Vitamin K

---

Introduction

Vitamin K we mean a group of vitameri fat-soluble which, at the metabolic level, in the biologically active form guarantees the correct functionality some specifications protein implicated in bond of football in bones and other fabrics, and in the coagulation of blood (anti-haemorrhagic activity).

Vitamin K allows proteins with which it interacts to to tie the calcium ions. Without vitamin K, blood clotting is severely impaired and can result uncontrolled bleeding

Chemically, the vitamin K family includes the 2-methyl-1,4-naphthochinone (3-) and its derivatives. In nature, vitamin K is made up of two vitamers: the vitamin K1 and vitamin K2. Vitamin K2, in turn, is made up of various chemical subtypes, with side carbon chains of different lengths and made up of groups of isoprenoid atoms.

Vitamin K1, also known as fillochinone, is produced by plants and is found in the highest quantities in green leafy vegetables - because it is directly involved in photosynthesis - and can be considered the vegetable shape of vitamin K. This is able to carry out the normal biological functions of the typical form of the animal organism, the K2 o menachinone, but it can still be converted into it; this process can take place thanks to the intestinal microbiota or endogenously.

The bacterial flora is also capable of stretch the isoprenoid side chain of vitamin K2 for to produce typology different of menaquinone, especially the homologs MK-7 and MK-11. All forms other than MK-4 (menatetrenone) can be produced alone from anaerobic bacterial organisms, which exploit them for their own breathing cellular. MK-7 and other forms of vitamin K2 of bacterial origin show activity identical to ordinary menaquinone and it is unclear whether they may be of greater utility.

Vitamin K can also be obtained in a way synthetic, getting the vitamin K3 o menadione, K4 and K5. However, menadione interferes with the function of the glutathione thus proving to be toxic DON'T it is more used as remedy to the shortage of vitamin K.

Through nutrition, the right amount of vitamin K can be achieved simply by following a balanced diet. However, it has recently been suggested that the deficit of this nutrient may be related to a greater predisposition toOsteoporosis and favor the calcification of the arteries and of others "Fabrics soft. Several studies are still ongoing in this regard.

Health

Health of the newborn

Vitamin K is given as an injection to Infants to prevent deficiency bleeding. The blood clotting factors of newborns are about 30–60% of those of the adult values; this may be due to the reduced synthesis of the protein ​​precursors and sterility initial bowel. Breast milk contains 1–4 μg / L of vitamin K1, while milk derived from the formula can contain up to 100 μg / L in supplemented ones. The concentrations of vitamin K2 in breast milk appear to be much lower than those of vitamin K1. The presence of vitamin K deficiency bleeding in the first week of a baby's life is estimated at 0,25-1,7%, with a prevalence of 2-10 cases per 100.000 births. The children premature they have even lower levels of vitamin K, so they have a higher risk.

Bleeding in children due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and even death. The supplement can prevent most cases of deficiency bleeding. Intramuscular administration is more effective in preventing late deficiency bleeding than oral administration.

Vitamin K and osteoporosis

There is no evidence that vitamin K supplementation is beneficial for the bone health of postmenopausal women, but deficiency could be a risk factor.

Vitamin K and cardiovascular health

An in-depth appropriate Vitamin K intake is associated withinhibition area of calcification and dell 'stiffening arterial, but there have been few studies and no sufficient evidence that theintegration of vitamin K is of benefit in prevention primary of the cardiovascular diseases.

A population study carried out by Rotterdam showed a clear and significant report reverse among the highest levels of intake of menachinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) e cardiovascular diseases e mortality to all causes in older men and women.

Vitamin K and cancer

Vitamin K has been promoted in the form of supplement to slow down the growth of tumor; However, none test medica supports these claims.

Physiology

Vitamin K Physiology

Vitamin K1 (phylloquinone), the precursor to most vitamin K in nature, is an important chemical in green plants, where it acts as an electron acceptor in photosystem 1 during photosynthesis. For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants, but appears in small quantities in other plant tissues (roots, fruits, etc.). There iceberg lettuce el 'indivia belga chicory they contain relatively little. The function of phylloquinone in plants appears to bear no resemblance to its subsequent metabolic and biochemical function in animals, where it carries out an entirely different biochemical reaction.

In animals, vitamin K is involved in the carboxylation of some glutamate residues in proteins to form residues gamma-carboxyglutamates (Gla). Modified residues are often (but not always) located within specific protein domains called Gla domains. Gla residues are generally involved in calcium binding and are essential for the biological activity of all known Gla proteins.

At this time, 17 human proteins with Gla domains have been discovered, which play key roles in the regulation of three physiological processes:

1. Blood clotting: prothrombin (factor II), factors VII, IX and X and proteins C, S and Z;
2. Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP), periostin, and the recently discovered Gla-rich protein (GRP);
3. Vascular biology: specific protein 6 for growth arrest (Gas6);
4. Unknown function: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxylic glutamyl proteins (TMG) 3 and 4.

When vitamin K1 enters the body through food it comes absorbed through fasting el 'ileo in 'bowel outfit and, like other fat-soluble vitamins (A, D and E), it comes stored in liver and in adipose tissue.

Professional Chermisty

Introduction to the chemistry of vitamin K

As anticipated, vitamin K is the general term used to refer to 2-metil-1, 4 naftochinone and all his derivatives with an unsaturated isoprenoid side chain - starting from the C-3 of naphthoquinone.

The different natural forms of vitamin K include:

• Vitamin K1 or phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone): present in foods of plant origin;
• Vitamin K2 or menaquinone-n: of bacterial origin.

The structure of phylloquinone is characterized by the presence of a group wick. The structures of menaquinones are marked with a side chain poliisoprenilica which can contain from 6 to 13 units isopreniliche.

Synthetic forms of vitamin K include:

• Vitamin K3 o menadione;
• Vitamin K4;
• Vitamin K5.

These are used in various industries, including the pet food industry - particularly vitamin K3 - and to inhibit the growth of fungi - this is the case with vitamin K5.

Conversion of vitamin K1 into K2

The shape MK-4 of vitamin K2 is obtained from the endogenous conversion of vitamin K1; this occurs in the testicles, pancreas and arterial walls, not by the intestinal flora.

Not surprisingly, tissues that accumulate high amounts of MK-4 have a remarkable ability to convert up to 90% of the available K1 into MK-4. This conversion occurs by removal of the phytyl tail of K1 to obtain menadione as an intermediate, then condensed with a portion of activated geranyl geranyl to produce the MK-4 (menatetrenone) form.

Absorption

Absorption of vitamin K

The different forms of vitamin K are absorbed in the same way as lipids in the small intestine (ileus and jejunum), therefore they require the formation of micelles in the presence of bile and pancreatic juice. Generally the diet contains a mixture of menaquinones and phylloquinones, absorbed with an efficiency of 40-80%. Phylloquinone appears to be actively absorbed in the proximal part of the small intestine, while menaquinones and menadione are absorbed by passive diffusion. Passive diffusion also seems to occur in the colon and this would confirm the possibility of using the menaquinone produced by the intestinal bacterial flora.

Transport and Metabolism

Transport of vitamin K

After absorption, vitamin K becomes part of the chylomicrons and transported to the liver, where it is transferred to the VLDL and then to the LDL which transport it to the tissues. The main circulating form is phylloquinone (0,1 ÷ 0,7 ng / ml).

Storage organs are the liver (large amounts, which are quickly removed), adrenal glands, lungs, spinal cord, and kidneys (small amounts).

Vitamin K metabolism

Vitamin K has a very fast turnover; menadione is excreted in the urine in the form of menadiol phosphate, sulfate and glucuronide; phylloquinone and menaquinone are degraded more slowly; the side chains shortened by β-oxidation are eliminated as such or in the form of glucuronides.

functions

Functions of vitamin K

Vitamin K is transformed into the biologically active form of hydroquinone by a reductase dependent on the presence of sulfhydryl groups and NADH.

In the presence of hydroquinone and a carboxylase, some glutamate residues are carboxylated to γ-carboxyglutamate.

Among the proteins that undergo this reaction are mentioned:

• coagulation factors II (prothrombin), VII, IX, X;
• recently identified plasma proteins C, S, Z and M;
• osteocalcin, necessary for normal bone metabolism.

La blood clotting it occurs as a chain reaction in which the various factors come into action following a precise order, each activating the next. At the end of the cascade of reactions, fibrinogen is transformed into fibrin. Plasma thromboplastin activates factor IX which together with factor VIII and phospholipids, in the intrinsic system, activates factor X, which can also be activated by factor VII (itself activated by tissue thromboplastin) in the extrinsic system.

Once activated, factor X binds calcium ion and phospholipids catalyzing the activation of prothrombin (factor II) into thrombin which favors the transformation of fibrinogen into fibrin, which allows clot formation.

Protein C has an anticoagulant role, is activated by thrombin in the presence of thrombomodulin (endothelial cell protein) and acts with protein S by deactivating factors Va and VIIIa; acts as a brake of the cascade of the intrinsic system by means of a feedback mechanism triggered by thrombin; therefore people with congenital protein C deficiency are at high risk of thrombosis. The physiological functions of the M and Z proteins are not yet known.

Osteocalcin (or bone GLA protein) is synthesized by osteoblasts and is most likely involved in the regulation ofincorporation of calcium phosphate in bones.

GLA proteins have been isolated in rat dentin, kidney, sperm, hepatic mitochondria, urine and calcified atherosclerotic tissues, suggesting numerous functions of vitamin K.

According to the latest scientific research (not yet fully confirmed) in humans there is a relationship between low levels of vitamin K in the blood and osteoarthritis, bone fractures and osteoporosis.

Shortage

Vitamin K deficiency

In the past it was believed that vitamin K deficiency in humans was very rare, as:

• the body has a modest request for it;
• the body can regenerate it thanks to the action of reductase enzymes;
• it is partly synthesized by the intestinal bacterial flora.

Today, however, it is assumed that a good portion of the population may not have sufficient circulating levels of vitamin K. The deficiency of vitamin K, primary o secondary, can result from one or more causes or risk factors:

• Genetic defect of the specific transport protein;
• Functional disorders of the gastrointestinal system, such as reduced secretion of bile, liver disease, chronic inflammatory diseases of the intestine, etc.
• Resection of an intestinal portion;
• Chronic kidney disease;
• Cystic fibrosis;
• Deficiency of intestinal bacterial flora or microbiota with poor vitamin synthesis capacity;
• Use of drugs, such as anticoagulants such as dicumarol (antagonists), antibiotics, salicylates, barbiturates and cefamandole;
• Alcoholism;
• Old age
• Anorexia nervosa or bulimia nervosa;
• Very restrictive low calorie diets.

Warning! Taking broad-spectrum antibiotics can reduce the production of vitamin K in the gut by nearly 74%.

Newborns are particularly at risk for:

• Modest transport across the placenta;
• Intestinal sterility in the placenta until birth;
• Inadequate hepatic biosynthesis of coagulation factors;
• Low vitamin content in female milk.

Vitamin K deficiency symptoms

The deficiency is manifested by hemorrhagic syndrome due to inadequate synthesis of coagulation factors. It is defined as a vitamin K sensitive hypoprothrombinemia which increases the prothrombin time and can therefore lead to coagulopathy - a bleeding disorder. Symptoms of K1 deficiency include anemia, bruising, nosebleeds and gum bleeding in both sexes and excessive menstruation in women.

L'Osteoporosis and coronary heart disease relate to low levels of vitamin K2 (menaquinone). The level of vitamin K2 intake (such as menaquinones MK-4 to MK-10) is inversely correlated to the grave aortic calcification and mortality for all causes.

Toxicity

Vitamin K toxicity

Although a possible allergic reaction from supplementation cannot be ruled out, phylloquinones and menaquinones are not toxic even at high doses. A Tolerable Upper Intake Level (UL) has not been established.

Given intravenously rather than orally, vitamin K1 has been associated with severe adverse reactions such as bronchospasm and cardiac arrest.

Human blood clotting studies using 45 mg / day of vitamin K2 (like MK-4) and even up to 135 mg / day (45 mg three times a day) of K2 (like MK-4), have not shown no increased risk of blood clots. Even doses up to 250 mg / kg body weight in rats did not alter the tendency for blood clot formation.

Unlike the safe natural forms of Vitamin K1 and Vitamin K2 and their various isomers, the synthetic form K3 (menadione), is clearly toxic at high levels. The United States FDA has banned this form from being sold over the counter because high doses have been shown to cause allergic reactions, hemolytic anemia, cytotoxicity in liver cells with hyperbilirubinemia, and jaundice. It cannot even be used in the drug treatment of bleeding.

Interactions

Drug interactions of vitamin K

Phylloquinone (K1) or menaquinone (K2) are capable of reverse the anticoagulant activity of the anticoagulant warfarin (trade name Coumadin). Warfarin works by blocking the recycling of vitamin K, so that the body and tissues have lower levels of the active vitamin and therefore a deficiency.

The vitamin K supplement reverses the vitamin K deficiency caused by warfarin and thus reduces the expected anticoagulant action. Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more moderate. The correct anticoagulant action of the drug depends on the intake of vitamin K and the dose of the drug and, due to the different absorption, it must be personalized for each patient.

The new anticoagulants apixaban, dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K and can be taken with it.

Alimony

Food sources of vitamin K.

Vitamin K1 is widely distributed in foods of vegetable origin and especially type leafy o flower such as: spinach, lettuce, broccoli, cabbage, Brussels sprouts, turnip greens etc.

The close bond of vitamin K1 with the thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone. However, absorption is optimal in the presence of fats such as, for example, extra virgin olive oil. Fats increase the bioavailability of vitamin K by up to 13%.

On the other hand, fruits, roots and tubers, but even more cereals, pseudocereals and legumes, contain rather limited doses - in the latter three, vitamin K1 is concentrated more in the embryo or germ. Do exception avocados, kiwis and grapes, which are decent sources.

Some vegetable oils, especially soybean oil, contain vitamin K1 in modest quantities; To meet the recommended quantities, excessive quantities would be required, which is why they cannot be considered good food sources.

Finally, foods of animal origin are to be considered sources of vitamin K2 but of marginal importance. The only exceptions are the liver and egg yolk; fermented milk derivatives follow. Lastly, meat and fishery products.

Table of the major food sources of vitamin K1

Level of Recruitment

Recommended vitamin K ration

According to the LARN (Recommended Nutrient Intake Level for the population in your country), the recommended ration of vitamin K is 1 µg / kg of weight / day, which would be easily achievable with a balanced normocaloric diet.

In 1998 the "US Institute of Medicine (IOM)" updated the "Estimated Average Requirements (EARs)" - estimated average requirements - and the "Recommended Dietary Allowances (RDAs)" for vitamin K. No distinction is made between K1 and K2. Since there was not enough information available, the board of directors established an "Adequate Intakes (AI)" - adequate recruitment - with the knowledge to review them at a later time.

• Adult men and women aged 19 years or older: 90 and 120 μg / day;
• Pregnancy: 90 μg / day;
• Breastfeeding: 90 μg / day;
• Children up to 12 months: 2,0–2,5 μg / day;
• Children aged 1 to 18 years: 30-75 μg / day.

Regarding safety, the IOM does not establish "tolerable upper intake levels (UL)" - tolerable levels - for vitamins and minerals if the evidence is not considered sufficient. Vitamin K has no UL, as human data for adverse effects from high doses are inadequate.

The "European Food Safety Authority (EFSA)" has a "Population Reference Intake (PRI)" instead of RDA and "Average Requirement" instead of EAR.

• Adult men and women aged 18 years and over: 70 μg / day;
• Pregnancy: 70 μg / day;
• Breastfeeding: 70 μg / day;
• Children from 1 to 17 years: 12 - 65 μg / day
• Children up to 12 months: 2,0–2,5 μg / day;
• Children aged 1 to 18 years: 30-75 μg / day.

EFSA also argues that there is insufficient evidence to establish a UL for vitamin K.