Vitamin B12 Deficiency

Treatment of Vitamin B12 Deficiency 

By far the best method of treating Vitamin B₁₂ deficiency with all its undesirable consequences, is to avoid becoming deficient in the first place. Whilst generally this can be achieved through adequate dietary uptake in many instances the genetic make-up of an individual, infections, or the use of various drugs may lead either to reduced uptake of vitamin B12 from the gut, or may lead to excessive use or depletion of vitamin B12 stores in the liver, brain and other tissues. Once this has occurred the individual must make every effort to restore and maintain adequate vitamin B12 levels in the serum, liver and in particular the central nervous system including the brain.

Measurement of vitamin B12

Measurement of vitamin B12 is normally performed by analysis of circulating vitamin B12 levels in the blood. The standard test, however, measures not only the active forms of vitamin B12 (methylcobalamin and adenosylcobalamin) but also inactive forms of vitamin B12, such as CN-cobalamin and nitrosylcobalamin. This can lead to spuriously high levels of vitamin B12 being measured, despite the patient showing overt signs of clinical insufficiency. Compounding this is the insistence of Pathology labs around the world to quote vitamin B12 in reference to the range of data that they measure, and hence to determine levels as being "normal" if they fit within their standard "range" of measurement. As such the quoted levels include many individuals who have sub-clinical deficiency. Thus, in the USA and Australia, normal levels of vitamin B₁₂ have been determined by Pathology Labs to be in the range 180-750 pmol/L (244-1017 pg/ml), with 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). When this level of vitamin B12 is used to define the lower level of normal, it is estimated that functional vitamin B12 deficiency may be as high as 14-40% of the population even in omnivorous populations, and even higher in communities which are predominantly of vegetarian or vegan persuasion (see PDF),.

Vitamin B12 deficiency in the brain

Vitamin B12 loading of the brain occurs primarily during foetal development. Shortened foetal development, such as occurs in premature babies results in lower amounts of B12 in the brain. Brain levels stay reasonably constant through youth until the mid-twenties, from then on there is a gradual decline in levels of all forms of B12 in the brain, but particularly of methylcobalamin in the frontal region of the brain. To date there has been no animal or human study that has ever demonstrated effective replenishment of brain vitamin B12 through oral administration of small or large doses of vitamin B12. Even in enterally administered vitamin B12, very, very little material can be seen to enter the brain.

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 situations where there has been prolonged deficiency, which has resulted in extensive peripheral neuropathy due to demyelination of the nerves, it can take months to years to regenerate the myelin sheath on the nerves. During this time it is essential that vitamin B12 is administered with essential support from vitamin B2, Iodine, Selenium, Molybdenum, iron, biotin and vitamin D, all of which are by Schwann cells in the peripheral nervous system and Oligodendrocytes in the brain. In addition, the process of myelin repair is very slow, even in a nutritionally normal person.

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 that is absorbed from the standard supplements is too low, even in high dose supplements. In addition many supplements contain 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. Thus, Dangour and co-workers supplemented older people with 1 mg CNCbl per day for a period of 12 months. Whilst there was a big increase in serum B12 levels, there was a marginal drop in homocysteine, and no measurable effect on neuorological parameters.In addition, countless studies using 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 increased production of nitric oxide,  vitamin B₁₂ introduced by supplements is quickly inactivated to form nitrosylvitamin B₁₂. In addition, despite it being known for over 50 years, that functional vitamin B2 is essential for maintenance of vitamin B12 function and for conversion of cyanocobalamin to adenosyl and methyl cobalamin, NO supplementation study has been performed to date combining B12/folate/B2 and Iodine, Selenium and Molybdenum. There is a more extensive discussion on this at preventingdementia.org

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 the injected form of vitamin B₁₂, often with little change from provitamin forms (OHCbl or CNCbl) to the active forms (MeCbl and AdoCbl). Evidence suggests that persons with mutations in the methionine synthase reductase enzyme (MTRR) have trouble converting CN-Cbl and OH-Cbl to adenosyl and methylcobalamin. This mutation is relatively common and may explain why many individuals who have symptoms of vitamin B₁₂ deficiency do not respond to treatment with either CN-Cbl or OH-Cbl. It may also explain why many supplementation trials using CN-Cbl have not been effective in treating conditions that are apparently linked to vitamin B₁₂ deficiency (ie, dementia, AD, PD, MS). Thus, even with injections, it is essential to ensure sufficient vitamin B2/Iodine/Selenium/Molybdenum/iron and vitamin D, in order for supplementation to reverse peripheral neuropathy.

Topical Vitamin B₁₂

A topical form of vitamin B₁₂ has recently been developed. This preparation is easy to administer, contains the natural forms of the vitamin (adenosyl and methylcobalamin), is able to deliver therapeutic amount of vitamin B₁₂ and has the added advantage of providing a prolonged release of the vitamin over several hours.  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 hyperhomocysteinemia. This is not possible with the much lower dose of vitamin B₁₂ that is delivered via supplements See b12oils.com   .

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. Continued high dose injection of methylcobalamin has been shown to reverse the clinical signs of dementia.

Further Information on Treatment of Vitamin B₁₂ deficiency

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

http://www.abc.net.au/radionational/programs/healthreport/vitamin-b12-supplementation-and-ageing/5031170

http://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/ NIHPDF

http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/

http://blogs.psychcentral.com/therapy-soup/2013/02/could-vitamin-b12-help-your-anxiety-depression/ 

http://www.nrv.gov.au/nutrients/vitamin%20b12.htm

http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/ 

http://www.abc.net.au/radionational/programs/healthreport/vitamin-b12-supplementation/3823160#transcript PDF

http://www.youtube.com/watch?feature=player_embedded&v=BvEizypoyO0

References about Treatment with vitamin B₁₂

Hill et al, 2013 A vitamin B12 supplement of 500 ug/d for eight weeks does not normalize urinary Methylmalonic acid or other biomarkers of vitamin B12 status in elderly people with moderately poor vitamin B12 status. J. Nutrition 143, 142-147

Harris etal, 2015 Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients 7:3796-3812

Harris etal, 2012 Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: Hum Phychopharmacol. 27: 370-377

Cathou and Buchanan 1963 Enzymatic synthesis of the methyl group of Methionine JBC 238, 1746-1751

Katzen and Buchanan, 1965 Enzymatic synthesis of the methyl group of Methionine.. JBC 240, 825-835

Hyland, et al, 1988 Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurol, 39,459-62

Leclerc et al, 1998 Cloning and mapping of a cDNA for methionine synthase reductase,  flavoprotein defective in patients with homocystinuria PNAS, 95 2059-64.

Greibe et al, 2017 Effect of 8-week oral supplementation with 3 ug cyano-B12 or hydroxo-B12 in a vitamin B12-deficient population. Eur J Nut

Serapinas et al 2017 The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Reprod Tox 72: 159-163