Vitamin K1, K2, K3 – Deficiency – Overdosing & Side effects

Vitamin K1, K2, K3 - Deficiency - Overdosing & Side effects

Vitamin K is a fat-soluble vitamin named after its ability to make the blood coagulate. The vitamin was discovered by Danish scientist Henrik Dam in connection with his observation that chickens who ate a low-fat diet developed leaky blood vessels. It turned out that the low-fat diet led to lack of what Dam called “coagulation factor” which later became vitamin K.

The vitamin K consists of a whole family of structurally similar compounds that are important for cardiovascular health, primarily by controlling the body’s use of calcium. This regulatory function ensures that the calcium goes into the bones and teeth where it should be and that it is not stored in blood vessels and other soft tissues that would then become calcified. In addition, vitamin K has anti-inflammatory and insulin-controlling functions. Vitamin K also occurs in high concentrations in the brain where it contributes to the production of myelin that protects the nerves, as well as other important compounds.

 

Chemical profile and function

Vitamin K consists of two natural forms: phylloquinone (K1) which accounts for about 90 percent of the total intake of vitamin K in the western world, and menaquinone (K2) which accounts for about 10 percent of the intake.

The name phylloquinone is derived from the Greek word phyllo which means “leaf”, while mena in menaquinone has to do with the molecular ring structure of the vitamin. The ring structure looks exactly the same in the K1 and K2 vitamins, but they have side chains that look different.

Menaquinone (K2) comprises a whole group of compounds called MK-4 to MK-13. (The number represents the number of isoprene molecules in the side chain). Of these, MK-4, MK-7, and MK-9 are the most studied. The most common menaquinones in us humans are the short-chain MK-4, which is mainly formed in the conversion of K1 to K2 in the body, as well as the long-chain MK-7, MK-8, MK-9 and MK-10 produced by small intestine bowel bacteria.

 

 

 

 

 

 

 

K1 is found primarily in plants and algae and formed by the photosynthesis. As the name suggests, phylloquinone is associated with the content of chlorophyll: the darker the green color the plants have, the more chlorophyll and vitamin K they contain. Diets with K1 in it is leafy vegetables and cabbage plants, as well as in uncured vegetable oils, including rapeseed and soybean oil. Vitamin K1 from the diet can be converted to vitamin K2 in the body, but it is a fairly small percentage because the absorption of K1 from vegetables is low- about 5 percent, or up to 13 percent if the vegetables are eaten with a little fat (because vitamin K is fat-soluble). On the other hand, the amount of K2 from food is the higher. Virtually all vitamin K2 contained in the food is absorbed. Vitamin K2 occurs in moderate amounts in animal food, especially in cheese and organ meats, as well as in fermented vegetables such as the soy product natto, sauerkraut and Korean kimchi (especially the long-chain variants MK-7,

Vitamin K1 from the diet can be converted to vitamin K2 in the body, but it is a fairly small percentage because the absorption of K1 from vegetables is low- about 5 percent, or up to 13 percent if the vegetables are eaten with a little fat (because vitamin K is fat-soluble). On the other hand, the amount of K2 from food is the higher. Virtually all vitamin K2 contained in the food is absorbed. Vitamin K2 occurs in moderate amounts in animal food, especially in cheese and organ meats, as well as in fermented vegetables such as the soy product natto, sauerkraut and Korean kimchi (especially the long-chain variants MK-7,

Vitamin K2 occurs in moderate amounts in animal food, especially in cheese and organ meats, as well as in fermented vegetables such as the soy product natto, sauerkraut and Korean kimchi (especially the long-chain variants MK-7, MK-8, and MK-9). Natto is the largest known source of vitamin K in the diet and contains mainly MK-7.

There is also a third vitamin K called vitamin K3 (menadion). It is a much simpler variant that is primarily manufactured synthetically, but the intestinal bacteria can produce small amounts of natural K3 out of K1. K3 has been used in the research on the vitamin K anti-cancer effect. It has been observed that it enhances the effect of chemotherapy and vitamin C given intravenously in high doses. Because K3 has a toxic effect, it has not been approved for use in dietary supplements. The main task of vitamin K1 is to control the blood clotting factors, while K2 has a significantly larger scope. It contributes to the bone formation of the body and protects against loss of bone mass, blood vessel calcification and oxidation of LDL cholesterol. In addition, K2 is a fifteen times more powerful antioxidant than K1, and is the dominant form of vitamin K in all tissues, except the liver.

 

Metabolism 

Vitamin K is absorbed in the small intestine with the help of bile salts, fatty acids and pancreatic enzymes. It is then stored in the liver using it to form coagulators allowing blood to clot when an injury occurs. When K1 and MK-4 are absorbed via the intestine they are taken up in triglycerides and soon removed from the body by the liver. However, the long chain menaquinones are taken up by low-density lipoproteins (LDL, VLDL) that again gets distributed in the body. Since LDL has a long half-life in blood the circulation, long-chain menaquinones remain in the body for longer periods of time, which means they have higher bioavailability for different tissues such as bone and blood vessels compared to K1 and MK-4. While K1 is eliminated by the liver within a few hours, measurable levels of MK-7 can be seen up to three days after ingestion.

 

Calcium regulation by carboxylation.

Vitamin K affects the blood clotting ability and the body’s bone formation through a process called carboxylation. In this process, vitamin K is included in the enzyme gamma-glutamyl carboxylase which converts residues of glutamic acid into certain proteins to Gla (gamma carboxyglutamic acid). The process is called carboxylation because the proteins are supplied to two groups of carboxylic acids. Gla is included in the production of calcium-binding substances in these proteins. This allows them to effectively bind to calcium ions.

Thus, by the carboxylation, the so-called Gla proteins are activated so that they can perform their functions in the body. They are needed for blood clotting, bone metabolism, the repair of blood vessels, the prevention of blood vessel calcification and other soft tissues and the regulation of cell growth and signal transmission.

K1 is used primarily in the carboxylation (activation) of coagulation factors in the liver. K2 is preferably used in the rest of the body to carboxylate (activate) other K vitamin dependent Gla proteins, including osteocalcin, a calcium-binding protein that is primarily found in the bones, and matrix Gla protein (MGP) that prevents calcification of soft tissue such as blood vessels, heart, breast and kidney. MPG occurs mostly in the cartilage and blood vessels walls. If there is too little vitamin K in the body, the carboxylation cannot be performed. Then these proteins remain inactive and inoperative. They are said to be “non-carboxylated”. As a consequence, bone formation is deteriorated.

 

Vitamin K prevents blood vessel calcification

The MGP protein is the substance in the body that is best at blocking the calcification of tissues. The importance of the protein for vascular health was first discovered in experimental animals raised to have a lack of MGP. They all died of massive atherosclerosis within 6-8 weeks after birth. MGP is manufactured by small muscle cells in the cardiovascular system. When carboxylated using vitamin K2, it protects against calcification in several ways, including by inhibiting a so-called bone morphogenesis (BMP-2) that is included in the blood vessel calcification. It also activates the gene encoding the enzyme NAD (P) H-kinon-dehydrogenase that is important for the recovery of vitamin K and contributes to increased activity of osteoclast- bone cells that break down blood vessel calcification.

Non-carboxylated MGP has been identified as a key player in the increasing calcification seen in the development of varicose veins, as well as other vascular diseases. Researchers who compared healthy veins with veins affected by vascular fractures in male patients saw that men with varicose veins had high levels of non-carboxylated MGP. This indicates that the local availability of vitamin K in their veins was insufficient to allow carboxylation of all newly formed MGPs. Supplements of vitamin K2 have also been shown to reduce varicose calcifications in cell cultures, indicating that the carboxylation of MGP can be increased.

Vitamin K2 can also inhibit calcification in the heart and vessels, as well as in the kidneys. Calcified kidneys can lead to diabetes and the need for dialysis treatment. According to research, women who eat a vitamin K2 diet have a significantly lower proportion of breast calcification compared to women whose diet contains a little K2. In women, breast tissue calcification has been associated with 132% increased risk of cardiovascular disease, 141% increased risk of stroke and 152% increased risk of heart failure.

 

Therapeutic use

Osteoporosis (brittle-bone disease) and osteopenia (lack of bone mass). According to several epidemiological studies and intervention studies, lack of vitamin K, with associated high levels of non-carboxylated osteokalcin, may cause poorer bone density and increased risk of fractures. Conversely, vitamin K2 supplementation has been shown to increase the activation of osteocalcin (by carboxylation), promote bone formation and reduce the risk of fractures.

An additional factor is that a number of clinical trials have shown that a combination of vitamins K2 and D3 is more effective in preventing bone mass loss than if taken individually. In a study of 173 women with osteoporosis receiving both K2 and D3, bone density increased by 4.92% on average, compared to only 0.13% in the participants who only received K2. In another experiment, the effects of vitamin D and vitamin K were evaluated in combination or separately by dividing 92 postmenopausal women into four groups. Group 1 received only K2 (45 mg/day), group 2 only received D3, group 3 received both K2 and D3 and group 4 received calcium lactate. In group 4 who only had calcium, bone density decreased in the lumbar spine. Groups 1 and 2 receiving either K2 or D3 had a slight increase in bone density. In group 3, receiving both K2 and D3, bone density in the lumbar spine increased by an average of 1.35%.

According to another study from 2008, good vitamin K status gave better protection against hip fractures. It was shown that a combination of calcium, magnesium, zinc and vitamin D is needed for strong bones, but natural vitamin K2 (M K-7) was identified as the key factor for optimal bone health.

 

Atherosclerosis

When cholesterol in the body oxidizes, calcification# can occur in the blood vessels. If too much calcium is deposited in the vessels, they are further calcified. Thickening and lack of elasticity cause the blood pressure to rise and the vessels risk to be damaged by the increased friction. Because vitamin K2 prevents blood vessel calcification, it provides an indirect protection against high blood pressure and other vascular diseases.

K2 also promotes the elasticity of blood vessels directly by protecting the elastin, the most important protein of the muscle fibers, which is primarily responsible for the elasticity of the vessel wall. Calcification in the vessels does not only damage the existing elastite, but also inhibits the production of new elastin.

The question of whether a high K vitamin intake protects against atherosclerosis was placed for the first time in the Rotterdam study, a major clinical trial involving 4 807 people aged 55 and over and lasting for 7-10 years. It showed that a high intake of vitamin K2 (but not K1) through the diet was associated with lower risk of aortic calcification and mortality from cardiovascular diseases. The participants who had the highest intake of vitamin K2 in the diet had a 52% lower risk of severe aortic calcification, 57% lower risk of cardiovascular disease and 26% lower risk of total mortality. The intake of vitamin K1, on the other hand, showed no relation to the positive outcomes.

The difference between K1 and K2 was also illustrated in a three-year observation study of 387 renal patients on dialysis. It showed that vitamin K1 deficiency was the strongest risk factor for spinal fractures, while vitamin K2 deficiency (MK-4) was a risk factor for vascular calcification.

In a clinical intervention study, 78 women between 55 and 65 years of age received K2 vitamin supplement (1 mg / day) or placebo. After three years, participants receiving K2 had unchanged vessel status (elasticity and expansibility), while the vascular elasticity of the placebo group had deteriorated by 10-13 percent.

 

Relationship between osteoporosis and atherosclerosis

Osteoporosis and atherosclerosis were previously considered as two completely separate conditions, but now research suggests that there is indeed a link between them.

Aortic calcification has a particularly positive connection with osteoporosis fractures and the development of poorer bone density in the lumbar spine. In a study of 195 women after menopause, the relationship between carotid artery plaque, low bone density and fractures was so strong that the researchers suggested that this could partly explain why osteoporotic fractures were linked to increased mortality. Similar links have also been found in men. Similar correlations were also found in men.

One explanation for the link between osteoporosis and atherosclerosis is now being developed in studies analyzing the two diseases underlying mechanisms. They seem to coincide in a common factor: lack of vitamin K.

 

Best sources of vitamin K

Cabbage, dark green leafy vegetables, algae and some oils are good sources of Vitamin K1. Meat, liver, egg yolk and aged cheese (especially Brie and Gouda) contain higher levels of vitamin K2. K2 is formed by bacteria in the gastrointestinal tract in humans and animals but is also found in higher levels in fermented foods, especially natto. Other fermented soy products such as miso and tempeh do not contain as much K2. This is because only certain bacteria (such as Bacillus subtilis and Bacillus licheniformis) produce K2.

The content of vitamin K in foods is influenced by factors such as the variety and cultivation- and storage conditions#. Vitamin K1 is light sensitive but relatively heat-stable. Studies indicate that the bioavailability of K1 in vegetables is relatively low, but that it increases if the meal contains fat.

 

High content:> 100 micrograms / 100 grams

  • Natto (MK-7)
  • Leafy greens such as spinach, chard, and lettuce (not iceberg lettuce)
  • Broccoli
  • Rapeseed oil, soybean oil
  • Kale, Brussels sprouts
  • Pesto

Moderate content: 20-100 micrograms / 100

  • Iceberg lettuce, squash, asparagus
  • Sugar peas, fresh soybeans, cucumber, avocado
  • Olive oil, flaxseed oil
  • Cabbage, red cabbage
  • Egg yolk
  • Turkey, chicken

 

Cooking

Vitamin K is stable in heat, light, air, moisture and insoluble in water. Only very small amounts are destroyed by moderate heating. However, when exposed to sunlight for prolonged periods and cooking with fat in high temperatures, larger amounts of the vitamin are destroyed.

 

Intake

The American Institute of Medicine (IoM) estimates a sufficient intake according to the following values:

 

Group/age and recommended daily intake

  • Children under 6 months – 2 micrograms
  • Children 7-12 months – 2,5 micrograms
  • Children 1-3 years – 30 micrograms
  • Children 4-8 years – 55 micrograms
  • Children 9-13 years – 60 micrograms
  • Children 14-18 years – 75 micrograms
  • Women – 90 micrograms
  • Men – 120 micrograms

 

Needs

Thanks to the enzyme VKOR that the body uses to recycle vitamin K in a very efficient manner, human needs for vitamin K are low. We only need 45 micrograms per day, at least of the most potent form, MK-7. It is unusual for such a large deficiency of vitamin K (especially K1) that it is not enough for the body’s coagulation needs.

However, the level required for the blood to coagulate is much lower than required (in the form of K2) for optimal bone and vascular health. Studies of healthy adults have shown high levels of non-carboxylated osteocalcin and MGP in all subjects tested.

However, the need for vitamin K increases with age. People over 70 need higher levels to maintain low levels of non-carboxylated K vitamin-dependent proteins.

 

The following groups may have a greater need for vitamin K:

  • Newborn children in the first two weeks, especially if they have diarrhea, chronic liver diseases, bowel disease, celiac disease or prolonged diarrhea.
  • Newborns, born to women who have taken blood thinners or medicines for diarrhea or infections during pregnancy.
  • People with reduced fat absorption or reduced amount of bile salts.
  • People who have undergone gastrointestinal- or gallbladder surgery.
  • People with an increased bleeding tendency (especially nasal blood), osteoporosis and arteriosclerosis.
  • Burn patients.
  • Women over the age of 50.
  • Pople who does not eat a lot of vegetables and eats a lot of  hydrogenated fats#
  • People with long-term medicational intake, including repeated intake of antibiotics.

 

In the US, rapeseed and soybean oil are the primary dietary sources of vitamin K. If the oils are cured, the vitamin K1 contained in the oil has transformed into another form (dihydrofyllokinone) that can not carboxylate osteocalcin and other vitamin K dependent proteins. Of the 2 544 women and men who participated in a partial study of the known Framingham study, those whose vitamin K intake was mainly derived from cured oils had the lowest bone density in the neck, hips, and spine. People who eat highly refined foods with hardened fats can thus have a greater risk of vitamin K deficiency.

Vitamin K injection at birth

Most children are born with a low vitamin K level and are at some risk of increased bleeding tendency if they have too low vitamin K level. The risk increases if the mother’s breast milk contains a little vitamin K, if the child has a problem with fat intake (eg in jaundice) or if the child’s K vitamin-forming bacteria in the intestine do not grow. Newborns, therefore, receive a vitamin K1 injection as a preventive measure.

 

Analysis and measurement methods

Vitamin K is often measured by measuring prothrombin in plasma. However, normal prothrombin time (coagulation time in seconds) does not indicate if there is enough vitamin K for the carboxylation of osteocalcin or MGP. Therefore, to measure the vitamin K level, osteocalcin should be tested. It gives an indication of the amount of non-carboxylated osteocalcin (UCOC) present in the blood. High levels of UCOC indicate insufficient vitamin K levels for optimal bone health.

 

Dietary supplement form of preparation

K1 and K2 in the form of MK-4 and MK-7 are available as dietary supplements. MK-4 is then a synthetic variant called menatetrenone, while MK-7 is found as a natural extract, that comes from either natto or chickpeas. MK-7 seems to be the most active form of K2.

In most studies that evaluated the effect of vitamin K to prevent osteoporosis and atherosclerosis, have used K2 (MK-4). MK-4 is the form of K2 the body preferably converts to K1. MK-4 appears rapidly in the blood, but as half-life is only 1-2 hours, high doses are required (usually 45 milligrams, divided into 15 mg three times daily). Such high doses cannot be used by people taking blood-thinning medicines (eg warfarin).

MK-7 is a very bioavailable and bioactive form. In the large Rotterdam study, it was shown that a very small dose of 45 micrograms per day was sufficient for the osteocalcin to be carboxylated (activated). Since MK-7 has a much longer half-life (three days), the body is able to build a buffer that can supply all K2 vitamin tissues around the clock.

Overdosing

Neither K1 or K2 produces side effects in people who are not medicated with blood thinners such as warfarin. There is no indication that the body’s coagulation factors become overactive if you supplement with vitamin K1 or K2. For this reason, the American Institute of Medicine has chosen not to set an upper limit for vitamin K.

However, one should be careful if you suffer from hemophilia or liver impairment. Too high doses to infants can also be harmful.

K3, or menadione – a synthetic form of vitamin K, promotes the body’s production of free radicals. High doses of K3 have therefore been used in cancer research precisely because of this ability to create oxidative stress that kills cells. However, K3 has induced nausea, vomiting, jaundice and hemolytic anemia in infants, even in lower doses. Therefore, the FDA has banned the use of K3 in dietary supplements.

 

Interactions with drugs

Vitamin K counteracts the effect of warfarin (Coumadin) and other drugs that inhibit blood clotting. The drugs block the recovery of vitamin K by stopping the activation of the enzyme VKOR. This reduces the amount of vitamin K available for the production of coagulants, but also for the calcium-dependent proteins that build up the bones and protect against calcification of soft tissues. This means, paradoxically, an increased risk of osteoporosis and calcified blood vessels when these medications are taken for an extended period of time.

Sometimes patients are advised not to eat foods containing vitamin K in order not to affect the treatment with blood-thinning medicines. However, because a healthy diet contains some vitamin K, the American NIH recommends that you instead try to keep the vitamin K intake constant so that the drug dose can be adjusted accordingly. Omega-3 fatty acids, which also form part of a healthy diet is also a blood thinner, without affecting vitamin K function or the calcium-dependent proteins.

 

Interactions with nutrients

 

Vitamin B2: For the body’s recycling of vitamin K, the enzyme NAD (P) H-quinone dehydrogenase, which is formed from riboflavin (B2), is needed. Therefore, our vitamin K status is dependent on sufficient amounts of riboflavin.

Vitamin D and A: A number of studies suggest that vitamin A protects against possible vitamin D poisoning by reducing the expression of MGP, which means that vitamin K is saved. Vitamin A thus counteracts depletion of vitamin K at elevated levels of vitamin D.

In animal experiments on rats and poultry, it has been observed that high doses of vitamin A appear to protect both against soft tissue calcification and specifically against calcification of the kidneys by high levels of vitamin D3.Since the retinoic acid of vitamin A and vitamin D’s calcitol compete for the same receptors, their effects are likely naturally balanced when taken together.

One theory is that vitamin D poisoning can be avoided through a balanced intake of vitamins D, A and K. Taking into account the synergistic relationship between these three fat-soluble vitamins, vitamin D would likely be able to give greater therapeutic effect at lower doses, but could also be given in higher therapeutic doses without incurring the risks associated with D-hypervitaminosis (D -poisoning).

– Recommended vitamin K2 Supplements by Nutrainfo.net

Sources

Written

Gaby, Allan. Nutritional Medicine. Concord, New Hampshire: Fritz Perlberg Publishing; 2011.
Stenvinkel P. Vaskulär förkalkning: ett vanligt men förbisett tillstånd. Läkartidningen. 2013;110:CCMW.
Wilhelmsson, Peter. Näringsmedicinska uppslagsboken. 2 rev. uppl. Falun: Örtagårdens bokförlag; 2007.

Electronic

Livsmedelsverket: http://www.livsmedelsverket.se/livsmedel-och-innehall/naringsamne/vitaminer-och-antioxidanter/
Internetmedicin.se: http://www.internetmedicin.se/page.aspx?id=4004
Pizzorno L. Vitamin D and Vitamin K Team Up to Lower CVD Risk. Longevity Medicine Review: http://www.lmreview.com/articles/view/vitamin-d-and-vitamin-k-team-up-to-lower-cvd-risk-part-II/
University of Maryland Medical Center: http://umm.edu/health/medical/ency/nutrition
U.S. National Institutes of Health: https://ods.od.nih.gov/factsheets/list-all/