Vitamin B12 Deficiency: What are the consequences?

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Vitamin B12 : Essential for Life

Vitamin B12 (cobalamin), has a deep red colour and is an important member of the B group water soluble vitamins. It has a key role in the functioning of the brain and nervous system, in the production of energy in mitochondria and in the formation of red blood cells. Severe lack of vitamin B12 can result in anaemia, whilst even a moderate continued lack has been associated with several conditions including neuritis, multiple sclerosis, cognitive impairment, dementia and Alzheimer's disease.

Forms of vitamin B12 in the body

Vitamin B12 has a central cobalt atom (in pink on the structure model), to which are attached different functional groups, which lead to different forms (vitamers) of the vitamin depending upon the group. In the body the two main forms of vitamin B12 are adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are each used by a different set of enzymes within the cell. The majority of injected vitamin B12 preparations, supplements, or food additives have a synthetic  form of vitamin B12 called cyanocobalamin that does not occur in nature. Technically cyanocobalamin is not a vitamin as it is biologically inert and has to be converted to the active form in the body, with the release of toxic cyanide.

Adenosylcobalamin is an essential co-factor for the enzyme methylmalonyl coenzyme A-mutase, which functions in the catabolism of isoleucine, valine, threonine, methionine, thymine, and odd-chain fatty acids. Adenosylcobalamin deficiency has been associated with mitochondrial dysfunction and with inabiliity to use odd chain fatty acids, isoleucine, valine and threonine as energy sources.

Methylcobalamin is the specific vitamin B12 form used by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. The enzyme is required to transfer the methyl group from methylcobalamin to homocysteine, thereby forming methionine, which is  a precursor in the production of S-adenosylmethionine (SAM), and essential methyl donor in the cell (see the section on MTHFR). Deficiency of methylcobalamin is associated with reduced methylation, low intracellular glutathione levels.

Absorption of Vitamin B12 

Absorption of vitamin B12 from the intestine requires that it be released from food through the action of various enzymes in the intestine. It then must be bound by a specific transport protein, called intrinsic factor which is released in the stomach. Patients who are deficient in intrinsic factor, or who have antibodies against intrinsic factor can become deficient in vitamin B12.  which may eventually lead to pernicious anaemia. The capacity of the vitamin B12- intrinsic factor mediated uptake is very limited and in humans it is only possible to absorb 1-1.5 ug of vitamin B12 per feed. Absorption of vitamin B12 can be severely impaired in patients who have intrinsic factor deficiency or who may gastro-intestinal problems, such as gastric ulcers, atrophic gastritis, Crohn’s Disease and Ulcerative Colitis. Vitamin B12 deficiency can also be a result of  various intestinal parasites/bacteria including H. pylori infections, Giardia lamblia, and bacterial overload. Once the vitamin B12 has been absorbed from the intestine it is removed from intrinsic factor and transferred to transcobalamin (TCII). Vitamin B12 must be bound to transcobalamin II to be taken up by the majority of cells in the body.

Vitamin B12 Deficiency

Vitamin B12 deficiency is arguably the most under-diagnosed condition in the community. "In general, doctors are trained to recognize only the blood abnormalities associated with B12 deficiency - macrocytosis. B12 deficiency, however, mimics many other diseases and often physicians fail to confirm B12 deficiency and therefore fail to test for it. The development of vitamin B12 deficiency is a slow and insidious process, which may take several years to manifest itself. During this time there can be progressive loss of vitamin B12 in the cerebrospinal fluid (CSF), which precedes overt deficiency as measured in serum, and without anaemia or macrocytosis. Deficiency of the vitamin in the CSF can lead to brain atrophy (shrinkage) and subacute combined degeneration of the spinal cord, cerebrovascular disease, Parkinson's disease, dementia, Alzheimer's' disease, multiple sclerosis. Vitamin B12 deficiency in the elderly has been associated with an unstable gait, numbness and tingling in the hands and feet, urinary incontinence, hearing loss and an increased incidence of bone fracture.  Vitamin B12 deficiency in pregnant mothers is associated with an increased incidence of neural tube defects in the young and the development of Autism in the new born.  Apart from the conditions mentioned above deficiency in either vitamin B12 or folate often leads to hyperhomocystinaemia, which has been associated with MS, AD, dementia, cardiovascular disease and many other conditions. Once a person is deficient in vitamin B12, it is almost impossible to overcome this deficient through dietary supplementation, particularly if the underlying cause is not removed/cured. Thus persons who are deficient normally require regular injections of vitamin B12, Recently it has been found that it is possible to obtain vitamin B12 through application to the skin using specialized topical technology described in this site. Vitamin B12 deficiency can be further exacerbated in the presence of MTHFR genetic mutations.

 Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Low vitamin B12 levels have also been associated with multiple sclerosis,.

Pregnant women with vitamin B12 levels below 250 pmol/L have twice the incidence of children with neural tube defects than those with higher levels.

Post menopausal women with low levels of vitamin B12 have been shown to have a higher risk of breast cancer (see )

Causes of Vitamin B12 Deficiency

Vitamin B12 deficiency can occur after bowel resection, or gastric by-pass surgery. Vitamin B12 deficiency can occur due to atrophic gastritis, a condition that effects 10-30% of the elderly. Other causes of vitamin B12 deficiency include achlorhydria, ageing, excessive antibiotics or anti-convulsants (often used in persons with epilepsy), gastrectomy, especially of the cardiac or fundus, liver disease or cancer,  megadoses of vitamin C and/or copper, pregnancy, intestinal parasites such as Giardia, fish tapeworms, a primarily vegan or vegetarian diet, certain religions, such as 7th Day Adventists, Rastafarians, and excessive smoking.

Vitamin B12 deficiency has also been associated with the use of the following drugs, cholestyramine, cymetidine, clofibrate, colchicine, Isotretinoin (Accutane), methotrexate, methyldopa, neomycin, omeprazole, some oral contraceptives, phenobarbital, ranitidine, tetracyclines, valproic acid, anti-epileptic drugs (carbamazipine and others) and zidovudine (AZT).  Vitamin B12 deficiency can be a serious complication of Metformin use in people with diabetes.

Hypothyroidism is often also associated with vitamin B12 deficiency  Individuals with hypothyroidism have a reduced capacity to convert riboflavin (vitamin B2) to flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD).  This then results in the reduced capacity to recycle folate leading to "sacrificial" use of methyl cobalamin for the methylation cycle, ultimately leading to vitamin B12 deficiency (see the section on VB12 and MTHFR).

Dietary insufficiency of folate can reduce the ability to regenerate methyl B12, thereby causing vitamin B12 deficiency.  Dietary insufficiency of iodine, selenium and/or molybdenum can lead to functional vitamin B2 deficiency, due to their role in converting dietary vitamin B2 (riboflavin), into the two active forms of the vitamin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). The result is very similar to the effect of hypothyroidism, and supplementation with one or all of these metals is required to overcome the deficiency, even in the presence of adequate vitamin B2 (riboflavin) intake.

Mutations in the genes for several enzymes involved in the folate cycle and methylation can also lead to vitamin B12 deficiency (vzi MTHFR, MTR, MTRR, amongst others) and also in inherited genes involved in the proteins involved in vitamin B12 processing within the cell (cblA, B, C, D, E, F).

Vitamin B12 - Definition of Deficiency - levels in serum

In the USA and Australia, normal levels of vitamin B12 have been determined to be in the range 180-750 pmol/L (244-1017 pg/ml), with vegans normally much lower at around 110 pmol/L, being regarded as deficient. Recently, many studies looking at biological markers of vitamin B12 deficiency (MMA and Hcy) as well as neurological markers of deficiency, have suggested that deficiency may start at 300 pmol/L (406 pg/ml), which is also regarded as the lower level of the normal range by the Japanese health authority. It is estimated that as many as two thirds of the people who are in the lower range of serum vitamin B12 levels (190-300 pmol/L) may have functional vitamin B12 deficiency (see PDF), thus the true level of vitamin B12 deficiency may be as high as 14-40%, depending upon the population.

Subclinical deficiency in vitamin B12 (<250 pmol/L) can be monitored by rises in the level of homocysteine (Hcy) (>10 umol/L) and methylmalonic acid (>200 noml/L). Increased levels of Hcy is associated with vascular inflammatory disease and  increases in cardiovascular disease, whilst increases in MMA can result in destruction of the myelin sheath around neurones.

One of the problems with the measurement of vitamin B12 in serum is that current methods do not determine which analogue(s) is(are) present. Thus, if a subject has been injected with cyanocobalamin and then serum vitamin B12 is measured, the subsequent measurement, which shows increased vitamin B12 really only establishes that the injection has been successful. It does not "tell" you if the cyanocobalamin (CN-B12) has been converted to methyl or adenosyl B12.

More recently a new test, called the Active B12 test, has been added to the list of tests, pertaining to measure levels of vitamin B12 in serum. This test is poorly named, as the test measures the amount of vitamin B12 (of unknown identity) that is bound to transcobalamin II (the vitamin B12 carrier responsible for uptake into the cell). Once again it does not determine if in fact the subject has the active forms of vitamin B12 (adenosyl and methyl B12), and as such has very questionable utility. Unfortunately this aspect of the test is not stated on the general Information Sheets for the test.

Symptoms of Vitamin B12 Deficiency

Vitamin B12 deficiency can result in the following conditions

  • Ataxia (poor muscle do-ordination),

  • pernicious anemia,

  • Confusion,

  • Depression,

  • Disorientation, psychoses, schizophrenia, ADHD

  • Fatigue, being easily tired

  • Glossitis, impaired lymphocyte response,

  • Memory loss, dementia, cognitive decline, brain fog

  • Decreased libido, low sperm count, erectile dysfunction, low testosterone,

  • increased rate of miscarriage in women,  ,

  • Paresthesia (tingling of fingers, toes, arms, legs, etc),

  • Progressive peripheral neuropathy with pronounced anemia,

  • Spinal degeneration,

  • Brain atrophy,  and macrocytic cells.

  • Increased incidence of canker sores.

  • Alzheimer's disease

  • Vascular dementia, and

  • Parkinson's disease

  • Insomnia, or trouble sleeping through the night

  • Food intolerance, particularly to sulfites

  • Incontinence of bowel or bladder, including "having to get up during the night".

  • Irregular or poor control of blood pressure, and irregular breathing patterns

  • Itchy skin.

  • Inability to lose weight.

Why vitamin B12  levels in serum may be misleading

The methods used for measurement of vitamin B12 levels in serum do not determine what form of vitamin B12 is present in the serum, nor what the vitamin B12 is bound to. Thus, in individuals supplementing with high doses of vitamin B12, the subsequent measurement of vitamin B12 is generally a reflection of the analogue of vitamin B12 used in the supplements. Thus, if cyanocobalamin (the inactive vitamer) has been used in supplementation, this is the form measured, Similarly for hydroxycobalamin  Similarly the generally used detection methods do not distinguish if the vitamin B12 (of whatever form) is free, or bound to transcobalamin II (the form required for uptake into the cell) or to haptocorrin (the form that is unavailable to the cell). Care must therefore be taken in assuming that just because vitamin B12 levels have been increased or are high in serum the vitamin B12 may either not be bound to transcobalamin II, or it is  not the active forms, adenosyl or methylcobalamin.

Therapeutic use of Vitamin B12 

Vitamin B12 has been used in therapy for many conditions including AIDS/HIV support, anaemia, anaemia of pregnancy, pernicious anaemia, asthma, atherosclerosis, allergies, atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, bursitis, sciatica, canker sores, chronic fatigue syndrome, Alzheimer’s disease, dementia, depression, Crohn’s disease, diabetes mellitus, diabetic neuropathies, neuralgias, post-herpetic neuralgia, diabetic retinopathy, fatigue, herpes zoster, high cholesterol, high blood  homocysteine levels, insomnia, male infertility,   tinnitus, viral hepatitis, and vitiligo. Recent studies have shown that high dose vitamin B12 treatment can slow or prevent brain shrinkage and loss of cognitive impairment. High dose formulations have also been shown to reverse bowel and bladder incontinence.

Prevention of Vitamin B12 Deficiency

Vitamin B12 insufficiency can be prevented either by adherence to a diet that is sufficient in vitamin B12 (see link), by the use of supplements, by injection of vitamin B12 or via topical administration of vitamin B12. Persons who are deficient due to poor absorption, or through conditions affecting absorption require regular vitamin B12 supplementation either via vitamin B12 injections or  by regular application of topical vitamin B12.

Overcoming Vitamin B12 Deficiency

Unfortunately it is almost impossible to to overcome deficiency once it occurs, through either a change in diet or by the use of standard supplements. The normal uptake system in the gut for vitamin B12 is not sufficient to deliver enough vitamin B12 to overcome deficiency, a situation made even worse in those who have compromised intestinal uptake, are on various drugs or take metformin. Prompt treatment of B12 deficient patients is required to prevent progressive, irreversible neurological and cognitive impairment. In addition, measurement of serum vitamin B12 levels may not be indicative of deficiency in the central nervous system (CNS), particularly during periods of vitamin B12 supplementation, where it may be possible to significantly boost serum levels of vitamin B12, however, levels in the CNS may be relatively unchanged, or only slightly increased.

Vitamin B12 in Supplements

The use of vitamin B12 in supplements for treatment of deficiency is controversial with many studies showing no benefit being obtained from standard supplements as the amount of vitamin B12 in the standard supplements is too low, and because almost invariably the supplement contains cyanocobalamin (a synthetic pro-vitamin) rather than adenosylcobalamin or methylcobalamin, the two natural forms of the vitamin. Furthermore, studies with high dose oral supplements with cyanocobalamin were not effective in restoring normal levels of homocysteine or methylmalonic acid, in reversing clinical signs of deficiency, or in maintaining normal levels of serum vitamin B12 once supplements were ceased. In addition, high dose oral supplements have NOT been shown to be able to increase the concentration of vitamin B12 in the cerebral spinal fluid, or the brain. Furthermore, in inflammatory conditions where there are high circulating levels of homocysteine, vitamin B12 introduced by supplements is quickly inactivated to form homocysteinyl-vitamin B12.

Vitamin B12 Injections

Vitamin B12 injections can be administered in cases of insufficiency, however these are generally expensive, must be given by a medical practitioner, are painful and like oral supplements, invariably contain cyanocobalamin (a synthetic pro-vitamin) rather than adenosylcobalamin or methylcobalamin, the two natural forms of the vitamin. In some countries such as Europe and South America both the methyl and adenosyl-vitamin B12 forms of the vitamin are available for injection. Injections must be given every 4 to 6 weeks, as they do not seem to overcome deficiency, but merely provide a temporarily boost in circulating levels of vitamin B12

Topical Vitamin B12

A topical form of vitamin B12 has recently been developed. This preparation is easy to administer, contains the natural form of the vitamin, is able to deliver therapeutic amount of vitamin B12 and has the added advantage of providing a prolonged release of the vitamin over several days.  This prolonged release potentially allows for continuous loading of the various organs including the liver and more importantly the CNS and brain. Moreover, the high dose of vitamin B12 that is deliverable by this method is sufficient to act as a powerful anti-oxidant and also to neutralize circulating levels of homocysteine, thus reducing the incidence and severity of conditions associated with hyperhomocystinaemia. This is not possible with the much lower dose of vitamin B12 that is delivered via supplements. See ContactB12Oils

Further Information on Vitamin B12 and its uses

Further information on vitamin B12 and deficiency states, as well as potential use of vitamin B12 can found by following the links. NIHPDF PDF :

Pacholok, S.M. and Stuart, J. J. Could it be B12? An epidemic of misdiagnosis.