Vitamin B12
Systematic (IUPAC) name
α-(5,6-dimethylbenzimidazolyl)cobamidcyanide
Identifiers
CAS number	68-19-9
ATC code	B03BA01
PubChem	5479203
DrugBank	APRD00326
Chemical data
Formula	C63H88CoN14O14P
Mol. mass	1355. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Cobalt (ˈkoʊbɒlt is a hard lustrous silver-grey Metal, a Chemical element with symbol Co. Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Phosphorus, (ˈfɒsfərəs is the Chemical element that has the symbol P and Atomic number 15 The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 37 g/mol
Pharmacokinetic data
Bioavailability	readily absorbed in lower half ileum
Protein binding	Very high to specific transcobalamins plasma proteins Binding of hydroxocobalamin is slightly higher than cyanocobalamin. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of A drug's efficiency may be affected by the degree to which it binds to the proteins within Blood plasma. Transcobalamins are Carrier proteins which bind Cyanocobalamin (B12 Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds
Metabolism	hepatic
Half life	Approximately 6 days (400 days in the liver)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	?
Legal status	POM(UK)
Routes	oral, iv

Vitamin B-12 is a vitamin which is important for the normal functioning of the brain and nervous system, and for the formation of blood. Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The kidneys are complicated organs that have numerous biological roles The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life.

Vitamin B-12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin. Biosynthesis of the basic structure of the vitamin can only be accomplished by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. Biosynthesis is a phenomenon wherein Chemical compounds are produced from simpler Reagents Biosynthesis unlike Chemosynthesis, takes place within living A common form of the vitamin, cyanocobalamin, does not occur in nature, but is used as a supplement and food additive, due to its stability. Cyanocobalamin is an especially common Vitamer of the B-12 vitamin family. It is converted to other forms of the vitamin which are actually used in chemical reactions in the body.

Historically, vitamin B-12 was discovered from its relationship to the disease pernicious anemia, which was eventually discovered to result from an effective lack of this vitamin due to problems with the mechanisms in the body which normally absorb it. Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to Many other more subtle kinds of vitamin B12 deficiency, and biochemical effects from them, have since been elucidated. B12 deficiency is a reduction in Vitamin B12 from inadequate dietary intake or impaired absorption

Contents 1 Terminology 2 Structure 3 Synthesis 4 Functions 5 Human absorption and distribution 6 History of B-12 as a treatment for pernicious anemia 7 Symptoms and damage from deficiency 8 Sources 9 Recommendations 10 Allergies 11 Side effects, contraindications, and warnings 12 Other medical uses 13 Interactions 13.1 Interactions with drugs 13.2 Interactions with herbs and dietary supplements 14 References 15 External links

Terminology

The name vitamin B-12, known as vitamin B₁₂ (commonly B₁₂ or B-12 for short) generally refers to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however.

• In a broad sense B-12 still refers to a group of cobalt-containing vitamer compounds known as cobalamins: these include cyanocobalamin (an artifact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin (another medicinal form), and finally, the two naturally occurring cofactor forms of B-12: 5-deoxyadenosylcobalamin (adenosylcobalamin—AdoB-12), the cofactor of Methylmalonyl Coenzyme A mutase (MUT), and methylcobalamin (MeB-12), the cofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cobalt (ˈkoʊbɒlt is a hard lustrous silver-grey Metal, a Chemical element with symbol Co. The vitamers of a particular Vitamin are all of the chemical compounds which exhibit vitamin activity A cyanide is any Chemical compound that contains the cyano group (C≡N which consists of a Carbon Atom triple-bonded to a Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds A cofactor is a non-protein Chemical compound that is bound (either tightly or loosely to an Enzyme and is required for Catalysis. Cobamamide (also known as adenosylcobalamin and dibencozide) is a cofactor (active form of Cyanocobalamin. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Methylcobalamin is a cobalamin (MeB12 used in Peripheral neuropathy, Diabetic neuropathy etc 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene.

• The term B-12 may be properly used to refer to cyanocobalamin, the principal B-12 form used for foods and in nutritional supplements. Cyanocobalamin is an especially common Vitamer of the B-12 vitamin family. This ordinarily creates no problem, except perhaps in rare cases of eye nerve damage, where the body is only marginally able to use this form due to high cyanide levels in the blood due to cigarette smoking, and thus requires cessation of smoking, or else B-12 given in another form, for the optic symptoms to abate. ^[1] However, tobacco amblyopia is a rare enough condition that debate continues about whether or not it represents a peculiar B-12 deficiency which is resistant to treatment with cyanocobalamin. Amblyopia, otherwise known as lazy eye, is a disorder of the Visual system that is characterized by poor or indistinct vision in an eye that

Finally, so-called Pseudo-B-12 refers to B-12-like substances which are found in certain organisms, including spirulina (a cyanobacterium) and some algae. These substances are active in tests of B-12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B-12 and B-12-like compounds in blood. However, these substances do not have B-12 biological activity for humans, a fact which may pose a theoretical danger to vegans and others on limited diets who do not ingest B-12 producing bacteria, but who nevertheless may show normal "B-12" levels in the standard immunoassay which has become the normal medical method for testing for B-12 deficiency. ^[2]

Structure

Vitamin B-12 is a collection of cobalt and corrin ring molecules which are defined by their particular vitamin function in the body. Cobalt (ˈkoʊbɒlt is a hard lustrous silver-grey Metal, a Chemical element with symbol Co. A corrin is a Macrocycle related to the Porphyrin ring in Hemoglobin, consisting of 4 Pyrrole subunits joined on opposite sides by a C-CH3 All of the substrate cobalt-corrin molecules from which B-12 is made must be synthesized by bacteria. However, after this synthesis is complete, the body has a limited power to convert any form of B-12 to another, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom.

Cyanocobalamin is one such compound that is a vitamin in this B complex, because it can be metabolized in the body to an active co-enzyme form. Cyanocobalamin is an especially common Vitamer of the B-12 vitamin family. A vitamin is an Organic compound required as a Nutrient in tiny amounts by an Organism. The B vitamins are eight water-soluble Vitamins that play important roles in cell Metabolism. However, the cyanocobalamin form of B-12 does not occur in nature normally, but is a byproduct of the fact that other forms of B-12 are avid binders of cyanide (-CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Activated carbon, also called activated charcoal or activated coal, is a form of Carbon that has been processed to make it extremely porous and thus to Since the cyanocobalamin form of B-12 is deeply red colored, easy to crystallize, and is not sensitive to air-oxidation, it is typically used as a form of B-12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous with B-12, inasmuch as a number of substances (vitamers) have B-12 vitamin activity and can properly be labeled vitamin B-12, and cyanocobalamin is but one of them. The vitamers of a particular Vitamin are all of the chemical compounds which exhibit vitamin activity (Thus, all cyanocobalamin is vitamin B-12, but not all vitamin B-12 is cyanocobalamin). ^[3]

B-12 is the most chemically complex of all the vitamins. The structure of B-12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. A corrin is a Macrocycle related to the Porphyrin ring in Hemoglobin, consisting of 4 Pyrrole subunits joined on opposite sides by a C-CH3 A porphyrin is a heterocyclic Macrocycle derived from four Pyrroline subunits interconnected via their α carbon atoms via Methine bridges (=CH- A heme ( American English) or haem ( British English) is a Prosthetic group that consists of an Iron atom contained in the center of Chlorophyll is a green Pigment found in most Plants Algae and Cyanobacteria. Cytochromes are in general membrane-bound Hemoproteins that contain Heme groups and carry out Electron transport. The central metal ion is cobalt. Cobalt (ˈkoʊbɒlt is a hard lustrous silver-grey Metal, a Chemical element with symbol Co. Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH₃) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B-12 forms mentioned above. A cyanide is any Chemical compound that contains the cyano group (C≡N which consists of a Carbon Atom triple-bonded to a Hydroxyl in Chemistry stands for a molecule consisting of an Oxygen atom and a Hydrogen atom connected by a Covalent bond. In Chemistry, a methyl group is a Hydrophobic Alkyl Functional group named after Methane (4 Adenosine is a Nucleoside composed of a Molecule of Adenine attached to a Ribose sugar molecule ( Ribofuranose) moiety via a β-N9- The covalent C-Co bond is one of first examples of carbon-metal bonds in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds. A hydrogenase is an Enzyme that catalyses the reversible oxidation of molecular Hydrogen (H2 ^[4]

Synthesis

Vitamin B-12 cannot be made by plants or animals^[5] as only bacteria have the enzymes required for its synthesis. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have The total synthesis of B-12 was reported by Robert Burns Woodward^[6] and Albert Eschenmoser,^[7][8] and remains one of the classic feats of organic synthesis. In principle a total synthesis is the complete Chemical synthesis of complex organic Molecules from simpler pieces usually without the aid of biological Robert Burns Woodward ( April 10 1917 &ndash July 8 1979) was an American organic chemist. Albert Eschenmoser (born August 5, 1925) is a Swiss chemist working at the ETH Zurich and The Scripps Research Institute.

Species from the following genera are known to synthesize B-12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. A genus (plural genera from Γένος Latin genus "descent family type gender" is a low-level Taxonomic Agrobacterium is a Genus of Gram-negative Bacteria that uses Horizontal gene transfer to cause Tumors in plants Alcaligenes is a genus of Gram-negative, aerobic, rod-shaped bacteria Azotobacter is a Genus of usually motile oval or spherical Bacteria that form thick-walled cysts and may produce large quantities of capsular slime This page is about the bacterial genus For the class see Bacilli. Clostridium is a Genus of Gram-positive bacteria belonging to the Firmicutes. Corynebacterium is a Genus of Gram-positive,aerobic or facultatively anaerobic, non- Motile, non-sporulated rod-shaped Actinobacteria Flavobacterium is a genus of Gram-negative, non- Motile, rod-shaped Bacteria that consists of ten recognized species as well as three newly Micromonospora is a genus of bacteria of the family Micromonosporaceae. Mycobacterium is a Genus of Actinobacteria, given its own family the Mycobacteriaceae Nocardia is a Genus of Gram-positive, catalase-positive, rod-shaped Bacteria. Propionibacterium acnes is a relatively slow growing typically Aerotolerant Anaerobic Gram positive Bacterium that is linked to the In Greek mythology, Proteus (Πρωτεύς is an early sea-god one of several deities whom Homer calls the "Old Man of the Sea" whose name suggests the Pseudomonas is a Genus of gamma Proteobacteria, belonging to the larger family of Pseudomonads Recently 16S rRNA sequence Rhizobia (from the Greek words rhiza = root and bios = Life are Soil bacteria that fix Nitrogen ( Diazotrophy Salmonella is a Genus of rod-shaped Gram-negative enterobacteria that causes Typhoid fever, Paratyphoid fever Serratia is a Genus of Gram-negative, facultatively anaerobic, rod-shaped Bacteria of the Enterobacteriaceae Streptomyces, the largest Genus of Actinobacteria and type genus of the family Streptomycetaceae. Streptococcus is a Genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the Xanthomonas is a genus of Proteobacteria, many of which cause plant diseases. Industrial production of B-12 is through fermentation of selected microorganisms. Fermentation is the process of deriving energy from the oxidation of organic compounds such as carbohydrates using an endogenous electron acceptor which is ^[9] The species most often used, Pseudomonas denitrificans and Propionibacterium shermanii, are frequently genetically engineered and grown under special conditions to enhance yield. Pseudomonas denitrificans is a Gram-negative anaerobic Bacterium that performs Denitrification.

Functions

Vitamin B-12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body. Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Most "B-12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine. Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Thymine is one of the four bases in the Nucleic acid of DNA that make up the letters ATGC When sufficient folic acid is available, all known B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. Methylmalonic acid (MMA is a Dicarboxylic acid that is a C - methylated derivative of Malonate. Homocysteine is a Chemical compound with the formula HSCH2CH2CH(NH2CO2H

Coenzyme B-12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions. ^[10]

1. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine.
2. Methyl (-CH₃) group transfers between two molecules.

In humans, only two corresponding coenzyme B-12-dependent enzymes are known:

1. Methylmalonyl Coenzyme A mutase (MUT) which uses the AdoB-12 form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism). Methylmalonyl-CoA is the Coenzyme A linked form of Methylmalonic acid. Succinyl-Coenzyme A, generally abbreviated as Succinyl-CoA or SucCoA is a combination of Succinic acid and Coenzyme A. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level. Methylmalonic acid (MMA is a Dicarboxylic acid that is a C - methylated derivative of Malonate. Unfortunately, an elevated MMA, though sensitive to B-12 deficiency, is probably overly sensitive, and not all who have it actually have B-12 deficiency. For example, MMA is elevated in 90-98% of patients with B-12 deficiency; however 25-20% of patients over the age of 70 have elevated levels of MMA, yet 25-33% of them do not have B-12 deficiency. For this reason, MMA is not routinely recommended in the elderly. ^[11] The "gold standard" test for B-12 deficiency continues to be low blood levels of the vitamin. The MUT function cannot be affected by folate supplementation, and which is necessary for myelin synthesis (see mechanism below) and certain other functions of the central nervous system. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Other functions of B-12 related to DNA synthesis related to MTR dysfunction (see below) can often be corrected with supplementation with the vitamin folic acid, but not the elevated levels of homocysteine, which is normally converted to methionine by MTR. MTR, or Mass Transit Railway, is the Rapid transit Railway system in Hong Kong. Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 MTR, or Mass Transit Railway, is the Rapid transit Railway system in Hong Kong.
2. 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. This is a methyl transfer enzyme, which uses the MeB-12 and reaction type 2 to catalyze the conversion of the amino acid Hcy back into Met (for more see MTR's reaction mechanism). In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Homocysteine is a Chemical compound with the formula HSCH2CH2CH(NH2CO2H Methionine ( abbreviated as Met or M) is an α- Amino acid with the Chemical formula HO2CCH(NH2CH2CH2SCH3 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. ^[12] This functionality is lost in vitamin B-12 deficiency, and can be measured clinically as an increased homocysteine level in vitro. Homocysteine is a Chemical compound with the formula HSCH2CH2CH(NH2CO2H Increased homocysteine can also be caused by a folic acid deficiency, since B-12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Homocysteine is a Chemical compound with the formula HSCH2CH2CH(NH2CO2H Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 Without B-12, folate is trapped as 5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the 5-methyl-folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh sources of THF from the diet. 5-methyltetrahydrofolate-homocysteine methyltransferase, also known as MTR, is a human Gene. THF may be produced in the conversion of homocysteine to methionine, or may be obtained in the diet. Tetrahydrofolic acid is a Folic acid derivative Metabolism Human synthesis It is produced from Dihydrofolic acid by Dihydrofolate It is converted by a non-B-12-dependent process to 5,10-methylene-THF, which is involved in the synthesis of thymine. Thymine is one of the four bases in the Nucleic acid of DNA that make up the letters ATGC Reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production cells with rapid turnover, in particular blood cells, and also intestinal wall cells which are responsible for absorption. The failure of blood cell production results in the once-dreaded and fatal disease, pernicious anemia. Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to All of the DNA synthetic effects, including the megaloblastic anemia of pernicious anemia, resolve if sufficient folate is present (since levels of 5,10-methylene-THF still remain adequate with enough dietary folate). Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to Thus the best known function of B-12 (that which is indirectly involved with DNA synthesis and restoration of cell-division and anemia) is actually a facultative function which is mediated by B-12 conservation of active folate which can be used for DNA production. ^[13]

If folate is present in quantity, then of the two absolutely B-12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system. Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Since the late 1990s folic acid has begun to be added to fortify flour in many countries, so that folate deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate mediated-biochemical effects are more often directly detected), the MTR dependent effects of B-12 deficiency are becoming apparent not as anemia (as they were classically), but now mainly as an elevation of homocysteine in the blood and urine (homocysteinuria). Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Red blood cells are the most common type of Blood cell and the Vertebrate body's principal means of delivering Oxygen to the body tissues via the Blood MTR, or Mass Transit Railway, is the Rapid transit Railway system in Hong Kong. Homocystinuria, also known as Cystathionine beta synthase deficiency, is an inherited disorder of the Metabolism of the Amino acid Methionine This condition may result in long term damage to arteries and in clotting (stroke and heart attack), but is difficult to separate from other processes associated with atherosclerosis and aging.

The B-12 dependent MTR reactions may have neurological effects through an indirect mechanism. MTR, or Mass Transit Railway, is the Rapid transit Railway system in Hong Kong. Adequate methionine (which must otherwise be obtained in the diet) is needed to make S-adenosyl-methionine, which is in turn necessary for methylation of myelin sheath phospholipids. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism. See Chemical synapse for an introduction to concepts and terminology used in this article These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated with B-12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts. MTR, or Mass Transit Railway, is the Rapid transit Railway system in Hong Kong.

The specific myelin damage resulting from from B-12 deficiency has also been connected to B-12 reactions related to MUT, which is needed to convert methylmalonyl coenzyme A into succinyl coenzyme A. Mut, which means mother, was an Ancient Egyptian Mother goddess with multiple aspects that changed over the thousands of years of the culture Failure of this second reaction to occur results in elevated levels of methylmalonic acid (MMA), a myelin destabilizer. Excessive MAA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise methanism(s) are not known with certainty, the result is subacute combined degeneration of central nervous system and spinal cord. ^[14] Whatever the cause, it is known that B-12 deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present. Neuropathy is a medical term usually short for Peripheral neuropathy.

Human absorption and distribution

The human physiology of vitamin B-12 is complex, and therefore is prone to mishaps leading to vitamin B-12 deficiency. The vitamin as it occurs in foods enters the digestive tract bound to proteins, known as salivary R-binders. The salivary glands in mammals are exocrine glands that produce saliva Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes referred to as pepsin. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following Proteolysis is the directed degradation ( digestion) of Proteins by cellular Enzymes called Proteases or by intramolecular digestion pH is the measure of the acidity or alkalinity of a Solution. The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link (Even small amounts of B-12 taken in supplements bypasses these steps and thus any need for gastric acid, which may be blocked by antacid drugs). An antacid is any substance generally a base or Basic salt, which counteracts stomach acidity.

The free B-12 then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells in response to histamine, gastrin and pentagastrin, as well as the presence of food. Intrinsic factor is a Glycoprotein produced by the Parietal cells of the Stomach. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following Parietal cells (also called oxyntic cells) are the Stomach Epithelium cells that secrete Gastric acid and Intrinsic factor The generation of this intrinsic factor-B12 complex will allow absorption of the vitamin as well as protect the vitamin from catabolism by intestinal bacteria. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B-12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to Due to the complexity of B-12 absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increased risk of B-12 deficiency. ^[15]

The conjugated vitamin B-12-intrinsic factor complex (IF/B-12) is then normally absorbed by the terminal ileum of the small bowel. Intrinsic factor is a Glycoprotein produced by the Parietal cells of the Stomach. In Anatomy of the Digestive system, the ileum is the final section of the Small intestine. In Biology the small Intestine is the part of the Gastrointestinal tract (gut between the Stomach and the Large intestine, and comprises Absorption of food vitamin B-12 therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following The Exocrine Pancreas has ducts that are arranged in clusters called Acini (singular acinus) Intrinsic factor is a Glycoprotein produced by the Parietal cells of the Stomach. In Biology the small Intestine is the part of the Gastrointestinal tract (gut between the Stomach and the Large intestine, and comprises Problems with any one of these organs makes a vitamin B-12 deficiency possible.

Once the IF/B-12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B-12), which serves as the plasma transporter of the vitamin. Transcobalamins are Carrier proteins which bind Cyanocobalamin (B12 Genetic deficiencies of this protein are known, also leading to functional B-12 deficiency.

For the vitamin to serve inside cells, the TC-II/B-12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysozyme, and free B-12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above).

Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B-12 and infantile megaloblastic anemia, and abnormal B-12 related biochemistry, even in some cases with normal blood B-12 levels. Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production ^[16]

Individuals who lack intrinsic factor have a decreased ability to absorb B-12. This results in 80-100% excretion of oral doses in the feces versus 30-60% excretion in feces as seen in individuals with adequate intrinsic factor. ^[17]

The total amount of vitamin B-12 stored in body is about 2,000-5,000 mcg in adults. Around 80% of this is stored in the liver^[18]. Approximately 0. 1% of this is lost per day by secretions into the gut as not all these secretions are reabsorbed. How fast B-12 levels change depends on the balance between how much B-12 is obtained from the diet, how much is secreted and how much is absorbed. B-12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable or may not appear for decades. In infants, B-12 deficiency can appear much more quickly^[19].

History of B-12 as a treatment for pernicious anemia

B-12 deficiency is the cause of pernicious anemia, a usually-fatal disease of unknown etiology when it was first described in medicine. Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to The cure was discovered by accident. George Whipple had been inducing anemia in dogs by bleeding them, and then conducting experiments in which he fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. George Hoyt Whipple ( August 28, 1878 &ndash February 1, 1976) was an American physician biomedical researcher and medical school educator In the process, he discovered that ingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss, and hypothesized that therefore liver ingestion be tried for pernicious anemia, an anemic disease of the time with no known cause or cure. He tried this and reported some signs of success in 1920. After a series of careful clinical studies George Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. George Richards Minot ( December 2, 1885 in Boston, Massachusetts &ndash February 25, 1950) won the 1934 Nobel They found further that the partly isolated water-soluble liver-substance which cured pernicious anemia in humans, was something else entirely different -- and which had no effect at all on canines under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. These experiments were reported by Minot and Murphy in 1926, marking the date of the first real progress with this disease, though for several years, patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice.

In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. Edwin Joseph Cohn ( 17 December 1892 &ndash 1 October 1953) was an early protein scientist The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine. The Nobel Prize in Physiology or Medicine (Nobelpriset i fysiologi eller medicin is awarded once a year by the Swedish Karolinska Institute.

The active ingredient in liver was not isolated until 1948 by the chemists Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. Karl August Folkers ( September 1, 1906 – December 7, 1997) was an American Biochemist, working at Merck, and Alexander Robertus Todd Baron Todd, PC, OM, FRS ( 2 October 1907 &ndash 10 January 1997) was a Scottish The substance was a cobalamin called vitamin B-12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily. ^[20]

The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data. Analytical chemistry is the study of the Chemical composition of natural and artificial Materials. Dorothy Crowfoot Hodgkin, born Dorothy Mary Crowfoot OM, FRS ( 12 May 1910 &ndash 29 July 1994) was a British Year 1956 ( MCMLVI) was a Leap year starting on Sunday (link will display full calendar of the Gregorian calendar. Crystallography is the experimental science of determining the arrangement of Atoms in Solids In older usage it is the scientific study of Crystals The Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease.

Symptoms and damage from deficiency

Vitamin B-12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, depression, and poor memory may be experienced. In the fields of Psychology and Psychiatry, the terms depression or depressed refer to both expected and pathologically chronic or severe In Psychology, memory is an organism's ability to store retain and subsequently retrieve information ^[21] However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.

Vitamin B-12 deficiency has the following pathomorphology and symptoms:^[22]

Pathomorphology includes: A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. Oedema (or Edema in American English formerly known as dropsy or hydropsy, is the increase of Interstitial fluid in any organ &mdash swelling The myelin decays, along with axial fiber. Myelin is an electrically-insulating Dielectric Phospholipid layer that surrounds only the Axons of many Neurons It is an outgrowth In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord, and to pyramidal tracts in lateral cords.

In the brain itself, changes are less severe: they occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, an also round hemorrhages with a torus of glial cells. Astrocytes (also known collectively as astroglia) are characteristic star-shaped glial cells in the Brain and Spinal cord. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.

Clinical symptoms : The main syndrome of vitamin B-12 deficiency is Biermer's disease (pernicious anemia). Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of Megaloblastic anemia due to It is characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (Megaloblastic anemia)
2. Gastrointestinal symptoms
3. Neurological symptoms

Each of those symptoms can occur either alone or along with others. Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production The neurological complex, defined as myelosis funicularis, consists of the following symptoms:

1. Impaired perception of deep touch, pressure and vibration, abolishment of sense of touch, very annoying and persistent paresthesias. Paresthesia (pron /ˌpɛɹɪsˈθiʒə/ paraesthesia in British English, pron
2. Ataxia of dorsal cord type
3. Decrease or abolishment of deep muscle-tendon reflexes;
4. Pathological reflexes - Babinski, Rossolimo and others, also severe paresis. Ataxia (from Greek α- as a negative prefix + -τάξις, meaning "lack of order" is a neurological sign and symptom consisting Paresis is a condition typified by partial loss of movement or impaired movement

During the course of disease, mental disorders can occur which include: irritability, focus/concentration problems, depressive state with suicidal tendencies, paraphrenia complex. Paraphrenia is a particularly paranoid form of Schizophrenia occurring in the elderly as opposed to adolescents These symptoms may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.

Sources

Vitamin B-12 is naturally found in foods of animal origin including meat (especially liver and shellfish) and milk products. Milk is an opaque white liquid produced by the Mammary glands of female Mammals (including Monotremes. Animals, in turn, must obtain it directly or indirectly from bacteria, and these bacteria may inhabit a section of the gut which is posterior to the section where B-12 is absorbed. Thus, herbivorous animals must either obtain B-12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope fæces. Herbivory is a form of Predation in which an Organism, known as a herbivore, consumes principally Autotrophs ref name=Campbell>Campbell The rumen, also known as a paunch, forms the larger part of the Reticulorumen, which is the first chamber in the Alimentary canal of Ruminant The Hindgut (or epigaster) is the Posterior ( Caudal) part of the Alimentary canal. Cecotropes (also "caecotrophes" also known as "night faeces" are the product of the Cecum, a part of the digestive system in Mammals of the Eggs are often mentioned as a good B-12 source, but they also contain a factor that blocks absorption. An egg is a round or oval body laid by the female of many animals consisting of an Ovum surrounded by layers of Membranes and an outer casing which acts to nourish ^[23] Certain insects such as termites contain B-12 produced by their gut bacteria, in a manner analogous to ruminant animals. The termites are a group of Social Insects usually classified at the taxonomic rank of order Isoptera (but see also taxonomy ^[24] An NIH Fact Sheet lists a variety of food sources of vitamin B-12.

Plants only supply B-12 to humans when the soil containing B-12-producing microorganisms has not been washed from them. Vegan humans who eat only washed vegetables must take special care to supplement their diets accordingly. According to the U. K. Vegan Society, the only reliable vegan sources of B-12 are foods fortified with B-12 (including some plant milks, some soy products and some breakfast cereals), and B-12 supplements. The Vegan Society is a Registered charity in the United Kingdom, promoting Veganism. ^[25] Fortified breakfast cereals are a particularly valuable source of vitamin B-12 for vegetarians and vegans. A breakfast cereal (often simply called cereal is a packaged food product made from Cereal intended to be consumed as part of a Breakfast. Vegetarianism is the practice of a diet that excludes Meat (including game and slaughter by-products Fish (including Shellfish and other sea

While lacto-ovo vegetarians usually get enough B-12 through consuming dairy products, vitamin B-12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B-12 fortified foods. A lacto-ovo-vegetarian is a vegetarian who does not eat beef pork poultry fish shellfish or animal flesh of any kind but is willing to consume dairy and Dairy products are generally defined as Foodstuffs produced from Milk. A multivitamin is a preparation intended to supplement a human diet with Vitamins Dietary minerals and other nutritional elements Examples of fortified foods often consumed include fortified breakfast cereals, fortified soy-based products, and fortified energy bars. An energy bar is a Dietary supplement often consumed by athletes or other physically active people to maintain their calorific needs in light of their strenuous Claimed sources of B-12 that have been shown through direct studies^[26] of vegans to be inadequate or unreliable include, laver (a seaweed), barley grass, and human gut bacteria. Laver is an edible Seaweed that has a high Mineral salt content particularly Iodine and Iron. Seaweed is a loose colloquial term encompassing macroscopic Multicellular, benthic marine Algae. Barley ( Hordeum vulgare) is an annual Cereal Grain, which serves as a major animal Feed crop, with smaller amounts used for People on a vegan raw food diet are also susceptible to B-12 deficiency if no supplementation is used^[27]. Raw foodism (or rawism) is a lifestyle promoting the consumption of un- cooked, un- processed, and often Organic foods as a large percentage

The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat foods fortified with B-12 or take a daily or weekly B-12 supplement. The Vegan Society is a Registered charity in the United Kingdom, promoting Veganism. The Physicians Committee for Responsible Medicine (PCRM is a Non-profit organization based in Washington D ^[25][28][29]

Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver. Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds Methylcobalamin is a cobalamin (MeB12 used in Peripheral neuropathy, Diabetic neuropathy etc Cobamamide (also known as adenosylcobalamin and dibencozide) is a cofactor (active form of Cyanocobalamin.

Vitamin B-12 can be supplemented in healthy subjects also by liquid, strip, nasal spray, or injection and is available singly or in combination with other supplements.

The sublingual route, in which B-12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 micrograms of cobalamin. ^[30]

Injection is sometimes used in cases where digestive absorption is impaired, but there is some evidence that this course of action may not be necessary with modern high potency oral supplements (such as 500 to 1000 mcg or more). Even pernicious anemia can be treated entirely by the oral route. ^[31][32][33] These supplements carry such large doses of the vitamin that the many different components of the B-12 absorption system are not required, and enough of the vitamin (only a few mcg a day) is obtained simply by mass-action transport across the gut.

However, if patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treating with intravenous or intramuscular hydroxocobalamin is needed. Methylmalonic acidemia (MMA also called methylmalonic aciduria, is an Autosomal Recessive Metabolic disorder. Homocystinuria, also known as Cystathionine beta synthase deficiency, is an inherited disorder of the Metabolism of the Amino acid Methionine Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds ^{[34][35][36][37][38]}

Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake. Diet Coke Plus (also known as Coca Cola Light Plus) is a new formulation of Diet Coke fortified with vitamins and minerals Energy drinks are Soft drinks advertised as providing more Energy than a typical drink However, 500 mcg would be needed to reverse biochemical signs of vitamin B-12 deficiency in older adults. ^[39]

Recommendations

The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms) per day. The Dietary Reference Intake (or DRI is a system of Nutrition recommendations from the Institute of Medicine (IOM of the US National Academy of Sciences

Vitamin B-12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B-12 in pregnant women is 2. Pregnancy ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female 6 µg per day and 2. 8 µg during lactation periods. Lactation describes the secretion of Milk from the Mammary glands the process of providing that milk to the young and the period of time that a Mother There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B-12 during pregnancy.

Allergies

Vitamin B-12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients. Allergy is a disorder of the Immune system often also referred to as Atopy. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, other causes should be sought.

Side effects, contraindications, and warnings

• Dermatologic: Itching, rash, transitory exanthema, and urticaria have been reported. Itch ( Latin: pruritus) is an unpleasant Sensation that evokes the desire or Reflex to scratch A rash is a change of the Skin which affects its color appearance or Texture. An exanthem (from Greek "exanthema" a breaking out) is a widespread Rash usually occurring in Children. Vitamin B-12 (20 micrograms/day) and pyridoxine (80mg/day) has been associated with cases of rosacea fulminans, characterized by intense erythema with nodules, papules, and pustules. Pyridoxine is one of the compounds that can be called Vitamin B6, along with Pyridoxal and Pyridoxamine. Rosacea (rəʊˈzeɪʃə is a common but often misunderstood condition that is estimated to affect over 45 million people worldwide Erythema is redness of the Skin caused by Capillary congestion A papule is a small and solid elevation of the Skin. Papules do not contain Pus, which distinguishes them from Pustules Papules often occur in clusters A pustule is a small collection of Pus in the top layer of Skin ( epidermis) or beneath it in the Dermis. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy. Corticosteroids are a class of Steroid hormones that are produced in the Adrenal cortex.

• Gastrointestinal: Diarrhea has been reported. In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea
• Hematologic: Peripheral vascular thrombosis has been reported. Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory Treatment of vitamin B-12 deficiency can unmask polycythemia vera, which is characterized by an increase in blood volume and the number of red blood cells. Primary Polycythemia, often called Polycythemia vera (PCV polycythemia rubra vera (PRV or erythremia occurs when excess red blood cells are produced The correction of megaloblastic anemia with vitamin B-12 can result in fatal hypokalemia and gout in susceptible individuals, and it can obscure folate deficiency in megaloblastic anemia. Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production Hypokalemia refers to the condition in which the concentration of Potassium in the blood is low Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid. Caution is warranted.
• Leber's disease: Vitamin B-12 in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Leber’s hereditary optic neuropathy (LHON or Leber optic atrophy is a mitochondrially inherited (mother to all offspring degeneration of Retinal Leber’s hereditary optic neuropathy (LHON or Leber optic atrophy is a mitochondrially inherited (mother to all offspring degeneration of Retinal The optic nerve, also called cranial nerve II, is the Nerve that transmits visual information from the Retina to the Brain. Atrophy is the partial or complete Wasting away of a part of the Body. Cyanocobalamin can cause severe and swift optic atrophy, but other forms of vitamin B-12 are available. However, the sources of this statement are not clear, while an opposing view^[40] concludes: "The clinical picture of optic neuropathy associated with vitamin B-12 deficiency shows similarity to that of Leber's disease optic neuropathy. Leber’s hereditary optic neuropathy (LHON or Leber optic atrophy is a mitochondrially inherited (mother to all offspring degeneration of Retinal Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B-12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B-12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded. "

Other medical uses

Hydroxycobalamin, or hydoxocobalamin, also known as Vitamin B-12a, is used in Europe both for vitamin B-12 deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate. Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds Hydroxocobalamin (OHCbl is a natural analog of Vitamin B-12, a basic member of the cobalamin family of compounds A cyanide is any Chemical compound that contains the cyano group (C≡N which consists of a Carbon Atom triple-bonded to a Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Sodium thiosulfate ( Na 2 S 2 O 3 is a colorless Crystalline compound that is more familiar as the Pentahydrate ^[41] The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B-12 complex is excreted in urine. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Urine is a liquid waste product of the body secreted by the Kidneys by a process of filtration from Blood and Excreted through the Urethra. In the United States, the FDA approved (in 2006) the use of hydroxocobalamin for acute treatment of cyanide poisoning. The United States of America —commonly referred to as the

Interactions

Interactions with drugs

• Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B-12 absorption from the gastrointestinal tract.

• Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B-12 absorption, possibly by as much as 55%, as part of a general malabsorption syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred, usually after doses of 8 to 12 grams/day for several months. Vitamin B-12 levels should be monitored in people taking aminosalicylic acid for more than one month.

• Antibiotics: An increased bacterial load can bind significant amounts of vitamin B-12 in the gut, preventing its absorption. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl) can actually improve vitamin B-12 status. Metronidazole ( INN) (mɛtrəˈnaɪdəzoʊl is a Nitroimidazole anti-infective medication used mainly in the treatment of infections caused by susceptible The effects of most antibiotics on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B-12 levels. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have

• Hormonal contraception: The data regarding the effects of oral contraceptives on vitamin B-12 serum levels are conflicting. Hormonal contraception refers to Birth control methods that act on the hormonal system Some studies have found reduced serum levels in oral contraceptive users, but others have found no effect despite use of oral contraceptives for up to 6 months. When oral contraceptive use is stopped, normalization of vitamin B-12 levels usually occurs. Lower vitamin B-12 serum levels seen with oral contraceptives probably are not clinically significant.

• Chloramphenicol (Chloromycetin): Limited case reports suggest that chloramphenicol can delay or interrupt the reticulocyte response to supplemental vitamin B-12 in some patients. Chloramphenicol is a Bacteriostatic Antimicrobial originally derived from the Bacterium Streptomyces venezuelae, isolated by Reticulocytes are immature Red blood cells typically composing about 1% of the red cells in the human body Blood counts should be monitored closely if this combination cannot be avoided. A complete blood count ( CBC) also known as full blood count ( FBC) or full blood exam ( FBE) or blood panel, is
• Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitamin B-12. A cobalt bomb, a type of salted bomb is a Nuclear weapon originally proposed by physicist Leó Szilárd, who suggested that it would be capable of destroying A cobalt bomb, a type of salted bomb is a Nuclear weapon originally proposed by physicist Leó Szilárd, who suggested that it would be capable of destroying In Biology the small Intestine is the part of the Gastrointestinal tract (gut between the Stomach and the Large intestine, and comprises

• Colchicine: Colchicine in doses of 1. Colchicine is a highly poisonous Natural product and Secondary metabolite, originally extracted from plants of the genus Colchicum ( Autumn 9 to 3. 9mg/day can disrupt normal intestinal mucosal function, leading to malabsorption of several nutrients, including vitamin B-12. Malabsorption is a state arising from abnormality in Digestion or Absorption of food nutrients across the gastrointestinal(GI tract. A nutrient is food or chemicals that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment Lower doses do not seem to have a significant effect on vitamin B-12 absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B-12 levels should be monitored in people taking large doses of colchicine for prolonged periods.

• Colestipol (Colestid), Cholestyramine (Questran): These resins used for sequestering bile acids in order to decrease cholesterol, can decrease gastrointestinal (GI) absorption of vitamin B-12. Colestipol is a Bile acid sequestrant. Cholestyramine or colestyramine ( Questran Questran Light, Cholybar) is a Bile acid sequestrant, which binds Bile in the Gastrointestinal Resin, not to be confused with Rosin, is a Hydrocarbon Secretion of many Plants particularly coniferous trees. The bile acid sequestrants are a group of medications used for binding certain components of Bile in the gastrointestinal tract. Cholesterol is a Lipid found in the Cell membranes and transported in the Blood plasma of all Animals It is an essential component of mammalian It is unlikely that this interaction will deplete body stores of vitamin B-12 unless there are other factors contributing to deficiency. In a group of children treated with cholestyramine for up to 2. 5 years there was not any change in serum vitamin B-12 levels. Routine supplements are not necessary.

• H₂-receptor antagonists: include cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac). The H2-receptor antagonists (H2RA often shortened to H2 antagonist) are a class of drugs used to block the action of Histamine Cimetidine ( INN) (sɨˈmɛtɨdiːn/ /saɪ- is a histamine H2-receptor antagonist that inhibits the production of acid in the Stomach. Famotidine ( INN) (fəˈmɒtɪdiːn is a histamine H2-receptor antagonist that inhibits stomach acid production and it is commonly used Nizatidine is a histamine H2-receptor antagonist that inhibits stomach acid production and commonly used in the treatment of Peptic ulcer disease Ranitidine ( INN) (rəˈnɪtɨdiːn is a Histamine H2-receptor antagonist that inhibits stomach acid production Reduced secretion of gastric acid and pepsin produced by H₂ blockers can reduce absorption of protein-bound (dietary) vitamin B-12, but not of supplemental vitamin B-12. Gastric acid is one of the main Secretions of the Stomach, together with several Enzymes and Intrinsic factor. Pepsin is a digestive Protease ( released by the chief cells in the Stomach that functions to degrade food Proteins into Gastric acid is needed to release vitamin B-12 from protein for absorption. Clinically significant vitamin B-12 deficiency and megaloblastic anemia are unlikely, unless H₂ blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is rendered achlorhydric (with complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H₂ blockers. Achlorhydria and hypochlorhydria refer to states where the production of Gastric acid in the Stomach is absent or low respectively Vitamin B-12 levels should be monitored in people taking high doses of H₂ blockers for prolonged periods.

• Metformin (Glucophage): Metformin may reduce serum folic acid and vitamin B-12 levels. Metformin ( INN; trade names Glucophage, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, These changes can lead to hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes. Hyperhomocysteinemia is a medical condition characterized by an abnormally large level of Homocysteine in the Blood. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc There are also rare reports of megaloblastic anemia in people who have taken metformin for 5 years or more. Reduced serum levels of vitamin B-12 occur in up to 30% of people taking metformin chronically. ^[42][43] However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B-12 is adequate. Deficiency can be corrected with vitamin B-12 supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B-12 is reversible by oral calcium supplementation. ^[44] The general clinical significance of metformin upon B-12 levels is as yet unknown. ^[45]

• Neomycin: Absorption of vitamin B-12 can be reduced by neomycin, but prolonged use of large doses is needed to induce pernicious anemia. Neomycin is an Aminoglycoside Antibiotic that is found in many topical medications such as creams ointments and eyedrops Supplements are not usually needed with normal doses.

• Nicotine: Nicotine can reduce serum vitamin B-12 levels. Nicotine is an Alkaloid found in the Nightshade family of plants ( Solanaceae) which constitutes approximately 0 The need for vitamin B-12 supplementation in smokers has not been adequately studied.

• Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B-12 by oxidation. Nitrous oxide, commonly known as " laughing gas," is a Chemical compound with the Chemical formula N 2 O. Symptoms of vitamin B-12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B-12 deficiency. Neuropathy is a medical term usually short for Peripheral neuropathy. Spinal cord injury causes myelopathy or damage to white matter or myelinated fiber tracts that carry sensation and motor signals to and from the brain Encephalopathy /ɛnˌsɛfəˈlɒpəθi/ literally means Disease of the Brain. Anesthesia, or anaesthesia (see spelling differences; from Greek grc αν- an-, "without" and grc αἲσθησις Symptoms are treated with high doses of vitamin B-12, but recovery can be slow and incomplete. People with normal vitamin B-12 levels have sufficient vitamin B-12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (such as recreational use). Vitamin B-12 levels should be checked in people with risk factors for vitamin B-12 deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B-12 poisoning (usually from use of nitrous oxide as a recreational drug), however, may result in B-12 functional deficiency even with normal measured blood levels of B-12 ^[46]

• Phenytoin (Dilantin), phenobarbital, primidone (Mysoline): These anticonvulsants have been associated with reduced vitamin B-12 absorption, and reduced serum and cerebrospinal fluid levels in some patients. Phenytoin sodium is a commonly used Antiepileptic. Phenytoin acts to dampen the unwanted runaway brain activity seen in seizure by reducing electrical conductance among brain Phenobarbital ( INN) or phenobarbitone (former BAN) is a Barbiturate, first marketed as Luminal by Friedr Primidone is an Anticonvulsant of the Pyrimidinedione class whose active Metabolites Phenobarbital (major and phenylethylmalonamide (PEMA (minor The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic Cerebrospinal fluid ( CSF) Liquor cerebrospinalis, is a clear Bodily fluid that occupies the Subarachnoid space and the Ventricular system This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It is also suggested that reduced vitamin B-12 levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B-12 intake. Folate and vitamin B-12 status should be checked if symptoms of anemia develop.

• Proton pump inhibitors (PPIs): The PPIs include omeprazole (Prilosec, Losec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix, Pantoloc), and esomeprazole (Nexium). Proton pump inhibitors (or "PPI"s are a group of drugs whose main action is pronounced and long-lasting reduction of Gastric acid production Omeprazole ( INN) (oʊˈmɛprəzoʊl is a Proton pump inhibitor used in the treatment of Dyspepsia, peptic ulcer disease (PUD Gastroesophageal Lansoprazole (lan-SOE-pra-zole INN) is a Proton pump inhibitor which prevents the stomach from producing acid Rabeprazole is an antiulcer drug in the class of Proton pump inhibitors It was developed by Eisai Co Pantoprazole (brand names Pantopan in Italy Protium; Protonix; Pantozol; Pantor; Pantoloc; Astropan; Controloc The reduced secretion of gastric acid and pepsin produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B-12, but not supplemental vitamin B-12. Pepsin is a digestive Protease ( released by the chief cells in the Stomach that functions to degrade food Proteins into Gastric acid is needed to release vitamin B-12 from protein for absorption. Reduced vitamin B-12 levels may be more common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B-12 deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B-12 levels should be monitored in people taking high doses of PPIs for prolonged periods.

• Zidovudine (AZT, Combivir, Retrovir): Reduced serum vitamin B-12 levels may occur when zidovudine therapy is started. Zidovudine ( INN) or azidothymidine ( AZT) (also called ZDV is a nucleoside analog reverse transcriptase inhibitor (NRTI a type of Antiretroviral This adds to other factors that cause low vitamin B-12 levels in people with HIV, and might contribute to the hematological toxicity associated with zidovudine. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome However, data suggests vitamin B-12 supplements are not helpful for people taking zidovudine.

Interactions with herbs and dietary supplements

• Folic acid: Folic acid, particularly in large doses, can mask vitamin B-12 deficiency by completely correcting hematological abnormalities. Folic acid (also known as Vitamin M and Folacin) and Folate (the Anionic form are forms of the water-soluble Vitamin B9 In vitamin B-12 deficiency, folic acid can produce complete resolution of the characteristic megaloblastic anemia, while allowing potentially irreversible neurological damage (from continued inactivity of methylmalonyl mutase) to progress. Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production Methylmalonyl Coenzyme A mutase, also known as MUT, is a human Enzyme. Thus, vitamin B-12 status should be determined before folic acid is given as monotherapy.

• Potassium: Potassium supplements can reduce absorption of vitamin B-12 in some people. Potassium (pəˈtæsiəm is a Chemical element. It has the symbol K (kalium from qalīy Atomic number 19 and Atomic mass 39 This effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute to vitamin B-12 deficiency in some people with other risk factors, but routine supplements are not necessary. ^[47]

References

External links

• Jane Higdon, "Vitamin B-12", Micronutrient Information Center, Linus Pauling Institute
• Vitamin B-12. Oregon State University ( OSU) is a Coeducational public Research[[ university]] located in Corvallis, Oregon, United Medline Plus (National Library of Medicine). The United States National Library of Medicine ( NLM) operated by the United States federal government, is the world's largest Medical library. Part of it was used for this article (US Government public domain), specially for drug and other interactions.
• Vitamin B12 Deficiency
• Vitamin B-12 deficiency article in American Family Physician journal
• Vitamin B-12: Vital Nutrient for Good Health at the Weston A. American Family Physician (AFP is a semimonthly peer-reviewed Medical journal of the American Academy of Family Physicians. Price Foundation
• MeSH Cyanocobalamin

Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books

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