Vitamin B12

Complex cobalt containing molecule to which various groups are linked covalently to form cobalamine. These include:

1. Endogenous cobalamines –include methyl cobalamine, 5-deoxy adenosyl cobalamine
2. Exogenous cobalamines

Essential for DNA synthesis, fatty acid metabolism

Vit B12, Vit B6 & folic acid participate in metabolism of homocysteine. If accumulation of homocysteine occurs due to deficiency of these vitamins, atherosclerosis is accelerated.

Deficiency leads to:

1. Megaloblastic anemia
2. GI symptoms
3. Neurologic abnormalities

Deficiency may occur due to:

1. Decreased absorption
2. Inadequate supply

Chemistry

Consists of:

1. Porphyrin like ring with central cobalt atom attached to a nucleotide
2. Various organic groups may be covalently bound to cobalt atom forming cobalamines.

Pharmacodynamics

Accumulation of methyltetrahydrofolate and deficiency of tetrahydrofolate leads to methylfolate trap, due to deficiency of vitamin B12.

This is an important biochemical step, where metabolism of vitamin B12 and folic acid are linked; this is why megaloblastic anemia due to vitamin B12 deficiency can be partially corrected by folic acid.

Deoxyadenosyl cobalamine converts methylmalonyl-CoA to succinyl-CoA, which is an important step in propanoic acid metabolism, linking carbohydrate and lipid metabolism.

 Exogenous Cobalamines

Cyanocobalamine and hydroxycobalamine are exogenous cobalamines, available as pharmacological preparations used for correction of megaloblastic anemias.

In the body they are converted to deoxy adenosylcobalamine and methyl cobalamine respectively.

Pharmacokinetics

• Dietary requirement is 2 micrograms
• Stored in liver
• Storage pool is 3000-5000 micrograms

Transport & Absorption

• Complexes with intrinsic factor(glycoprotein) in stomach
• Absorbed in distal ileum by highly selective receptor mediated transport system
• In plasma bound to transcobalamin II
• Stored in hepatocytes in liver
• Loss is very slow
• Hepatic stores are sufficient for 5 years.

Source

• Animal source –meat, eggs, dairy products, liver
• Microbial synthesis

Deficiency of Vitamin B12

Vitamin B12 deficiency causes:

1. Blood related problems
2. Neurologic problems

Blood related problems

Megaloblastic macrocytic anemia, associated with:

1. Mild to moderate leukopenia
2. Thrombocytopenia
3. Hypercellular bone marrow with accumulation of erythroid and other precursor cells

Neurological Symptoms

Start with:

1. Paresthesias (in peripheral nerves)
2. Weakness

And progresses to

1. Spasticity
2. Ataxia
3. Other CNS dysfunctions

Causes

In the past, it was supposed to be caused by accumulation of L-methylmalonyl CoA

Now believed to be due to disruption in methionine synthesis.

Main uses include pernicious anemia and anemia caused by gastric resection.

Schilling’s Test

• Once diagnosis of megaloblastic anemia is made, first it is determined whether the cause is vitamin B12 deficiency or folic acid deficiency.
• This is done by measuring the vitamin levels.
• Performed by administering radioactive B12. If B12 is eliminated, problem is in its absorption.
• Treated by giving intrinsic factor.

Standard treatment is:

• Parenteral Vit B12 is given (cyanocobalamin, hydroxycobalamin) but if patient cannot tolerate go for oral or intranasal route. Hydroxy cobalamin is preferred as has high PPB and remains for a longer duration
• Malabsorptive disorder- life long treatment is required
• With parenteral vitamin B12, improvement comes in about 7 days. The deficiency normalizes in 1-2 months.

Dose

Initial therapy -100-1000 micrograms/day, I/M for 1-2 weeks

Maintenance therapy -100-1000 micrograms/month, I/M for the rest of life

If neurological abnormalities are present, for maintenance therapy injections should be given 1-2 weeks, for 6 months, after which given on monthly basis.

Vit B12 deficiency seen in;

1. Pernicious anemia (as vit B12 complexes with intrinsic factor)
2. Gastrectomy
3. Small bowel resection
4. Malabsorptive disorders
5. Inflammatory bowel disease
6. In strict vegetarians

Diagnosis

Increased homocysteine levels can be used to diagnose vitamin B12 deficiency

Adverse effects;

Very few and very uncommon, even at high doses. Sometimes allergic manifestations are observed.

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Folic acid

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