Vitamin K

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Vitamin_K

 

Vitamin K
Drug class
Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.
Class identifiers
Use	Vitamin K deficiency, Warfarin overdose
ATC code	B02BA
Biological target	Gamma-glutamyl carboxylase
Clinical data
Drugs.com	Medical Encyclopedia
External links
MeSH	D014812

Vitamin K is a group of structurally similar, fat-soluble vitamins found in foods and in dietary supplements. The human body requires vitamin K for complete synthesis of certain proteins that are needed for blood coagulation (K from koagulation, Danish for "coagulation") or for controlling 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. 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.

Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) 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.

Vitamin K₁, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the plant form of vitamin K. 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.

Bacteria in the gut flora can also convert K₁ into vitamin K₂ (menaquinone). In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K₂ to produce a range of vitamin K₂ forms, most notably the MK-7 to MK-11 homologues of vitamin K₂. All forms of K₂ other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K₂ exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.

Because a synthetic form of vitamin K, vitamin K₃ (menadione), may be toxic by interfering with the function of glutathione, it is no longer used to treat vitamin K deficiency.

Medical uses

Warfarin overdose and coumarin poisoning

Vitamin K is one of the treatments for bleeding events caused by overdose of the anticoagulant drug warfarin (Coumadin®). It can be administered by mouth, intravenously, or subcutaneously. Vitamin K is also used in situations when a patient's INR is greater than 10 and there is no active bleeding.

Vitamin K is also part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning).^[6] Vitamin K treatment may only be necessary in people who deliberately have consumed large amounts of rodenticide or have consumed an unknown amount of rodenticide. Patients are given oral vitamin K₁ to prevent the negative effects of rodenticide poisoning, and this dosing must sometimes be continued for up to nine months in cases of poisoning by "superwarfarin" rodenticides such as brodifacoum. Oral Vitamin K₁ is preferred over other vitamin K₁ routes of administration because it has less side effects.

Vitamin K deficiency bleeding in newborns

Vitamin K 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 may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains 1–4 μg/L of vitamin K₁, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K₂ concentrations in human milk appear to be much lower than those of vitamin K₁. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25–1.7%, with a prevalence of 2–10 cases per 100,000 births. Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency.

Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular injection, typically given shortly after birth, is more effective in preventing late vitamin K deficiency bleeding than oral administration.

Osteoporosis

There is no good evidence that vitamin K supplementation benefits the bone health of postmenopausal women.

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; however, no good medical evidence supports such claims.

Side effects

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. Specifically vitamin K₁ has been associated with severe adverse reactions such as bronchospasm and cardiac arrest when given intravenously as opposed to orally.

Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K₂ (as MK-4) and even up to 135 mg per day (45 mg three times daily) of K₂ (as MK-4), 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.

Interactions

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 nor vitamin K shows much effect in the first 24 hours after they are given.

The newer anticoagulants apixaban, dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K.

Chemistry

Vitamin K₂ (menaquinone). 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 structure of phylloquinone, Vitamin K₁, is marked by the presence of a phytyl group. The structures of menaquinones are marked by the polyisoprenyl side chain present in the molecule that can contain four to 13 isoprenyl units.

A sample of phytomenadione for injection, also called 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).

Conversion of vitamin K₁ to vitamin K₂

Vitamin K₁ (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain.

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 K₁ in 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 (menatetrenone) form.

Vitamin K₂

Vitamin K₂ (menaquinone) includes several subtypes. The two most studied ones are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).

Physiology

Vitamin K₁ (phylloquinone), the precursor of most vitamin K in nature, is an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K₁ is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale, and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.

Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.

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

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

When Vitamin K₁ enters the body through foods in a person's diet, it is absorbed through the jejunum and ileum in the small intestine, and like other lipid-soluble vitamins (A, D, and E), vitamin K is stored in the fatty tissue of the human body.

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, the elderly have a reduction in vitamin K₂.

Dietary recommendations

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin K in 1998. The IOM does not distinguish between K₁ and K₂ – both are counted as vitamin K. At that time, sufficient information was not available to establish EARs and RDAs for vitamin K. In instances such as these, the board sets Adequate Intakes (AIs), 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 up are 90 and 120 μg/day, respectively. AI for pregnancy is 90 μg/day. AI 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 IOM sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. Vitamin K has no UL, as human data for adverse effects from high doses are inadequate. Collectively, the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18 the AI is set at 70 μg/day. AI for pregnancy is 70 μg/day, ad for lactation 70 μg/day. For children ages 1–17 years, the AIs increase with age from 12 to 65 μg/day. These AIs are lower than the U.S. RDAs. The EFSA also reviewed the safety question and reached the same conclusion as in United States – that there was not sufficient evidence to set a UL for vitamin K.

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, 100% of the Daily Value was 80 μg, but as of May 27, 2016, it was revised upwards to 120 μg, to bring it into agreement with the AI. A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017, the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies.

Food sources

Vitamin K₁

Food	Serving size	Vitamin K1 (μg)		Food	Serving size	Vitamin K1 (μg)
Kale, cooked	1 cup	531		Parsley, raw	​1⁄4 cup	246
Spinach, cooked	​1⁄2 cup, 77g	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
Dandelion, green leaves	100 gram	778.4 μg or 741% of daily dose.
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.

Vitamin K₁ is found chiefly in leafy green vegetables such as spinach, swiss chard, lettuce and Brassica vegetables (such as cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils. Some fruits, such as avocados, kiwifruit and grapes, also contain vitamin K. Some vegetable oils, notably soybean oil, contain vitamin K, but at levels that would require relatively large calorie consumption to meet the recommended amounts.

The tight binding of vitamin K₁ to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.

Vitamin K₂

Vitamin K₂ can be found in eggs, dairy, and meat, as well as fermented foods such as cheese and yogurt.

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 K deficiency has been defined as a vitamin K-responsive hypoprothrombinemia which increase prothrombin time and thus 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. 

Osteoporosis and coronary heart disease are strongly associated with lower levels of K₂ (menaquinone). Vitamin K₂ (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality.

Biochemistry

Function in animals

Mechanism of action of vitamin K₁.

 

Vitamin K hydroquinone

 

Vitamin K epoxide

In both cases R represents the isoprenoid side chain

The function of vitamin K₂ in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein". The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions. The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below.

Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time. The carboxylation and epoxidation reactions are said to be coupled. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle. Humans are rarely deficient in vitamin K₁ because, in part, vitamin K₁ is continuously recycled in cells.

Warfarin and other 4-hydroxycoumarins block the action of VKOR. This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.

Gamma-carboxyglutamate proteins

The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant protein C and protein S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown. Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.

Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood-clotting system. In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus. These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.

Methods of assessment

Vitamin K status can be assessed by:

• The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.
• Undercarboxylated prothrombin (PIVKA-II); in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II", and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing.
• Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men, but an article by Schurgers et al. reported no correlation between responses in a food frequency questionnaire and plasma phylloquinone.
• Urinary γ-carboxyglutamic acid responds to changes in dietary vitamin K intake. Several days are required before any change can be observed. In a study by Booth et al., increases of phylloquinone intakes from 100 μg to between 377 and 417 μg for five days did not induce a significant change. Response may be age-specific.
• Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K and bone strength in developing rat tibiae. Another study following 78 post-menopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.

Function in bacteria

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K₂ (menaquinone-7 or MK-7, up to MK-11), but not vitamin K₁ (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration). For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.

Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic respiration, the final oxidant is molecular oxygen (O₂), which accepts four electrons from an electron donor such as NADH to be converted to water. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.

History

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC). McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow. They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites. Dam found that these defects could not be restored by adding purified cholesterol to the diet. It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K. Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K₁ and K₂) published in 1939. Several laboratories synthesized the compound(s) in 1939.

For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et. al.) isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla). The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

Bile

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Bile

Bile (yellow material) in a liver biopsy in the setting of bile stasis (that is, cholestasis). H&E stain.

Bile, or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile) and stored and concentrated in the gallbladder. After eating, this stored bile is discharged into the duodenum.

The composition of hepatic bile is (97–98)% water, 0.7% bile salts, 0.2% bilirubin, 0.51% fats (cholesterol, fatty acids, and lecithin), and 200 meq/l inorganic salts. The two main pigments of bile are bilirubin, which is orange–yellow, and its oxidised form biliverdin, which is green. When mixed, they are responsible for the brown colour of faeces. About 400 to 800 millilitres of bile is produced per day in adult human beings.

Function

Action of bile salts in digestion

 

Recycling of the bile

Bile or gall acts to some extent as a surfactant, helping to emulsify the lipids in food. Bile salt anions are hydrophilic on one side and hydrophobic on the other side; consequently, they tend to aggregate around droplets of lipids (triglycerides and phospholipids) to form micelles, with the hydrophobic sides towards the fat and hydrophilic sides facing outwards. The hydrophilic sides are negatively charged, and this charge prevents fat droplets coated with bile from re-aggregating into larger fat particles. Ordinarily, the micelles in the duodenum have a diameter around 1–50 μm in humans.

The dispersion of food fat into micelles provides a greatly increased surface area for the action of the enzyme pancreatic lipase, which actually digests the triglycerides, and is able to reach the fatty core through gaps between the bile salts. A triglyceride is broken down into two fatty acids and a monoglyceride, which are absorbed by the villi on the intestine walls. After being transferred across the intestinal membrane, the fatty acids reform into triglycerides (re-esterified), before being absorbed into the lymphatic system through lacteals. Without bile salts, most of the lipids in food would be excreted in faeces, undigested.

Since bile increases the absorption of fats, it is an important part of the absorption of the fat-soluble substances, such as the vitamins A, D, E, and K.

Besides its digestive function, bile serves also as the route of excretion for bilirubin, a byproduct of red blood cells recycled by the liver. Bilirubin derives from hemoglobin by glucuronidation.

Bile tends to be alkali on average. The pH of common duct bile (7.50 to 8.05) is higher than that of the corresponding gallbladder bile (6.80 to 7.65). Bile in the gallbladder becomes more acidic the longer a person goes without eating, though resting slows this fall in pH. As an alkali, it also has the function of neutralizing excess stomach acid before it enters the duodenum, the first section of the small intestine. Bile salts also act as bactericides, destroying many of the microbes that may be present in the food.

Clinical significance

In the absence of bile, fats become indigestible and are instead excreted in feces, a condition called steatorrhea. Feces lack their characteristic brown color and instead are white or gray, and greasy. Steatorrhea can lead to deficiencies in essential fatty acids and fat-soluble vitamins. In addition, past the small intestine (which is normally responsible for absorbing fat from food) the gastrointestinal tract and gut flora are not adapted to processing fats, leading to problems in the large intestine.

The cholesterol contained in bile will occasionally accrete into lumps in the gallbladder, forming gallstones. Cholesterol gallstones are generally treated through surgical removal of the gallbladder. However, they can sometimes be dissolved by increasing the concentration of certain naturally occurring bile acids, such as chenodeoxycholic acid and ursodeoxycholic acid.

On an empty stomach – after repeated vomiting, for example – a person's vomit may be green or dark yellow, and very bitter. The bitter and greenish component may be bile or normal digestive juices originating in the stomach. Bile may be forced into the stomach secondary to a weakened valve (pylorus), the presence of certain drugs including alcohol, or powerful muscular contractions and duodenal spasms. This is known as biliary reflux.

Biliary obstruction

Biliary obstruction refers to a condition when bile ducts which deliver bile from the gallbladder or liver to the duodenum become obstructed. The blockage of bile might cause a build up of bilirubin in the bloodstream which can result in jaundice. There are several potential causes for biliary obstruction including gallstones, cancer, trauma, choledochal cysts, or other benign causes of bile duct narrowing. The most common cause of bile duct obstruction is when gallstone(s) are dislodged from the gallbladder into the cystic duct or common bile duct resulting in a blockage. A blockage of the gallbladder or cystic duct may cause cholecystitis. If the blockage is beyond the confluence of the pancreatic duct, this may cause gallstone pancreatitis. In some instances of biliary obstruction, the bile may become infected by bacteria resulting in ascending cholangitis.

Society and culture

In medical theories prevalent in the West from Classical Antiquity to the Middle Ages, the body's health depended on the equilibrium of four "humors", or vital fluids, two of which related to bile: blood, phlegm, "yellow bile" (choler), and "black bile". These "humors" are believed to have its roots in the appearance of a blood sedimentation test made in open air, which exhibits a dark clot at the bottom ("black bile"), a layer of unclotted erythrocytes ("blood"), a layer of white blood cells ("phlegm") and a layer of clear yellow serum ("yellow bile").

Excesses of black bile and yellow bile were thought to produce depression and aggression, respectively, and the Greek names for them gave rise to the English words cholera (from Greek χολή kholē, "bile") and melancholia. In the former of those senses, the same theories explain the derivation of the English word bilious from bile, the meaning of gall in English as "exasperation" or "impudence", and the Latin word cholera, derived from the Greek kholé, which was passed along into some Romance languages as words connoting anger, such as colère (French) and cólera (Spanish).

Bile soap

Soap can be mixed with bile from mammals, such as ox gall. This mixture, called bile soap or gall soap, can be applied to textiles a few hours before washing as a traditional and effective method for removing various kinds of tough stains.

Bile in food

"Pinapaitan" is a dish in Philippine cuisine that uses bile as flavoring. Other areas where bile is commonly used as a cooking ingredient include Laos and northern parts of Thailand.

Bears as a bile source

In regions where bile products are a popular ingredient in traditional medicine, the use of bears in bile-farming has been widespread. This practice has been condemned by activists, and some pharmaceutical companies have developed synthetic (non-ursine) alternatives.

Principal bile acids

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  Cholic acid
  
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  Chenodeoxycholic acid
  
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  Glycocholic acid
  
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  Taurocholic acid
  
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  Deoxycholic acid
  
• 

  Lithocholic acid
  

Gallbladder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Gallbladder 

 

Gallbladder
The gallbladder sits beneath the liver.
Details
Precursor	Foregut
System	Digestive system
Artery	Cystic artery
Vein	Cystic vein
Nerve	Celiac ganglia, Vagus nerve
Identifiers
Latin	Vesica biliaris, vesica fellea
MeSH	D005704
TA	A05.8.02.001
FMA	7202

In vertebrates, the gallbladder is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although the structure and position of the gallbladder can vary significantly among animal species. It receives and stores bile, produced by the liver, via the common hepatic duct and releases it via the common bile duct into the duodenum, where the bile helps in the digestion of fats.

The gallbladder can be affected by gallstones, formed by material that cannot be dissolved – usually cholesterol or bilirubin, a product of haemoglobin breakdown. These may cause significant pain, particularly in the upper-right corner of the abdomen, and are often treated with removal of the gallbladder called a cholecystectomy (cholecyst means gallbladder). Cholecystitis, inflammation of the gallbladder, has a wide range of causes, including result from the impaction of gallstones, infection, and autoimmune disease.

Structure

The gallbladder is a hollow organ that sits in a shallow depression below the right lobe of the liver, that is grey-blue in life. In adults, the gallbladder measures approximately 7 to 10 centimetres (2.8 to 3.9 inches) in length and 4 centimetres (1.6 in) in diameter when fully distended. The gallbladder has a capacity of about 50 millilitres (1.8 imperial fluid ounces).

The gallbladder is shaped like a pear, with its tip opening into the cystic duct. The gallbladder is divided into three sections: the fundus, body, and neck. The fundus is the rounded base, angled so that it faces the abdominal wall. The body lies in a depression in the surface of the lower liver. The neck tapers and is continuous with the cystic duct, part of the biliary tree. The gallbladder fossa, against which the fundus and body of the gallbladder lie, is found beneath the junction of hepatic segments IVB and V.^[5] The cystic duct unites with the common hepatic duct to become the common bile duct. At the junction of the neck of the gallbladder and the cystic duct, there is an out-pouching of the gallbladder wall forming a mucosal fold known as "Hartmann's pouch".

Lymphatic drainage of the gallbladder follows the cystic node which is located between cystic duct and common hepatic ducts. Lymphatics from the lower part of the drain into lower hepatic lymph nodes. All the lymph finally drains into celiac lymph nodes.

Microanatomy

Micrograph of a normal gallbladder wall. H&E stain.

The gallbladder wall is composed of a number of layers. The gallbladder wall's innermost surface is lined by a single layer of columnar cells with a brush border of microvilli, very similar to intestinal absorptive cells. Underneath the epithelium is an underlying lamina propria, a muscular layer, an outer perimuscular layer and serosa. Unlike elsewhere in the intestinal tract, the gallbladder does not have a muscularis mucosae, and the muscular fibres are not arranged in distinct layers.

The mucosa, the inner portion of the gallbladder wall, consists of a lining of a single layer of columnar cells, with cells possessing small hair-like attachments called microvilli. This sits on a thin layer of connective tissue, the lamina propria. The mucosa is curved and collected into tiny outpouchings called rugae.

A muscular layer sits beneath the mucosa. This is formed by smooth muscle, with fibres that lie in longitudinal, oblique and transverse directions, and are not arranged in separate layers. The muscle fibres here contract to expel bile from the gallbladder. A distinctive feature of the gallbladder is the presence of Rokitansky–Aschoff sinuses, deep outpouchings of the mucosa that can extend through the muscular layer, and which indicate adenomyomatosis. The muscular layer is surrounded by a layer of connective and fat tissue.

The outer layer of the fundus of gallbladder, and the surfaces not in contact with the liver, are covered by a thick serosa, which is exposed to the peritoneum. The serosa contains blood vessels and lymphatics. The surfaces in contact with the liver are covered in connective tissue.

Variation

Abdominal ultrasonography showing gallbladder and common bile

The gallbladder varies in size, shape, and position between different people. Rarely, two or even three gallbladders may coexist, either as separate bladders draining into the cystic duct, or sharing a common branch that drains into the cystic duct. Additionally, the gallbladder may fail to form at all. Gallbladders with two lobes separated by a septum may also exist. These abnormalities are not likely to affect function and are generally asymptomatic.

The location of the gallbladder in relation to the liver may also vary, with documented variants including gallbladders found within, above, on the left side of, behind, and detached or suspended from the liver. Such variants are very rare: from 1886 to 1998, only 110 cases of left-lying liver, or less than one per year, were reported in scientific literature.

An anatomical variation can occur, known as a Phrygian cap, which is an innocuous fold in the fundus, named after its resemblance to the Phrygian cap.

Development

The gallbladder develops from an endodermal outpouching of the embryonic gut tube. Early in development, the human embryo has three germ layers and abuts an embryonic yolk sac. During the second week of embryogenesis, as the embryo grows, it begins to surround and envelop portions of this sac. The enveloped portions form the basis for the adult gastrointestinal tract. Sections of this foregut begin to differentiate into the organs of the gastrointestinal tract, such as the esophagus, stomach, and intestines.

During the fourth week of embryological development, the stomach rotates. The stomach, originally lying in the midline of the embryo, rotates so that its body is on the left. This rotation also affects the part of the gastrointestinal tube immediately below the stomach, which will go on to become the duodenum. By the end of the fourth week, the developing duodenum begins to spout a small outpouching on its right side, the hepatic diverticulum, which will go on to become the biliary tree. Just below this is a second outpouching, known as the cystic diverticulum, that will eventually develop into the gallbladder.

Function

1. Bile ducts: 2. Intrahepatic bile ducts, 3. Left and right hepatic ducts, 4. Common hepatic duct, 5. Cystic duct, 6. Common bile duct, 7. Ampulla of Vater, 8. Major duodenal papilla
9. Gallbladder, 10–11. Right and left lobes of liver. 12. Spleen.
13. Esophagus. 14. Stomach. 15. Pancreas: 16. Accessory pancreatic duct, 17. Pancreatic duct.
18. Small intestine: 19. Duodenum, 20. Jejunum
21–22. Right and left kidneys.
The front border of the liver has been lifted up (brown arrow).^[14]

The main function of the gallbladder is to store bile, also called gall, needed for the digestion of fats in food. Produced by the liver, bile flows through small vessels into the larger hepatic ducts and ultimately through the cystic duct (parts of the biliary tree) into the gallbladder, where it is stored. At any one time, 30 to 60 millilitres (1.0 to 2.0 US fl oz) of bile is stored within the gallbladder.

When food containing fat enters the digestive tract, it stimulates the secretion of cholecystokinin (CCK) from I cells of the duodenum and jejunum. In response to cholecystokinin, the gallbladder rhythmically contracts and releases its contents into the common bile duct, eventually draining into the duodenum. The bile emulsifies fats in partly digested food, thereby assisting their absorption. Bile consists primarily of water and bile salts, and also acts as a means of eliminating bilirubin, a product of hemoglobin metabolism, from the body.

The bile that is secreted by the liver and stored in the gallbladder is not the same as the bile that is secreted by the gallbladder. During gallbladder storage of bile, it is concentrated 3-10 fold by removal of some water and electrolytes. This is through the active transport of sodium and chloride ions across the epithelium of the gallbladder, which creates an osmotic pressure that also causes water and other electrolytes to be reabsorbed.

Clinical significance

Gallstones

3D still showing Gallstones.

Gallstones form when the bile is saturated, usually with either cholesterol or bilirubin. Most gallstones do not cause symptoms, with stones either remaining in the gallbladder or passed along the biliary system. When symptoms occur, severe "colicky" pain in the upper right part of the abdomen is often felt. If the stone blocks the gallbladder, inflammation known as cholecystitis may result. If the stone lodges in the biliary system, jaundice may occur; and if the stone blocks the pancreatic duct, then pancreatitis may occur. Gallstones are diagnosed using ultrasound. When a symptomatic gallstone occurs, it is often managed by waiting for it to be passed naturally. Given the likelihood of recurrent gallstones, surgery to remove the gallbladder is often considered. Some medication, such as ursodeoxycholic acid, may be used; and lithotripsy, a procedure used to break down the stones, may also be used.

Inflammation

Known as cholecystitis, inflammation of the gallbladder is commonly caused by obstruction of the duct with gallstones, which is known as cholelithiasis. Blocked bile accumulates, and pressure on the gallbladder wall, may lead to the release of substances that cause inflammation, such as phospholipase. There is also the risk of bacterial infection. An inflamed gallbladder is likely to cause pain and fever, and tenderness in the upper, right corner of the abdomen, and may have a positive Murphy's sign. Cholecystitis is often managed with rest and antibiotics, particularly cephalosporins and, in severe cases, metronidazole.

Gallbladder removal

A cholecystectomy is a procedure in which the gallbladder is removed. It may be removed because of recurrent gallstones, and is considered an elective procedure. A cholecystectomy may be an open procedure, or one conducted by laparoscopy. In the surgery, the gallbladder is removed from the neck to the fundus, and so bile will drain directly from the liver into the biliary tree. About 30 percent of patients may experience some degree of indigestion following the procedure, although severe complications are much rarer. About 10 percent of surgeries lead to a chronic condition of postcholecystectomy syndrome.

Complication

Biliary injury (bile duct injury) is the traumatic damage of the bile ducts. It is most commonly an iatrogenic complication of cholecystectomy — surgical removal of gall bladder, but can also be caused by other operations or by major trauma. The risk of biliary injury is more during laparoscopic cholecystectomy than during open cholecystectomy. Biliary injury may lead to several complications and may even cause death if not diagnosed in time and managed properly. Ideally biliary injury should be managed at a center with facilities and expertise in endoscopy, radiology and surgery.

Biloma is collection of bile within the abdominal cavity. It happens when there is a bile leak, for example after surgery for removing the gallbladder (laparoscopic cholecystectomy), with an incidence of 0.3–2%. Other causes are biliary surgery, liver biopsy, abdominal trauma, and, rarely, spontaneous perforation.

Cancer

Cancer of the gallbladder is uncommon and mostly occurs in later life. When cancer occurs, it is mostly of the glands lining the surface of the gallbladder (adenocarcinoma). Gallstones are thought to be linked to the formation of cancer, and other risk factors include large (>1 cm) gallbladder polyps and having a highly calcified "porcelain" gallbladder.

Cancer of the gallbladder can cause attacks of biliary pain, yellowing of the skin (jaundice), and weight loss. A large gallbladder may be able to be felt in the abdomen. Liver function tests may be elevated, particularly involving GGT and ALP, with ultrasound and CT scans being considered medical imaging investigations of choice. Cancer of the gallbladder is managed by removing the gallbladder, however As of 2010 the prognosis remains poor.

Cancer of the gallbladder may also be found incidentally after surgical removal of the gallbladder, with 1-3% of cancers identified in this way. Gallbladder polyps are mostly benign growths or lesions resembling growths that form in the gallbladder wall and are only associated with cancer when they are larger in size (>1 cm). Cholesterol polyps, often associated with cholesterolosis ("strawberry gallbladder", a change in the gallbladder wall due to excess cholesterol), often cause no symptoms and are thus often detected in this way.

Tests

Abdominal ultrasonography showing biliary sludge and gallstones.

Tests used to investigate for gallbladder disease include blood tests and medical imaging. A full blood count may reveal an increased white cell count suggestive of inflammation or infection. Tests such as bilirubin and liver function tests may reveal if there is inflammation linked to the biliary tree or gallbladder, and whether this is associated with inflammation of the liver, and a lipase or amylase may be elevated if there is pancreatitis. Bilirubin may rise when there is obstruction of the flow of bile. A CA 19-9 level may be taken to investigate for cholangiocarcinoma.

Ultrasound is often the first medical imaging test performed when gallbladder disease such as gallstones are suspected. An abdominal X-ray or CT scan is another form of imaging that may be used to examine the gallbladder and surrounding organs. Other imaging options include MRCP (magnetic resonance cholangiopancreatography), ERCP and percutaneous or intraoperative cholangiography. A cholescintigraphy scan is a nuclear imaging procedure used to assess the condition of the gallbladder.

Society and culture

To have 'gall' is associated with bold behaviour, whereas to have 'bile' is associated with bitterness.

In the Chinese language, the gallbladder (Chinese: 膽) is associated with courage and a myriad of related idioms, including using terms such as "a body completely [of] gall" (Chinese: 渾身是膽) to describe a brave person, and "single gallbladder hero" (Chinese: 孤膽英雄) to describe a lone hero.

In the Zangfu theory of Chinese medicine, the gallbladder not only has a digestive role, but is seen as the seat of decision-making.

Other animals

Most vertebrates have gallbladders, but the form and arrangement of the bile ducts may vary considerably. In many species, for example, there are several separate ducts running to the intestine, rather than the single common bile duct found in humans. Several species of mammals (including horses, deer, rats, and laminoids), several species of birds, lampreys and all invertebrates lack a gallbladder altogether.

The bile from several species of bears is used in traditional Chinese medicine; bile bears are kept alive in captivity while their bile is painfully extracted, in an industry characterized by animal cruelty.

History

Depictions of the gallbladder and biliary tree are found in Babylonian models found from 2000 BCE, and in ancient Etruscan model from 200 BCE, with models associated with divine worship.

Diseases of the gallbladder have been recorded in humans since antiquity, with gallstones found in the mummy of Princess Amenen of Thebes dating to 1500 BCE. Some historians believe the death of Alexander the Great may have been associated with an acute episode of cholecystitis. The existence of the gallbladder has been noted since the 5th century, but it is only relatively recently that the function and the diseases of the gallbladder has been documented, particularly in the last two centuries.

The first descriptions of gallstones appear to have been in the Renaissance, perhaps because of the low incidence of gallstones in earlier times owing to a diet with more cereals and vegetables, and less meat. Anthonius Benevinius in 1506 was the first to draw a connection between symptoms and the presence of gallstones. Courvoisier after examining a number of cases in 1890 that gave rise to the eponymous Courvoisier's law stating that in an enlarged, nontender gallbladder, the cause of jaundice is unlikely to be gallstones.

The first surgical removal of a gallstone (cholecystolithotomy) was in 1676 by physician Joenisius, who removed the stones from a spontaneously occurring biliary fistula. Stough Hobbs in 1867 performed the first recorded cholecystotomy, although such an operation was in fact described earlier by French surgeon Jean Louis Petit in the mid eighteenth century. German surgeon Carl Langenbuch performed the first cholecystectomy in 1882 for a sufferer of cholelithiasis. Before this, surgery had focused on creating a fistula for drainage of gallstones. Langenbuch reasoned that given several other species of mammal have no gallbladder, humans could survive without one.

The debate whether surgical removal of the gallbladder or simply gallstones was preferred was settled in the 1920s, with consensus that removal of the gallbladder was preferred. It was only in the mid and late parts of the twentieth century that medical imaging techniques such as use of contrast medium and CT scans were used to view the gallbladder. The first laparoscopic cholecystectomy performed by Erich Mühe of Germany in 1985, although French surgeons Phillipe Mouret and Francois Dubois are often credited for their operations in 1987 and 1988 respectively.