Vitamin B12, Homocysteine and Methylmalonic Acid

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What is Vitamin B12?

B12 is a group of cobalt-containing vitamins. Hydroxocobalamin and cyanocobalamin are synthetic forms of vitamin B12. The two forms of vitamin B12 naturally occurring in foods are methylcobalamin and adenosylcobalamin. These forms are biologically equivalent.

B12 is produced by a number of different species of bacteria which is found in the soil, on the surface of some plants and some red and green algae. 1 With increased awareness of the importance of hygiene such as washing food and cooking, the amount of bacteria has been reduced since since the beginning of the twentieth century. It is fortunate that death from typhoid (191), diarrhoea (1101) and puerperal septicaemia – childbirth fever (71) have been eliminated in Australia. It has, however, reduced the amount of B12-producing bacteria. The number in brackets represent the number of deaths in 1907. 2

B12 is involved in: 3

  • Activation of folate to its active form
  • Conversion of homocysteine to methionine
  • Fat metabolism
  • Synthesis of DNA
  • Synthesis of myelin, component of nerve cells
  • Acts as an antioxidant by reducing the amount of glutathione

Determining deficiency can be problematic. Some indications are:

  • Definite deficiency is indicated by serum vitamin B12 < 150 pmol/ L.
  • Creatinine > 5 micro g/ mg indicates deficiency.
  • Access to a microscope can show hyper-segmentation of the nuclei of neutrophils. More than 25% of neutrophils having 5 or more lobes indicate deficiency. 4
  • If urinary methylmalonic acid (MMA) is less than 0.5 micromol/L then vitamin B12 deficiency is unlikely.

Some practitioners are concerned with cyanocobalamin because of the presence of the cyano-group attached to the single cobalt atom (Co-C=N). The cyano-group is not cyanide. Hydroxocobalamin is used to treat cyanide poisoning as it converts cyanide to non-toxic cyanocobalamin.


Sources in Diet

Seventh-day Adventist Health Study-2 (AHS-2) shows that the major sources of vitamin B12 in the diet are: 5

  • Beef, lamb, goat, pork, poultry
  • Fish, seafood
  • Milk, yogurt, cheese, cheese, ice cream, cream
  • Foods made with milk and eggs such as cakes and desserts
  • Fortified cereals
  • Fortified meat substitutes
  • Fortified milk substitutes
  • Brewer’s yeast, torula yeast
  • B12 supplements

Health Risks of Low Vitamin B12 and Elevated Homocysteine

Seventh-day Adventist health studies (AHS-2) show that:

The prevention of low and marginal vitamin B12 status is important because inadequate vitamin B12 can lead to serious neurologic and neuropsychiatric abnormalities among adults and the elderly, even without associated anemia. A marginal vitamin B12 deficiency has been shown to be associated with a higher homocysteine level and increased risk of vascular disease, which can lead to cardiovascular disease and neurological deficits. 6

Folate deficiency and maternal low B12 status and B12 deficiency during pregnancy and lactation can have serious consequences for the offspring which includes neural tube defects. 7

People with a low intake of B12 in the diet that are supplemented with folic acid “may aggravate their B12 deficiency”. 8

Similarly, a combination of low levels of B12 and increased levels of folate was associated with higher concentrations of methylmalonic acid and total plasma homocysteine. 9

Studies have consistently shown that mean serum vitamin B12 is reduced and homocysteine is elevated in vegetarians, particularly among vegans. 10 11 12


Previously, it was believed that excess vitamin B12 was excreted by the kidneys. A number of recent studies have indicated that excess vitamin B12 can have serious health consequences.

However, care needs to be taken when examining such papers that there are no confounding factors and that the conclusions are not blemished by “reverse causation”. One example of “reverse causation” is the observation that people who watch more TV and are physically inactive are more likely to be unhealthy. The reverse is also true and more relevant – people who are unhealthy and unable to be physically active end up watching more TV. A number of nutrition studies adjust for TV watching, physical activity and even BMI which is inappropriate.

The conclusion of a 2020 paper stated:

These findings suggest that higher levels of plasma concentrations of vitamin B12 were associated with increased risk of all-cause mortality after adjusting for age, sex, renal function, and other clinical and laboratory variables. 13

Consequences of Mismanaged Treatments

“High levels of serum vitamin B12 levels is a frequent and underestimated anomaly which can be
paradoxically accompanied by signs of deficiency. This may be related to defects in uptake and action of vitamin B12.” 14

Practitioners may prescribe additional B12 which exacerbates the problem. A number of products contain riboflavin, pyridoxine, folate, B12 and methionine way in excess of dietary requirements in an attempt to resolve B12 metabolism problems.

Many magnesium supplements contain pyridoxine which is usually unnecessary and possibly detrimental.

Great care needs to be exercised to determine our bodies real requirements instead of haphazardly self-prescribing medications.

A number of recent studies show that elevated B12 is associated with a much reduced life expectancy. Folate is rarely deficient in western diets, especially with the mandatory supplementation of cereals and flours. The mandatory fortification with folic acid of wheat was introduced in Australia in September 2009. This resulted in a 77% reduction in the in the prevalence of low serum folate levels from 9.3% to 2.1%. There was a 31% increase in mean serum folate level from 17.7 nmol/L to 23.1 nmol/L. The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia. 15


Animal foods contain about four times as much methionine compared with plant-based foods. Major sources are eggs, cheese, fish, beef, pork and poultry. It is an essential amino acid that is also contained in seeds, oats and beans. The high level of sulphur produces rotten egg gas when eggs decay.

Methionine in the diet is metabolised into homocysteine and sulphur dioxide. One effect of this is to increase the acidity of the blood.

Lack of vitamin B12 can cause serious neurological effects and babies have been born with permanent and crippling spinal defects. We need such a tiny amount of B12 and it is stored in the liver for years. Using a B12 spray once or twice a month is usually more than sufficient.

Reference range for homocysteine is less than 12 μmol / L. An optimal level is probably 8 μmol / L or less.


A Personal Example

A recommendation from a naturopath included advice to increase the supplementation of B12 to overcome a perceived lack of B12. A product was also recommended that included high amounts of riboflavin, pyridoxine, folate, B12 which was not taken. Taking this product would have greatly exacerbated the problem.

B12 and pyridoxine results were significantly more than the reference range and the folate far exceeded the usual intakes.

TestResultUnitRef range
B121090pmol / L135 - 650
TSH21.0mIU / L0.40 - 5.00
PTH9.8pmol / L1.6 - 6.9
Thyroid
Antbodies
10.3IU / L< 4.1
Vit B6 (P5P)1370nmol / L20 - 190
Folate28.7nmol / L> 7.0

A MMA pathology test was 0.181 micromol/L with a reference range of < 0.5. The homocysteine result was 7.1 micromol / L with a reference range of 5.0 – 12.0 with the accompanying comment “methylmalonic acid level indicates that Vitamin B12 deficiency is unlikely”.

A pathology test for vitamin B6 (pyridoxal-5-phosphate) revealed a result of many times above the reference range. The pathology comment indicated that the high levels of B6 “may be associated with sensory neuropathy. Symptoms will gradually resolve after B6 supplements are ceased”.

This demonstrates the potential dangers of using B12 supplements haphazardly without adequately determining the status of B12, folate and pyridoxine (vitamin B6).

Footnotes

  1. Watanabe, F. & Bito, T. (2018) Vitamin B12 sources and microbial interaction. Experimental Biology and Medicine. 243 (2), 148–158.
  2. Commonwealth Bureau of Census and Statistics (1901) Year Book of the Commonwealth of Australia.
  3. Zimmermann, M. (2001) Pocket Guide to Micronutrients in Health and Disease. Stuggart: Thieme.
  4. Zimmermann, M. (2001) Pocket Guide to Micronutrients in Health and Disease. Stuggart: Thieme.
  5. Damayanti, D. et al. (2018) Foods and Supplements Associated with Vitamin B12 Biomarkers among Vegetarian and Non-Vegetarian Participants of the Adventist Health Study-2 (AHS-2) Calibration Study. Nutrients. 10 (6), 722.
  6. Damayanti, D. et al. (2018) Foods and Supplements Associated with Vitamin B12 Biomarkers among Vegetarian and Non-Vegetarian Participants of the Adventist Health Study-2 (AHS-2) Calibration Study. Nutrients. 10 (6), 722.
  7. Green, R. et al. (2017) Vitamin B12 deficiency. Nature Reviews Disease Primers. 3 (1), 17040.
  8. Green, R. et al. (2017) Vitamin B12 deficiency. Nature Reviews Disease Primers. 3 (1), 17040.
  9. Green, R. et al. (2017) Vitamin B12 deficiency. Nature Reviews Disease Primers. 3 (1), 17040.
  10. Elmadfa, I. & Singer, I. (2009) Vitamin B-12 and homocysteine status among vegetarians: a global perspective. The American Journal of Clinical Nutrition. 89 (5), 1693S-1698S.
  11. Key, T. J. et al. (2006) Health effects of vegetarian and vegan diets. Proceedings of the Nutrition Society. 65 (01), 35–41.
  12. Green, R. et al. (2017) Vitamin B12 deficiency. Nature Reviews Disease Primers. 3 (1), 17040.
  13. Flores-Guerrero, J. L. et al. (2020) Association of Plasma Concentration of Vitamin B 12 With All-Cause Mortality in the General Population in the Netherlands. JAMA Network Open. 3 (1), e1919274.
  14. Andres, E. et al. (2013) The pathophysiology of elevated vitamin B12 in clinical practice. QJM. 106 (6), 505–515.
  15. Brown, R. D. et al. (2011) The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population. Medical Journal of Australia. 194 (2), 65–67.

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