Vitamin K

Vitamin K (Figure 1) is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are needed for blood coagulation (blood clotting) and which the body also needs for controlling the binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise.

In menaquinone, the side chain is composed of a varying number of isoprenoid residues. The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone. The three synthetic forms of vitamin K are vitamins K₃ (menadione), K₄, and K₅, which are used in many areas, including the pet food industry (vitamin K₃) and to inhibit fungal growth (vitamin K₅).

Figure 1: (left) Vitamin K₁ (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain. (right) Vitamin K₂ (menaquinone).

The MK-4 form of vitamin K₂ is produced by conversion of vitamin K₁ in the testes, pancreas, and arterial walls. While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats and in parenterally-administered K₁in rats. In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K₁ into MK-4. There is evidence that the conversion proceeds by removal of the phytyl tail of K₁ to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K₂ in the MK-4 (menatetrione) form.

Health effects of Vitamin K

Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Preliminary clinical research indicates that deficiency of vitamin K may weaken bones, potentially leading to osteoporosis, and may promote calcification of arteries and other soft tissues. Our main sources of vitamin K are from leafy green vegetables and from the production by bacteria in our large intestine.

• Osteoporosis: A review of 2014 concluded that there is positive evidence that monotherapy using MK-4, one of the forms of Vitamin K₂, reduces fracture incidence in post-menopausal women with osteoporosis, and suggested further research on the combined use of MK-4 with bisphosphonates. In contrast, an earlier review article of 2013 concluded that there is no good evidence that vitamin K supplementation helps prevent osteoporosis or fractures in postmenopausal women. A Cochrane systematic review of 2006 suggested that supplementation with Vitamin K₁ and with MK4 reduces bone loss; in particular, a strong effect of MK-4 on incident fractures among Japanese patients was emphasized. A review article of 2016 suggested to consider, as one of several measures for bone health, increasing the intake of foods rich in vitamins K₁ and K₂.
• Cardiovascular health: Adequate intake of vitamin K is associated with the inhibition of arterial calcification and stiffening, but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease. One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women.
• Cancer: Vitamin K has been promoted in supplement form with claims it can slow tumor growth; there is however no good medical evidence that supports such claims.
• Coumarin poisoning: Vitamin K is part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning).

Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K₁) or menaquinone (vitamin K₂) forms of vitamin K, so no tolerable upper intake level (UL) has been set. Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4)[12] and even up to 135 mg per day (45 mg three times daily) of K2 (as MK-4),[13] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg, body weight did not alter the tendency for blood-clot formation to occur. Unlike the safe natural forms of vitamin K₁ and vitamin K₂ and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic at high levels. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.

Phylloquinone (K₁) or menaquinone (K₂) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K. Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs. Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more predictable. The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient. The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither warfarin or vitamin K shows much effect in the first 24 hours after they are given.

Absorption and Dietary Need

Previous theory held that dietary deficiency is extremely rare unless the small intestine was heavily damaged, resulting in malabsorption of the molecule. Another at-risk group for deficiency were those subject to decreased production of K₂ by normal intestinal microbiota, as seen in broad spectrum antibiotic use. Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics. Diets low in vitamin K also decrease the body's vitamin K concentration. Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype. Additionally, in the elderly there is a reduction in vitamin K₂ production. Like other lipid-soluble vitamins (A, D and E), vitamin K is stored in the fatty tissue of the human body.

The National Academy of Medicine (NAM) updated an estimate of what constitutes an Adequate Intake (AI) for vitamin K in 2001. The NAM does not distinguish between K₁ and K₂ – both are counted as vitamin K. At that time there was not sufficient evidence to set the more rigorous Estimated Average Requirement (EAR) or recommended dietary allowance (RDA) given for most of the essential vitamins and minerals. The current daily AIs for vitamin K for adult women and men are 90 μg and 120 μg respectively. The AI for pregnancy and lactation is 90 μg. For infants up to 12 months the AI is 2–2.5 μg, and for children aged 1 to 18 years the AI increases with age from 30 to 75 μg. As for safety, the FNB also sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. In the case of vitamin K no UL is set, as evidence for adverse effects is not sufficient. Collectively EARs, RDAs, AIs and ULs are referred to as dietary reference intakes.

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value (%DV). For vitamin K labeling purposes the daily value was 80 μg, but as of May 2016 it has been revised upwards to 120 μg. A table of the pre-change adult daily values is provided at Reference Daily Intake (Table \(\PageIndex{1}\)). Food and supplement companies have until 28 July 2018 to comply with the change.

Deficiency

Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K₁ deficiency can result in coagulopathy, a bleeding disorder. Symptoms of K₁ deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women.

Table \(\PageIndex{1}\): Vitamin K

Food	Serving size	Vitamin K1 (μg)		Food	Serving size	Vitamin K1 (μg)
Kale, cooked	^1⁄2 cup	531			Parsley, raw	^1⁄4 cup	246
Spinach, cooked	^1⁄2 cup	444			Spinach, raw	1 cup	145
Collards, cooked	^1⁄2 cup	418			Collards, raw	1 cup	184
Swiss chard, cooked	^1⁄2 cup	287			Swiss chard, raw	1 cup	299
Mustard greens, cooked	^1⁄2 cup	210			Mustard greens, raw	1 cup	279
Turnip greens, cooked	^1⁄2 cup	265			Turnip greens, raw	1 cup	138
Broccoli, cooked	1 cup	220			Broccoli, raw	1 cup	89
Brussels sprouts, cooked	1 cup	219			Endive, raw	1 cup	116
Cabbage, cooked	^1⁄2 cup	82			Green leaf lettuce	1 cup	71
Asparagus	4 spears	48			Romaine lettuce, raw	1 cup	57
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.

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