CAUSES AND CONDITIONS ASSOCIATED WITH REDUCED LEVEL OF VITAMIN B12: A REVIEW

CAUSES AND CONDITIONS ASSOCIATED WITH REDUCED LEVEL OF VITAMIN B₁₂: A REVIEW

Chandrakant Belwal

Sterling Biotech Research Center, Vadodara, Gujarat, India

ABSTRACT

Vitamin B₁₂ plays an important role in building of genetic material, in development of normal red blood cells and in maintenance of nervous system. Major deficiency symptoms of Vitamin B₁₂ include anemia and neurological disorders. The daily recommended intake of vitamin B₁₂ for an adult is 1.5μg a day. Eating a diet containing required amount of vitamin B₁₂ is the best way to treat the conditions associated with its low level. Vitamin B₁₂ found only in animal based foods such as meats, liver, kidney, fish, eggs, milk and milk products, oysters and shellfish. Hence, vegetarians are more likely to have low level of Vitamin B₁₂.

Animal products

INTRODUCTION: Vitamins were discovered in the early part of the twentieth century, In 1912, Polish scientist Cashmir Funk named the special nutritional parts of food as a "vitamine" after "vita" meaning life and "amine" from compounds found in the thiamine he isolated from rice husks. Vitamine was later shortened to vitamin. Funk isolated vitamin B₁ (thiamine) from rice ¹.

There are two types of vitamins, fat-soluble (A, D, E, and K) and water-soluble (B and C). Water-soluble vitamins dissolve easily in water and, in general, are readily excreted from the body, to the degree that urinary output is a strong predictor of vitamin consumption ². Because they are not readily stored, consistent daily intake is important. Many types of water-soluble vitamins are synthesized by bacteria ³. Fat-soluble vitamins are absorbed through the intestinal tract with the help of lipids.

Eight of the water-soluble vitamins are known as the B-complex group: thiamin (vitamin B₁), riboflavin (vitamin B₂), niacin, vitamin B₆, folate, vitamin B₁₂, biotin and pantothenic acid. These vitamins are widely distributed in foods. Their influence is felt in many parts of the body. They function as coenzymes that help the body obtain energy from food. They also are important for normal appetite, good vision, healthy skin, healthy nervous system and red blood cell formation. Beriberi, pellagra and pernicious anemia are three well-known B-vitamin deficiencies.

Vitamin B₁₂ aids in building of genetic material, aids in development of normal red blood cells and aids in maintenance of nervous system. Major deficiency symptoms of Vitamin B₁₂ include anemia and neurological disorders. Vitamin B₁₂ found only in animal based foods such as meats, liver, kidney, fish, eggs, milk and milk products, oysters and shellfish. Hence vegetarians are more likely to have low level of Vitamin B₁₂.

Vitamin B₁₂ works with the B vitamin folate to make DNA, our body’s genetic material. B₁₂ is needed to protect nerve cells from damage. It also helps keep blood levels of the amino acid homocysteine low. This may help to decrease heart disease risk in some people ⁴.

Vitamin B₁₂ is essential for two types of enzymatic reactions in humans; methyl group transfer and transfer of a hydrogen atom from one carbon to an adjacent carbon atom.

Vitamin B₁₂ participates in three essential enzymatic reactions in the human body. Methionine synthetase requires methylcobalamin for conversion of homocysteine to methionine. Methylmalonyl CoA mutase requires 5’-deoxyadenosylcobalamin to convert L-methylmalonyl CoA to succinyl CoA. Leucine aminomutase requires 5’-deoxyadenosylcobalamin to isomerize L-leucine and beta-leucine

Structure and chemical composition of Vitamin B₁₂: Vitamin B₁₂ is the largest and most complex of all the vitamins. The name vitamin B₁₂ is generic for a specific group of cobalt-containing corrinoids with biological activity in humans. Interestingly it is the only known metabolite to contain cobalt, which gives this water-soluble vitamin its red colour. This group of corrinoids is also known as cobalamins.

The main cobalamins in humans and animals are hydroxocobalamin, adenosylcobalamin and methyl-cobalamin, the last two being the active coenzyme forms. Cyanocobalamin is a form of vitamin B₁₂ that is widely used clinically due to its availability and stability. It is transformed into active factors in the body.

In 1934, three researchers won the Nobel prize in medicine for discovering the lifesaving properties of vitamin B₁₂. They found that eating large amounts of raw liver, which contains high amounts of vitamin B₁₂, could save the life of previously incurable patients with pernicious anaemia. Vitamin B₁₂ was isolated from liver extract in 1948 and its structure was elucidated 7 years later by A. R. Todd in 1955.

The structure of vitamin B₁₂ (Figure 1) is based on a corrin ring, which has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Four of the six coordinations are provided by the corrin ring nitrogens, and a fifth by a dimethylbenzimidazole group. The sixth coordination partner varies, being a cyano group (-CN) (cyanocobalamin), a hydroxyl group (-OH) (hydroxocobalamin), a methyl group (-CH3) (methylcobalamin) or a 5'-deoxyadenosyl group (5-deoxyadenosylcobalamin) ^{5, 6, 7, 8, 9, 10, 11, 12, 13}.

FIGURE 1: GENERAL STRUCTURE OF VITAMIN B₁₂

R represent to either a cyano group (-CN) (cyanocobalamin), a hydroxyl group (-OH) (hydroxocobalamin), a methyl group (-CH3) (methylcobalamin) or a 5'-deoxyadenosyl group (5-deoxyadenosylcobalamin)

Vitamin B₁₂ is the only known essential biomolecule with a stable metal-carbon bond, it is an organometallic compound. The cobalt can link to:

1. A methyl group - as in methylcobalamin
2. A 5'-deoxyadenosine at the the 5' positon - as in adenosylcobalamin (coenzyme b₁₂ )
3. A cyanide group - as in vitamin b₁₂ - as synthesized and supplied from drug companies

Sources and Daily requirement of Vitamin B₁₂: Most microorganisms, including bacteria and algae, synthesize vitamin B₁₂, and they constitute the only source of the vitamin ¹⁴. The vitamin B₁₂ synthesized in microorganisms enters the human food chain through incorporation into food of animal origin. In many animals, gastrointestinal fermentation supports the growth of these vitamin B₁₂ synthesizing microorganisms, and subsequently the vitamin is absorbed and incorporated into the animal tissues.

This is particularly true for the liver, where vitamin B₁₂ is stored in large concentrations. Products from herbivorous animals, such as milk, meat, and eggs, thus constitute important dietary sources of the vitamin, unless the animal is subsisting in one of the many regions known to be geochemically deficient in cobalt ¹⁵. Milk from cows and humans contains binders with very high affinity for vitamin B₁₂, though whether they hinder or promote intestinal absorption is not entirely clear. Omnivores and carnivores, including humans, derive dietary vitamin B₁₂ almost exclusively from animal tissues or products (i.e. milk, butter, cheese, eggs, meat, and poultry).

It appears that the vitamin B₁₂ required by humans is not derived from microflora in any appreciable quantities, although vegetable fermentation preparations have been reported as being possible sources of vitamin B₁₂ ^{16, 17}.

Recommended Dietary Intake (RDI) for vitamin B₁₂ (Table 1) were set in 1998 by the National Academy of Sciences. Recommended Dietary Intake (RDI) for vitamin B₁₂ is summarized in table-1 ^{18, 19}.

TABLE 1: RECOMMENDED DIETARY INTAKE (RDI) FOR VITAMIN B₁₂

Metabolic processes and Vitamin B₁₂: There are only two vitamin B₁₂-dependent enzymes ²⁰. One of these enzymes, methionine synthase, uses the chemical form of the vitamin which has a methyl group attached to the cobalt and is called methylcobalamin. The other enzyme, methylmalonyl coenzyme (CoA) mutase, uses a form of vitamin B₁₂ that has a 5-adeoxyadenosyl moiety attached to the cobalt and is called 5-deoxyadenosylcobalamin, or coenzyme B₁₂.

In nature, there are two other forms of vitamin B₁₂: hydroxycobalamin and aquacobalamin, where hydroxyl and water groups, respectively, are attached to the cobalt. The synthetic form of vitamin B₁₂ found in supplements and fortified foods is cyanocobalamin, which has cyanide attached to the cobalt. These three forms of vitamin B₁₂ are enzymatically activated to the methyl- or deoxyadenosylcobalamins in all mammalian cells ²¹.

Measurement techniques of Vitamin B₁₂: There are several methods to assay and calculate vitamin B₁₂. Some of these methods are used in medical field, and some others in pharmacological studies/investigations, these methods are ^{22, 23}:

1. Electroluminescence (ECL)
2. Inductive-coupled plasma (ICP) - mass spectrometry (MS) (ICP-MS)
3. Atomic absorption spectroscopy
4. Radioimmunoassay (RIA)
5. High-performance liquid chromatography (HPLC)
6. Capillary electrophoresis

Causes of low level of Vitamin B₁₂ in humans: Vegetarian diets can be classified as lacto vegetarian (dairy products), ovovegetarian (eggs), lactoovo-vegetarian (both dairy products and eggs), or vegan (no animal products at all). Vegan diets have very low content of vitamin B₁₂ ²⁴. Lack of vitamin B₁₂ may be caused by insufficient intake of vitamin or by malabsorption of the vitamin ²⁵.

Pernicious anaemia: Pernicious anaemia is the most common cause of B₁₂ deficiency. It is an autoimmune disease. The immune system normally makes antibodies to attack bacteria, viruses and other germs. But if a person is suffering from autoimmune disease, the immune system makes antibodies against certain tissues of body resulting the vitamin cannot be absorbed into the body. Pernicious anaemia usually develops over the age of 50. Women are more commonly affected than men, and it tends to run in families. It occurs more commonly in people who have other autoimmune diseases such as thyroid diseases.

Stomach or Gut Problems: Various problems of the stomach or gut can be a cause of vitamin B₁₂ deficiency. Such as:

• Surgery to remove the stomach or the end of the small intestine. This will mean absorption of vitamin B₁₂ may not be possible.
• Some diseases that affect the end of the small intestine where vitamin B₁₂ is absorbed may affect the absorption of the vitamin. i.e.  Crohn's disease.

Drugs: Certain drugs used for other conditions may affect the absorption of vitamin B₁₂. The most common example is metformin which is a drug commonly used for diabetes.

Dietary causes: The people who take no animal or dairy produce are more prone for vitamin B₁₂ deficiency.

 Conditions associated with reduced level of Vitamin B₁₂: Vitamin B₁₂ deficiencies manifest primarily as anemia and neurologic changes, although a deficiency of this vitamin inhibits DNA synthesis, which affects growth and repair of all cells.

Pernicious anemia is a form of megaloblastic anemia caused by either inadequate vitamin B₁₂ intake or reduced gastric secretion of intrinsic factor, which inhibits absorption. The hematologic effects of vitamin B₁₂ deficiency are indistinguishable from those of folate deficiency.

These include pallor of skin, tiredness, syncope, headache, shortness of breath, and palpitations. Hematologic complications are completely reversed by treatment with vitamin B₁₂.

Neurologic changes due to vitamin B₁₂ deficiency can occur in the absence of any hematologic abnormalities. Depending on the duration of symptoms, neurologic complications of vitamin B₁₂ deficiency may or may not be reversible following treatment.

The main Condition associated with reduced level of Vitamin B₁₂ is Biermer's disease (pernicious anemia). It is characterized by:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
2. Gastrointestinal symptoms: These are thought to be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia.
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), sub acute combined degeneration of spinal cord, or even symptoms of dementia and or other psychiatric symptoms may be present. The presence of peripheral sensorymotor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B₁₂ deficiency instead of folate deficiency.

Pernicious anaemia is a condition where vitamin B₁₂ cannot be absorbed into the body. It is the most common cause of vitamin B₁₂ deficiency. Vitamin B₁₂ deficiency is easily treated by regular injections of vitamin B₁₂, by taking oral supplements of vitamin B₁₂ and by taking diet rich in vitamin B₁₂.

The other condition associated with reduced level of Vitamin B₁₂ is the fact that Vitamin B₁₂ deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.

CONCLUSION: Vitamin B₁₂ play an important role in the formation of blood and in the normal functioning of the brain and nervous system. The daily recommended intake for an adult is 1.5μg a day. Eating a diet containing required amount of vitamin B₁₂ is the best way to treat the conditions associated with its low level. Vegetarians should consider taking a regular vitamin B₁₂ supplement to prevent the conditions associated with its low level.

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    How to cite this article:

    Belwal C: Causes and Conditions associated with reduced level of Vitamin B₁₂: A Review. Int J Pharm Sci Res. 3(10); 3651-3655.

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