Vitamin B12 Deficiency

 

 

Vitamin B12 Deficiency, a much under-diagnosed condition

 

The prevalence of vitamin B12 deficiency in the population appears to be increasing. Originally vitamin B12 deficiency was quite a rare condition, mainly associated with anaemia caused by antibodies to intrinsic factor or parietal cells (pernicious anaemia),. The condition is now much more common and can be the result of a wide range on conditions such as those caused by malabsorption due to atrophic gastritis, the use of PPIs, GORD medication, certain drugs, low dietary intake such as occurs in  veganism and vegetarianism, intestinal parasites such as Giardia lmblia, Blastocystis hominilis, fish tapeworms, Ascaris lumbricoides, Entomoeba histolytica, roundworms, hookworms, certain religions, such as 7th Day Adventists, Rastafarians, and excessive smoking. More recently vitamin B12 deficiency has been shown to also occur as a result in functional vitamin B2 deficiency as occurs in hypothyroidism and lack of dietary intake of vitamin B2, Iodine, Selenium and/or Molybdenum. As such the condition has become much more common and conservatively may affect up to 20% of the population.

 

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.

 

Vitamin B12 Deficiency and drug use.

Vitamin B12 deficiency has been associated with the use of the following drugs: Prilose, Yosprala, Prevacid, Dexilent, Aciphex, Protonix, Nexium, Vimovo, Zegerid, 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).

 

Consequences of Vitamin B12 Deficiency.

 

Deficiency of vitamin B12 in the cerebro-spinal fluid can lead to brain atrophy (shrinkage), subacute combined degeneration of the spinal cord, cerebrovasular disease, dementia, Alzheimer's disease and has been postulated as being causative for Parkinson's disease, and multiple sclerosis.

 

Vitamin B12 deficiency in the elderly has been associated with a slow and unstable gait, numbness and tingling in the hands and feet, urinary and fetal 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, an increased risk of thrombosis, reduced glomerular filtration rate, stroke, ischemic heart disease, mental retardation and seizures, ectopia lentis, secondary glaucoma, optic atrophy, retinal detachment, skeletal abnormalities, osteoporosis, neurological dysfunction, epilepsy, psychiatric symptoms, dementia, Parkinson's disease, neoplasia, cognitive impairment, autism, cretinism, allergy, depression, fatigue, low CoQ10, low creatine, 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 (<250 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 http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/ )

 

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, use of PPIs, use of Nitrous Oxide anaesthetics, 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, anorexia nervosa, certain religions, such as 7th Day Adventists, Rastafarians, and excessive smoking. Vitamin B12 deficiency can be a serious complication of Metformin use in people with diabetes. Recently it has been shown that vitamin B12 deficiency can be a serious complication of cancer chemotherapy using methotrexate following treatment of psoriasis and rheumatoid arthritis.

 

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 and VB12 and MTRR).

 

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. The definition of deficiency is very random and appears to vary from country to country. 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 or higher (406 pg/ml)(Ulak etal, 2016), which is also regarded as the lower level of the normal range by the Japanese health authority. In South Korea, vitamin B12 deficiency is defined as vitamin B12 <300 pg/ml. 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, 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 nmoll/L). Increased levels of Hcy is associated with vascular inflammatory disease and  increases in cardiovascular disease, as well as reduction in eGFR (Ahmed etal, 2019), 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). Many years ago, it was shown that measurement of Holo-TC was not predictive of B12 status as defined by macrocytosis (Wickramasinghe and Ratnayaka, 1996), however this information appears to have been ignored by those purveying the test. 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.

 

Paradoxical Vitamin B12 Deficiency

Measurement of serum vitamin B12 can lead to paradoxical results, thus a person may have many symptoms of vitamin B12 deficiency, but measurement of serum vitamin B12 does not show deficiency, a condition called "Paradoxical B12 Deficiency". Thus, whilst the serum may have elevated levels of vitamin B12, the vitamin B12 is an inactive analogue such as Co(II)B12, or more likely cyanocobalamin or hydroxycobalamin. Determination of active vitamin B12 is therefore better achieved through the measurement of MMA, Homocysteine, or elevations in Homovanillic acid, Vanillylmandelic acid, Quinolinic Acid, Kynurenic Acid, or 5-Hydroxyindoleacetic acid. Such determinations are readily obtained using a simple urinary Organic Acids Test.

 

Paradoxical vitamin B12 deficiency is arguably the most common form of vitamin B12 deficiency, its origin is very poorly understood and poses many problems for patients and clinicians, and often leads to rather erroneous conclusions regarding the utility, or not, of supplementing with vitamin B12. It should though be an "alert" warning for both as it indicates that the measured, or injected or orally administered vitamin B12 is not being properly processed to the two active forms Adenosylcobalamin or Methylcobalamin, thereby suggesting that potentially a functional B2 deficiency should be addressed prior to treatment. Numerous examples of publications where paradoxical vitamin B12 deficiency have been observed occur (Ahmed etal, 2019; Andres etal, 2013; Chiche etal, 2008; Arendt and Nexo, 2012; Deneuville etal, 2009; Corbetta eta; 2015), and have been associated with a wide range of conditions including hypothyroidism, Lyme disease, Chronic Fatigue Syndrome, functional B2 deficiency, anorexia nervosa, autism, solid neoplasms, myeloproliferative blood disorders and liver diseases.

 

Symptoms of Vitamin B12 Deficiency

Vitamin B12 deficiency can result in the following conditions

 

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, nor to improve mini mental score estimations in dementia. Furthermore, in inflammatory conditions where there are high circulating levels of homocysteine, vitamin B12 introduced by supplements is quickly inactivated to form Co(II)-cobalamin (Co(II)B12), which must be activated by the B2-dependent enzyme MTRR before it can be effective..

 

The main powerhouses for energy production within  the cell are the mitochondria. Within the mitochondria, fatty acids, sugars and amino acids can be converted to energy in the form of ATP via the glycolysis, Krebs cycle and the Electron Transport Chain. . Whilst is it is generally accepted that the B group vitamins play an essential role in energy production, vitamin B12 has several unique roles to play. Through its interaction with the folate and methylation cycles, methylcobalamin contributes the methyl group that is essential for the production of creatine (2-(Methylguanidino)ethanoic acid). In the muscles creatine and creatine phosphate supply "instant" energy through the conversion of creatine phosphate to ATP. Carnitine, formed from the break-down of N-methyl-lysine is essential for transport of free fatty acids into the mitochondria for use in energy production. In addition, methylcobalamin, through its role in the production of S-AdenosylMethionine (SAM), also is essential for the production of the electron-shuffle molecule ubiquinone (CoQ10), and in methyl B12 deficiency CoQ10 levels decrease. Elevated levels of SAM are also required in order to turn on the enzyme cystathionine beta synthase, and to pull the sulphur, originally resident in methionine, through CBS to generate iron-sulphur complexes, and in reduced B12 levels the activity of Fe-S proteins can be observed to decrease. The activity of one of these, aconitase, is critical for energy movement around Krebs cycle and in reduced B12, aconitase activity is reduces. Reduced aconitase activity has been associated with reduced mini mental score estimations, and dementia. In the mitochondria, adenosylcobalamin serves as an essential co-factor in the enzyme methylmalonyl-Co mutase, which utilizes odd chain fatty acids and odd chain amino acids for energy production. A deficiency of adenosylcobalamin can in itself lead to alterations in mitochondrial morphology and function.

 

Deficiency in adenosylcobalamin leads to the accumulation of methylmalonic acid, which disrupts normal glucose and glutamic acid metabolism in the cell due to its inhibitory activity on the Krebs cycle and by inhibition of ATP synthase. Continued deficiency of adenosylcobalamin, with resultant reduction in energy output can lead to anorexia, lacrimation, alopecia, and eventual emaciation. In addition there is a build up of lesions in the liver and the development of optic neuropathies.

 

Elevated MMA also results in the formation of faulty lipids for incorporation into the myelin sheath of nerves.

 

Several studies have also shown that mitochondrial function can be affected by the generation of reactive oxygen species (ROS), which can result from decreased levels of glutathione within the cells due to VB12 deficiency and also because vitamin B12 is known to be a scavenger of nitric oxide.

In summary vitamin B12 deficiency has a dramatic effect on energy levels within the cell due to decreased creatine phosphate, reduced fatty acid uptake into the mitochondria, the toxicity of methylmalonic acid and increased levels of ROS. .

 

Further Information on the role of vitamin B12 in energy production and mitochondria

 

http://www.ncbi.nlm.nih.gov/pubmed/6886087

http://www.ncbi.nlm.nih.gov/pubmed/16814759

http://www.ncbi.nlm.nih.gov/pubmed/19760748

Shetty etal. Management of Ocular Neuropathic pain with vitamin B12 supplements: A case report. Cornea 2015, 1324-5 PMID 26266431

Ulak etal, 2016 Vitamin status among breastfed infants in Bhaktapur, Nepal. PMC 4808878

Wickramasinghe SN1, Ratnayaka ID.Limited value of serum holo-transcobalamin II measurements in the differential diagnosis of macrocytosis.
J Clin Pathol. 1996 Sep;49(9):755-8. https://www.ncbi.nlm.nih.gov/pubmed/9038761

Armed etal, 2019 Vitamin B12 deficiency and hyperhomocysteinaemia in outpatients with stroke of transient ischaemic stroke.. PMC 6347886
Andres etal, 2013 The pathophysiology of elevated vitamin B12 in clinical practice
https://academic.oup.com/jmed/article/106/6/505/1538806
Chiche etal, 2008 Implications cliiques de la decourverte d'une hpervitaminemie B12 en medecien interne. Rev Med Interne 29, 187-194

Arendt and Nexo 2012 Cobalamin related parameters and disease patterns in patients with increased serum colabamin levels. PLoS ONE 9, e45979

Deneuville etal, Concentration plasmatique elevee de la vitamine B12.... REv Med Interne 2009 30, S73

Corbetta etal, 2015 Pardoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa. PMID 25446249
 

 

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