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Sources and physiological effects

Dietary sources
Vitamin B₁₂, also called cobalamin, is only found in animal foods in significant amounts. The consumption of meat (especially offal), fish, eggs, milk and dairy products helps to meet nutrient demands. Plant foods do not usually contain vitamin B₁₂. Only lactic fermented products (e.g. sauerkraut) or bacterially contaminated foods may contain traces of the vitamin, but these are generally not sufficient to meet requirements. Fermented vegetable foods and algae (exception: chlorella), may contain non-vitamin analogues that block the metabolic functions of the biologically active vitamin B₁₂. The supply of vitamin B₁₂ depends not only on the content of vitamin B₁₂ and its analogues in food, but also on absorption dependent on intrinsic factor secreted in the stomach. Vitamin B₁₂ losses during food preparation are comparatively low. Gentle food preparation methods only reduce the cobalamin content by about 10 %. Only with long heating or extensive soaking would higher losses be expected.
Physiological effects
Homocysteine metabolism	Remethylation of homocysteine to methionine
Blood	Support of erythrocyte formation
DNA synthesis	DNA synthesis, cell growth and replication
Neurotransmitter metabolism	Methylation of neurotransmitters

EFSA Health Claims

Health claims		EFSA opinion
Vitamin B12 (Cobalamin)	Contributes to a normal energy metabolism Contributes to normal functioning of the immune system Has a function in cell division Contributes to normal functioning of the nervous system Contributes to normal homocysteine metabolism Contributes to normal mental function Contributes to the reduction of fatigue and fatigue

Recommended intake

D-A-CH recommended nutrient intake (Reference values EFSA and NHI )
	Age	Vitamin B12 (µg/d)
Infants (months)
	0-4	0.5
	4-12	1.4
Children (years)
	1-4	1.5
	4-7	2.0
	7-10	2.5
	10-13	3.5
	13-15	4.0
Youth/Adults (years)		Women	Men
	15-19	4.0	4.0
	19-25	4.0	4.0
	25-51	4.0	4.0
	51-65	4.0	4.0
	> 65	4.0	4.0
Pregnancy	4.5
Stillende	5.5
Higher demand	Elderly, hyperthyroidism, nitro-stress, parasite infestation, liver and kidney disease, alcohol abuse, vegetarian diet, smoking, gastritis, lack of intrinsic factor, pancreatic insufficiency, bacterial overgrowth syndrome of the intestine
Special groups at risk of deficiency	Exclusively breastfed infants of vegan mothers, deficiency of intrinsic factor in elderly persons and patients with chronic gastritis

Recommended intake according to food labelling regulations		µg/d
(=100 % TB marking on the label)		2.5 µg/d
Safety of the nutrient
UL	Long-term daily intake, where no adverse health effects are expected	N/A
NOAEL	Maximum intake, with no observed adverse effect	3000 µg/d

Detailed information

Physiological functions and resorption of vitamin B₁₂

The term vitamin B₁₂ (cobalamin) refers to a group of similar atomic compounds with a central cobalt atom. Cyanocobalamin is a synthetic compound which, due to its higher stability against chemical and physical influences compared to other B₁₂ forms, is used in preparations for therapeutic nutritional supplements. Vitamin B₁₂ ingested with food is bound in the stomach by a glycoprotein from the gastric mucosa known as intrinsic factor. Vitamin B₁₂ can only be absorbed into the body in this complex form in the small intestine. In human metabolism, vitamin B₁₂ has several functions. It acts as a coenzyme in the degradation of homocysteine to methionine. Cobalamin is converted into its active form (methylcobalamin) by active folic acid (5-MTHF) and 5-MTHF then becomes THF. If cobalamin is missing, an indirect folic acid deficiency occurs and vice versa. This explains why many symptoms of vitamin B₁₂ deficiency are similar to those of folic acid deficiency (1). Furthermore, vitamin B₁₂ is involved in the degradation of fatty acids, in the synthesis of myelin, the protective layer of the nerve strands, and in the construction of DNA and thus in cell division (2).

Vitamin-B₁₂-deficiency in vegan diet

A vitamin B₁₂deficiency usually develops very slowly over several years due to existing stores in the body. People with purely plant-based diets (vegan) are at particular risk, since dietary sources of Vitamin B₁₂ are found only in animal products. Exclusively breastfed infants of vegan mothers are exposed to a particularly high risk (3) (1). Additionally, a correlation between reduced bone density and the cobalamin status of young vegetarians has also been reported (4, 13).

At risk nutrient for elderly people and in chronic gastritis

Elderly people show a decreased absorption of vitamin B₁₂ due to a decrease in secretion of intrinsic factor. It is estimated that 15 % of people over 60 years of age have inadequate vitamin B₁₂ status. If homocysteine levels are taken into account, as many as 30 – 60 % of people over 65 years of agemay have a deficient intake of vitamin B₁₂. It is possible that insufficient B₁₂ intake causes a disturbance in the methyl metabolism of the nerve cell, which has a negative influence on neurotransmitter metabolism and can be associated with neuropsychiatric symptoms in old age (depressed moods, forgetfulness) (5). For older people, a continuous intake of a high-dose vitamin B ₁₂supplements is therefore recommended (1).

Chronic atrophic gastritis can also lead to vitamin B₁₂ deficiency, as it leads to a reduced production of the intrinsic factor.

Impairment of absorption by medication

A regular intake of certain drugs may also impair vitamin B₁₂ absorption and cause a decrease in cobalamin plasma concentrations and an increase in homocysteine levels (6).

Vitamin B₁₂ for neurologic regeneration and in Alzheimer patients

Alzheimer's patients often have an inadequate B₁₂ status. It is possible that the insufficient B₁₂ status causes a disturbance in the methyl metabolism of the nerve cells, which negatively influences neurotransmitter metabolism. However, there is a difference between B₁₂-related neuropsychological disorders and those caused by Alzheimer's disease. B₁₂-related dementia is reversible and patients respond well to B₁₂ supplementation (7). The development of funicular myelosis, associated with spinal cord degeneration, sensory and reflex disorders, muscle coordination and paralysis disorders, is also caused by vitamin B₁₂ deficiency. In this case, a disturbed lipid synthesis caused by the lack of B12 leads to a defective build-up of the nerve myelin layer (1).

Homocysteine as a risk factor

Homocysteine is a substance produced by the body from the amino acid methionine. The vitamins B₆, B₁₂ and folic acid are required for the degradation of homocysteine to cysteine or for reconstruction to methionine. In hyperhomocysteinemia, these break-down and reconstruction mechanisms are disturbed, causing homocysteine to accumulate in the plasma. It has been established that increased homocysteine levels represent an independent health risk. For example, about 10% of atherosclerotic diseases are due to moderate hyperhomocysteinemia, and 40% of patients with vascular disease have elevated levels (9). Neurological and cognitive changes are also associated with high homocysteine levels. However, it is still unclear whether this is caused by the toxicity of homocysteine or by the deficiency of B12 and folic acid (10). An association between folic acid and B₁₂ status and neuropsychiatric symptoms, mood abnormalities and dementia has been demonstrated (11). Homocysteine levels are considered to be a dietary risk factor that can be influenced by supplementation with folic acid, vitamin B₁₂ and vitamin B₆ (12).

Reference values

Parameter	Substrae	Reference value	Description
Vitamin B₁₂	Serum/Plasma	200 - 1000 ng/l Limited value 200 – 400 ng/l	Fasting (12 h)
Interpretation
Decreased values		Vitamin-B₁₂-deficiency, malnutrition, surgical intervention on stomach and/or intestines
Increased values		For oral supplementation of very high doses or parenteral nutrition
Note on the measurement results
Heparin can interfere with the determination. Test kit: highly purified intrinsic factor, free of R proteins. Vitamin B₁₂ has a long half-life, parenteral nutrition or vitamin B₁₂ supplementation up to 3 months before blood sampling affect the result.

Nutrigenetics
Characteristic gene sites and their effects on vitamin requirements

Gene		risk SNP		Recommended nutrients
MTHFR	rs1801133	T	The transmethylation by this enzyme is reduced, the need for folic acid and vitamin B6 is increased This SNP is associated with increased homocysteine levels. Vitamin B2 (riboflavin) can increase the activity of the MTHFR enzyme, therefore an increased intake is recommended. Vitamin B6 and folic acid should always be taken together with vitamin B12 (14)(15)(16)(17).	B₂, B₆, B₁₂ and folic acid

Deficiency symptoms

Impact on	Symptoms
General health	Weakness, dizziness, pale skin and mucous membranes, shortness of breath, sleep disturbances
Nerve system	Neuralgias, paresthesia, muscle paresis, memory and concentration disorders
Mucous membrane	Diarrhea, mucosal atrophy, glossitis, stomatitis
Blood	Anemia, maturation disorders, thrombocytopenia, leukopenia, pernicious anemia Increase in serum homocysteine levels
Folate metabolism	Indirect folic acid deficiency

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For general prevention	10 - 50 µg/d
	For increased demands in sport, stress and for concentration difficulties	100 - 1000 µg/d
	For vitamin B₁₂-deficiencies due to long-term poor diet and malnutrition	400 µg/d
	To compensate for low intake among vegetarians and vegans	400 µg/d
	To increase low vitamin B₁₂ storage in older people and to compensate for drug interactions	400 µg/d

Administration

General mode of administration
When	Vitamin B₁₂ should be takenon an empty stomach or between meals. Notes: To improve absorption using the intrinsic factor secreted in the stomach, vitamin B₁₂ should be taken on an empty stomach. In severe vitamin B₁₂ deficiency, an i.v. or i.m. infusion may be necessary, especially if the deficiency was caused by a malabsorption.
Side effects
No side effects are known to date.
Contraindications
No contraindicators are known to date.

Interactions

Drug interactions
NSAIDs (e.g. ASS, Diclofenac)	NSAIDs can reduce the absorption of vitamin B₁₂ by damaging the intestinal mucosa.
Oral antidiabetics (e.g. metformin)	Increased vitamin B₁₂ requirement by reducing the calcium ions required for resorption.
Antacids (H₂-blockers, PPI's)	Inhibition of pH-dependent intestinal release of protein-bound cobalamin.
Estrogens (oral contraceptives)	Increased need for vitamin B₁₂.
Methotrexate	Methotrexate acts as a folic acid antagonist and can therefore influence the effect of vitamin B₁₂.
Antidepressants (e.g. sertraline, citalopram)	B vitamins, especially vitamin B₁₂ and folic acid, support the positive effects of antidepressants.
Nutrient interactions
Trace elements	High calcium levels are necessary for a good vitamin B₁₂ supply with metformin administration.
Vitamins	Vitamin B₁₂ works synergistically with all B vitamins, especially with folic acid and B₆.

Description and related substances

Description of the micronutrient

Water soluble vitamin of the B-complex

Related substances

Four forms of cobalamin are approved for NEM and ebD in the EU:

Cyanocobalamin:

Synthetic form, stable.

Hydroxycobalamin:

Natural deposit form. Stable. It is also used parenterally, as it has a stronger protein binding than cyanocobalamin and therefore better retention after intramuscular treatment.

Methylcobalamin:

The biologically active form in the body. Metabolized better than Cyanocobalamin.

5′ Desoxyadenosylcobalamin:

Also a biologically active form. Difficult to obtain as a raw material and currently not used.

References

1) Hahn, A. et al. Ernährung: Physiologische Grundlagen, Prävention, Therapie, 3. neu bearbeitete und erweiterte Auflage. Stuttgart: Wissenschaftliche Verlagsgesellschaft Stuttgart, 2016.
2) Burgerstein, L. et al. Burgersteins Handbuch der Nährstoffe, 1. Auflage. Stuttgart: Haug Verlag, 2002.
3) Centers of Disease Control and Prevention, Georgia. 2003. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin. MMWR Morb Mortal Wkly Rep. 52:61-4.
4) Dhonushke-Rutten, R. A. et al. 2005. Low bone mineral density and bone mineral content are associated with low cobalamin status in adolescents. Eur J Nutr. 44(6):341-7.
5) Porter, K. et al. 2016. Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing. Nutrients. 8(11): 725. doi: 10.3390/nu8110725.
6) Gröber, U. Orthomolekulare Medizin: Ein Leitfaden für Apotheker und Ärzte, 3. unveränderte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2008.
7) Osimani, A. et al. 2005. Neuropsychology of B12 deficiency in elderly dementia patients an control subjects. J Geriatr Psychiatry Neurol. 18(1):33-8.
8) Okada, K. et al. 2010. Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. Exp Neurol. 222(2):191-203. doi: 10.1016/j.expneurol.2009.12.017.
9) Stanger, O. et al. 2003. DACH-LIGA homocystein consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med. 41(11):1392-403.
10) Kado, D. M. et al. 2005. Homocystein versus vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: Mac Arthur Studies of Successful Aging. Am J Med. 118(2):161-7.
11) Reynolds, E. 2003. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 5(11):949-60.
12) Universität Wien: Koronare Herzerkrankungen. In: Österreichischer Ernährungsbericht 2003. Wien: Bundesministerium für Gesundheit und Frauen, 2003.
13) Roman-Garcia, P. et al. 2014. Vitamin B12–dependent taurine synthesis regulates growth and bone mass. J Clin Invest. 124(7):2988–3002. doi: 10.1172/JCI72606.
14) Olteanu, H. Munson, T. Banerjee, R. 2002. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 41(45):13378-85. .
15) Wilson, A. et al. 1999. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. (4):317-23.
16) Seibold, P. et al. Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. Int J Cancer. 129(6):1467-76.
17) Jiang-Hua, Q. et al. 2014. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B 12 intakes. Tumour Biol. 35(12):11895-901.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.