitamin across the placenta, and thus low fetal plasma vitamin K. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at between 1 in 60 and 1 in 250.
Human milk contains 0.85–9.2 μg/L of vitamin K₁, while infant formula is formulated in range of 24–175 μg/L. Late onset bleeding, with onset 2 to 12 weeks after birth, can be a consequence of exclusive breastfeeding, especially if there was no preventive treatment. Late onset prevalence reported at 35 cases per 100,000 live births in infants who had not received prophylaxis at or shortly after birth. Vitamin K deficiency bleeding occurs more frequently in the Asian population compared to the Caucasian population.
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, brain damage, and death. Intramuscular injection, typically given shortly after birth, is more effective in preventing vitamin K deficiency bleeding than oral administration, which calls for weekly dosing up to three months of age.

Managing warfarin therapy

is an anticoagulant drug. It functions by inhibiting an enzyme that is responsible for recycling vitamin K to a functional state. As a consequence, proteins that should be modified by vitamin K are not, including proteins essential to blood clotting, and are thus not functional. The purpose of the drug is to reduce risk of inappropriate blood clotting, which can have serious, potentially fatal consequences. The proper anticoagulant action of warfarin is a function of vitamin K intake and drug dose. Due to differing absorption of the drug and amounts of vitamin K in the diet, dosing must be monitored and customized for each patient. Some foods are so high in vitamin K₁ that medical advice is to avoid those entirely, and for foods with a modestly high vitamin content, keep consumption as consistent as possible, so that the combination of vitamin intake and warfarin keep the anti-clotting activity in the therapeutic range.
Vitamin K is a treatment for bleeding events caused by overdose of the drug. The vitamin can be administered by mouth, intravenously or subcutaneously. Oral vitamin K is used in situations when a person's International normalized ratio is greater than 10 but there is no active bleeding. The newer anticoagulants apixaban, dabigatran and rivaroxaban are not vitamin K antagonists.