Vitamin B12

Vitamins are organic nutrients that the body requires in small quantities for the performance of various biochemical reactions, but the body cannot synthesize them on its own, and so they must be supplied by the diet. Vitamins are classified as water-soluble (B-complex and vitamin C) or fat-soluble (A, D, E, and K). Vitamin B12 also termed as Cobalamin is a water-soluble vitamin that forms part of the vitamin B family. These vitamins are necessary for essential metabolic processes as they assist in DNA synthesis, support adrenal function, and maintain a healthy nervous system. Plants, animals, and fungi are incapable of producing vitamin B12. Only archaea and bacteria contain the necessary enzymes required for its synthesis. This essay is aimed at analyzing Vitamin B12 in detail regarding its structure, mechanisms of action, absorption, distribution and excretion, importance, sources, deficiency, dietary requirements, toxicity, and drug interactions.

Vitamin B12 is the largest of the vitamin B complex with a molecular weight of over 1,000. It is composed of a complex tetrapyrrole ring structure (corrin ring) and a cobalt ion at the center. The substrate cobalt-corrin molecules are synthesized by bacteria. Vitamin B12 has four forms (vitamers), and they are all red colored crystals because of the color of the cobalt-corrin ring. Methylcobalamin and adenosylcobalamin are enzymatically active forms of vitamin B12 that occur naturally in the body. These two become stored in the liver as AdoB12 and are converted to active forms when needed. Hydroxocobalamin is another Vitamin B12 form that is not found in the body. It has a high affinity for cyanide and can serve as an antidote for cyanide poisoning. Cyanocobalamin is another vitamer that is readily metabolized to an active coenzyme. It is a by-product of other vitamin B12 forms and does not occur naturally. It is used as a food additive in many multivitamins, because it crystallizes quickly and is not sensitive to oxidation by air.

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In its mechanism of action, vitamin B12 acts as a coenzyme for three types of enzymes, namely methyltransferases, isomerases, and dehalogenases. Methyltransferases utilize the methylcobalamin form of vitamin B12 to transfer methyl groups between two molecules. Isomerases use the adenosylcobalamin form of vitamin B12 in rearrangement reaction. This indicates that a hydrogen atom is transported between two neighboring atoms, but a concomitant exchange of the second substituent occurs so that this component can become a carbon atom, an amine, or an oxygen atom of alcohol. In dehalogenases, vitamin B12 helps to remove a halogen from an organic molecule.

Absorption of vitamin B12 requires two binding proteins, particularly R protein produced by saliva and intrinsic factor (IF) that is generated by parietal cells found in the gastric mucosa. Pepsin and gastric acid release of vitamin B12 is bound to protein in food and make it available to bind to R protein. In the duodenum, R protein gets hydrolyzed to release the vitamin for binding to IF. Vitamin B12 can only become absorbed when bound to IF as the receptors in the terminal ileum only recognize the B12-IF complex. Additionally, the IF serves to prevent the catabolism of the vitamin by the intestinal flora. After recognition by the ileal receptors, vitamin B12 is transferred to the portal circulation, and at this phase the vitamin arrives at the liver and bounds to transcobalamin II which is a plasma transporter. It releases the vitamin into the cytoplasm where it can become transformed into the proper coenzyme. 

Absorption of vitamin B12 requires proper functioning of small bowel, pancreas, and stomach. Problems with any of these organs as well as with IF results in the deficiency of vitamin B12. The people who lack IF are unable to absorb vitamin B12. Gastric acid assists in the release of the vitamin from food particles. Therefore, acid-blocking drugs and antacids may prevent its absorption.

The total amount stored in adults is about 2-5mg (50% in liver). A small proportion of it is lost daily through gut secretions while a majority of it gets excreted via bile or is recycled through the enterohepatic circulation. The liver can store about five years worth of vitamin B12 because of the efficient enterohepatic circulation; nutritional deficiency is, therefore, rare. If vitamin B12 is beyond the blood's binding capacity, it gets excreted in urine.

The vitamin under analysis is an essential nutrient that helps in the development and maintenance of red blood cells and nerve cells. It also assists in normal myelination of nerve cells and in the production of RNA, DNA, and neurotransmitters. Furthermore, it is helpful in fatty acid synthesis as well as energy production. The medical significance of vitamin B12 includes treatment of cobalamin deficiency, hereditary deficiency of transcobalamin II, and cyanide poisoning. It combines with cyanide to form cyanocobalamin that gets excreted through the kidneys. Additionally, vitamin B12 forms part of the Schilling test used to detect pernicious anemia.

The sources of vitamin B12 include animal products, fortified foods, and supplements. Liver and beef are the greatest sources of vitamin B12. Other sources include fish, meat, milk, eggs, and poultry. Fortified foods such as breakfast cereals, energy bars, nutritional yeast, and soy products are rich in vitamin B12. It is also available as a supplement in many multi-vitamin pills. B12 is also used to enrich grain-based foods like bread, and it is also common in energy drinks. Cyanocobalamin is the primary form of cobalamin found in most oral supplements. It is available as a nasal gel and as an injection. Over the counter preparations with cyanocobalamin include single-nutrient vitamin B supplements and vitamin B complex supplements.

Vitamin B12 deficiency can cause detrimental and irreversible brain damage and seriously harm the nervous system. Conditions that may become attributed to its deficiency include depression, Alzheimer's disease, peripheral neuropathy, and anemia. The most common cause of cobalamin deficiency is an autoimmune condition (pernicious anemia) that is congenital and results in the destruction of the cells that produce IF leading to inability to absorb vitamin B12. A strict vegetarian diet that excludes animal products can also cause vitamin B12 deficiency. Apart from this, stomach ulcers and excessive alcohol consumption may result in vitamin B12 deficiency. Atrophic gastritis leads to thinning of the stomach lining and, consequently, to cobalamin deficiency. Surgical procedures that involve removing part of the stomach or intestines can also lead to deficiency due to the interference in the body's ability to extract vitamin B12 from the food. Digestive conditions e.g. celiac disease, Crohn's disease, and autoimmune diseases like Graves' disease and lupus can also affect vitamin B12 absorption and lead to deficiency. Bacterial overgrowth and parasite infestation cause cobalamin deficiency too. Additionally, medications such as proton pump inhibitors and antacids for indigestion cause cobalamin deficiency. Symptoms of this deficiency include anemia (megaloblastic) which can present with fatigue, headaches, dyspnea, lethargy, feeling faint, and appetite loss. Besides this, patients frequently suffer from jaundice (skin yellowing), changes or loss in touch sensations, vision problems, walking difficulties, sore tongue, mouth ulcers, mood changes, irritability, depression, and symptoms of dementia.

Various treatment modalities are available depending on the cause. They are aimed at treating the deficiency and preventing complications that may arise. If the problem is pernicious anemia, the treatment is the replacement of vitamin B12 with injections which may become substituted later by oral doses or nasal spray for life. For elderly patients, multivitamins with vitamin B12 or daily vitamin B12 supplement is sufficient. For vegans, improving their diets, in particular, including animal products or vitamin B12 fortified food will alleviate the problem.

The daily vitamin B12 requirements depend on the age and are measured in micrograms. The national institute of health (NIH) recommends that from birth to six months the amount should be 0.4mcg/day. Infants who are 7-12 months should take 0.5mcg/day. Children 1-3 years old need around 0.9mcg/day, 4-8 years – 1.2mcg/day, and 9-13 years – 1.8mcg/day. Teenagers who are 14-18 years and adults should take 2.4mcg/day. For lactating mothers, the requirement is about 2.8mcg/day, while pregnant mothers should take 2.6mcg/day. People over 50 years should take vitamin B12 supplements or vitamin B12 fortified foods. For such individuals, doses of 25-100mcg/day are adequate to maintain adequate vitamin B12 levels.

Vitamin B12 has no associated toxicities even with large intakes from food or supplements in healthy individuals. Doses as high as 1mg monthly through intramuscular injections or 2mg/day orally have been used for the management of pernicious anemia without any significant toxicities. The explanation for this lack of toxicity lies in the fact that when high doses get administered, only a small amount is absorbed. The US Food and Nutrition Board has not yet set a tolerable upper limit due to its low toxicity. However, a few people may experience some side effects after taking vitamin B12, including diarrhea, itching, allergic reactions, and blood clots.

Many drugs interfere with the absorption of vitamin B12. Metformin, a drug for treating type 2 diabetes decreases cobalamin absorption by tying up free calcium that is needed for the absorption of the IF-B12 complex. Proton Pump Inhibitors (PPIs) e.g. omeprazole used for the treatment of GERD, significantly decrease gastric acid secretion that helps to release vitamin B12 from food. Continuous use of PPIs decreases vitamin B12 levels, and deficiency appears after around 3-5 years of use following the depletion of the liver stores. Histamine receptor agonists (gastric acid inhibitors) like cimetidine used to treat peptic ulcers also lead to reduced vitamin B12 absorption from food. All individuals taking medications that inhibit acid secretion should take vitamin B12 supplements, as these do not require gastric acid for absorption. Other drugs known to prevent vitamin B12 absorption include colchicine (for gout), cholestyramine (for high cholesterol), and antibiotics like neomycin and chloramphenicol. Nitrous oxide – an anesthetic agent inhibits the vitamin B12-dependent enzymes by oxidizing and inactivating vitamin B12 and may produce features of its deficiency such as neuropathy and megaloblastic anemia. People with undiagnosed cobalamin deficiency are taking folic acid to treat megaloblastic anemia, which can reduce the anemia effects without correcting the cobalamin deficiency leaving them at risk of developing irreversible neurologic impairment. As a result, all adults should limit their folic acid intake to 1mg/day.

In conclusion, vitamin B12 is the largest in the vitamin B12 complex with a molecular weight of more than 1000. It has a tetrapyrrole ring, a cobalt ion at the center, and four forms. The absorption of vitamin B12 requires two binding proteins R protein and IF, an intact ileum, pancreas, and stomach. Most of the vitamin B12 is stored in the liver and gets excreted through bile, gut secretions, or via urine. This vitamin helps in the production of red cells, DNA, RNA, neurotransmitters, in myelination, and treatment of cyanide poisoning. Sources of vitamin B12 are animal products like beef, liver, and eggs; it is also included in vitamin B12-fortified foods and vitamin B12 supplements. Some causes of vitamin B12 deficiency include atrophic gastritis, pernicious anemia, excessive alcohol use, vegan diet, etc. Symptoms of vitamin B12 deficiency comprise jaundice, anemia, sore tongue, and loss of sensations. Treatment of the deficiency aims to alleviate the causes. Daily requirements according to the NIH depend on the age, and the measurement is in micrograms. This vitamin has no toxicities but may trigger side effects such as diarrhea and allergies. Various drugs inhibit the absorption of vitamin B12, including metformin, nitric oxide, and PPIs.

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Mar 20, 2020 in Informative
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