B Vitamins

B Vitamins

The B vitamins are a group of 8 water-soluble vitamins necessary for energy production, nervous system function and the production of red blood cells. Some are also involved in the recycling of homocysteine, high levels of which are a key risk factor for a number of conditions including heart disease and Alzheimer’s. (1, 2) Unlike fat-soluble vitamins, the B vitamins cannot be stored, and must be consumed from the diet regularly to avoid the risk of deficiency. Health conditions which decrease B vitamin absorption are associated with symptoms caused by inefficient or blocked metabolic functions, e.g. decreased neurotransmitter (brain chemical) production leading to low mood, or low energy production leading to tiredness. 

Sources

While some B vitamins are found in relatively high amounts within a wide range of foods, others are found in lower amounts and in only very specific foods. Vitamin B12, for example, is only found in animal products, meaning that vegetarians and vegans are at risk of deficiency. The best sources of B-vitamins include meat, fish, eggs, dairy, whole grains, nuts & seeds, fruit & vegetables and legumes. Eating a wide variety of these whole foods on a regular basis should provide adequate intake of all 8 B-vitamins. B vitamins are, however, particularly sensitive to heat, moisture and exposure to air and light, so modern food processing, distribution and storage methods can significantly affect their stability and function. Unless you regularly eat raw, fresh (local) and organic whole foods, the quality of the B-vitamins in your food may be sub-optimal and insufficient for the demands of modern life. Many processed foods are now fortified with B-vitamins in an attempt to overcome vitamin loss during refining and processing. While food fortification could be viewed as beneficial, it should be remembered that highly processed and refined foods (the target for fortification) do not offer the same nutrient quality. Therefore, while they appear to deliver adequate amounts of micronutrients, these foods are inferior to fresh whole food sources. In addition, there are increasing concerns regarding the ‘usability’ of some of the micronutrients added to food. For example, the safety of folic acid, the synthetic form of folate that is used widely in the food and supplement industry, has been questioned in recent years. The basis of the concerns regarding the widespread fortification of breads and cereals with folic acid is that much of the population is genetically less able to use synthetic folic acid than folate. While higher circulating (food-sourced) folate is considered beneficial to health, the role of unmetabolised synthetic folic acid from high folic acid consumption is currently being questioned as a potential risk factor for a number of health conditions. (3)

Absorption

The B-vitamins are generally absorbed in the small intestine via active (saturable) and passive (non saturable) uptake mechanisms. In addition, some B-vitamins (such as niacin and riboflavin) require modification (usually an enzyme-mediated process that releases them from a carrier protein) before they can be absorbed; certain ‘favourable’ conditions (such as the production of enzymes and adequate stomach acid) are required, and if these are not met, absorption can be compromised. Therefore, while the diet may appear to be nutrient rich, there are circumstances where uptake may not be adequate to fulfil needs.

Factors that affect B-vitamin levels (in food and plasma)

Intensive farming methods negatively affect the level of all nutrients within whole foods, including the B-vitamins. In addition, food processing methods either strip out or affect the stability of nutrients within foods (hence the drive to fortify). As the B-vitamins are water-soluble, they are also easily depleted during cooking, especially vegetables cooked in water. As there are so many factors that influence the amount, type and stability of these essential nutrients, and the fact that they are not considered toxic when consumed in excess of the recommended intake, topping up levels via supplementation provides a safety net against deficiency. While it is possible to supplement with individual B-vitamins, because they often play a synergistic role in multiple pathways (riboflavin is, for example, the co-factor required for converting vitamin B6 to its active pyridoxal 5′-phosphate form) they are often found together in supplements as a B-Complex.

Supplementing

When seeking an effective supplement, it is vital to consider three factors: the forms of key nutrients, their bioavailability and the dose used. B-vitamins exist in multiple forms and it is the activated (also known as reduced or remethylated) form that is able to act as a co-factor. Because some B-vitamins are better absorbed in lower amounts (known as fractional absorption), supplements containing ‘mega’ amounts in a one-a-day tablet are not guaranteed to deliver adequate levels (more is not always best!). As the uptake of a nutrient is key to its benefits (it’s not how much you take, it’s how much is absorbed), choosing a B-complex that takes into account the factors that influence the ability of each nutrient’s capacity for absorption and delivers the appropriate level of that nutrient to ensure enhanced uptake will ultimately influence the efficacy of a finished product. Therefore, a product that delivers slow release (to overcome saturable pathways) combined with split-delivery (a smaller dose delivered twice daily rather than a larger once-daily dose) and scientifically established optimal levels of individual nutrients is likely to be the most effective for optimising the key health benefits of the individual nutrients.

Vitamin B1 (thiamine)

Thiamine is essential for energy production and normal heart, nervous system and psychological functioning. Acting as a coenzyme (a molecule that aids the activity of an enzyme) for three enzyme complexes involved in energy-generating pathways, thiamine helps facilitate a series of chemical reactions that result in energy release.  Thiamine is absorbed via both active and passive processes. Active transport is greatest in the small intestine (especially the jejunum and ileum) but it can be inhibited by alcohol consumption or by folate deficiency. At low concentrations, thiamine is taken up by active transport (saturable) and at higher concentrations, absorption also occurs via non-saturable passive diffusion and so high doses of thiamine hydrochloride are generally well absorbed. Thiamine hydrochloride is converted to the active co-enzyme form (thiamine pyrophosphate) involved in fatty acid, amino acid and carbohydrate metabolism. (4) Thiamine deficiency is associated with very heavy alcohol intake (Wernicke-Korsakoff syndrome), persistent vomiting (such as during pregnancy - hyperemesis gravidarum) and due to poor diet (known as beriberi and caused by insufficient intake of thiamine-containing food coupled with high refined carbohydrate intake). There are two types of beriberi, wet and dry. Wet beriberi affects the heart and circulatory system and can cause heart failure in extreme cases. Dry beriberi damages the nerves and can lead to decreased muscle strength, and eventually, muscle paralysis. Beriberi can be life-threatening if it isn’t corrected (5); unless you fall into the above categories you are unlikely to suffer any thiamine-related issues but maintaining adequate intake is still important. Daily requirements depend on the amount of carbohydrate eaten. 0.33 mg of thiamine is required for approximately every 1000Kcal consumed; as such, thiamine intake should be at least 0.8mg per day for women and 1mg for men. Those eating a highly refined carbohydrate diet should consider including more thiamine in their diet. Good sources of vitamin B1 include pork, vegetables, milk, eggs and wholegrain bread.

Vitamin B2 (riboflavin)

Riboflavin exists as free-form riboflavin and as two coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). FMN and FAD play vital roles in a variety of oxidation and reduction reactions in the body necessary for glucose, amino acids, and fatty acids to be converted into energy, thus reducing tiredness and fatigue. The conversion of folate to L-5-methyltetrahydrofolate (5-MTHF) is dependent on FAD, activation of pyridoxine to pyridoxal 5’-phosphate is dependent on FMN, and the synthesis of vitamin B12 is dependent on FAD. A riboflavin deficiency could therefore result in deficiencies of folate, vitamin B6 and vitamin B12 that may, in turn, lead to elevated levels of homocysteine, decreased red blood cell synthesis and impaired iron metabolism. There are two pathways that regulate homocysteine metabolism - transsulfuration and remethylation, and if not appropriately recycled, elevated homocysteine can increase the risk of heart disease, stroke and dementia.(1,2) Transsulfuration is dependent on vitamin B6 and converts homocysteine to cysteine and then to glutathione, with riboflavin then required to convert oxidised glutathione to reduced (active) glutathione.(6) Glutathione is a key antioxidant involved in protecting cells from free-radical-induced oxidative damage. The remethylation of homocysteine to methionine is dependent on vitamin B12, folate and riboflavin. This methylation ‘cycle’ helps to support a healthy nervous system by contributing to the synthesis of neurotransmitters.(7) Riboflavin also contributes to normal vision. As a necessary cofactor for reduced glutathione, the antioxidant that is essential in protecting the eye tissue from oxidative damage, deficiency in riboflavin is linked to the formation of cataracts.(8) The maintenance of normal mucous membranes and skin is also aided by riboflavin.


Most riboflavin in food is FAD, with a small proportion of free-form riboflavin and FMN comprising the remainder. Both FAD and FMN are bound to proteins and, in order to be absorbed by the small intestine, must be converted, with the help of hydrochloric acid and the enzyme phosphatase, to free-form riboflavin. Once absorbed, other enzymes then convert some of the free-form riboflavin back to FMN and FAD. Absorption of dietary riboflavin occurs through an intestinal transport mechanism that becomes saturated at high doses (>20 mg), and absorption can be delayed when taken on an empty stomach. A decrease in absorption is observed in individuals with liver problems such as obstructive biliary disease (in which a blockage of the bile duct reduces bile production), hepatitis and cirrhosis.(9) 


While deficiency in the UK is rare (due to food fortification) it can arise from a poor quality diet or through an inability to absorb dietary sources. The overall result of deficiency is a reduced ability to metabolise fats, which stunts growth and prevents normal development. Signs and symptoms may include badly cracked lips, a dry, painful mouth and tongue, dry skin and bloodshot eyes. The main sources of vitamin B2 are meat and dairy products, although eggs, nuts and leafy green vegetables provide good alternative sources. Adults should consume at least 1.4 mg every day. Riboflavin is light-sensitive, so is best stored in dark containers. In addition, as riboflavin is water soluble, much is lost during boiling and so some raw or lightly steamed vegetables should be included in the daily diet to ensure adequate levels are retained. Mushrooms, spinach and almonds are particularly tasty, excellent sources of vitamin B2. 

Vitamin B3 (niacin)

Niacin is the generic term for the B3 vitamins nicotinic acid and nicotinamide. As with riboflavin, niacin within foods also exists in two coenzyme forms: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). For absorption, NADP must to be converted into NAD and then NAD is further converted, a process that releases free nicotinamide. Nicotinamide and nicotinic acid are absorbed rapidly from the stomach and small intestine with carrier-mediated diffusion at lower concentrations and by passive diffusion at higher concentrations. Niacin contributes to the maintenance of normal skin and mucous membranes. Deficiency leads to pellagra, a disease characterised by inflammation of mucous membranes, skin lesions and diarrhoea. Excessive alcohol consumption associated with poor dietary intake of niacin can lead to severe nicotinamide loss and insufficient absorption. The body also synthesises niacin from the amino acid tryptophan (an essential amino acid which must be consumed from the diet), and the inability to absorb tryptophan (Hartnup’s disease) can therefore manifest as pellagra. As dietary intake of both niacin and tryptophan must be suboptimal for symptoms to manifest, pellagra is rare in the UK. As a supplement, nicotinic acid is the form of niacin that's often used; however, nicotinic acid can induce an unpleasant ‘flush’ reaction, and can also decrease insulin sensitivity when used long-term and so its use in standard health supplements should generally be avoided. (10) Nicotinamide is the preferred form for general supplementation as it has the benefits of not inducing skin flushing or decreasing insulin sensitivity. (11) Niacin is involved in multiple pathways, playing a role in the activity of signalling molecules necessary for the functioning of enzymes important for energy metabolism, nervous system and psychological functioning. The recommended daily intake of niacin is 16 mg and it is found in liver and organ meats as well as eggs, fish and legumes. 

Vitamin B5 (pantothenic acid)

Pantothenic acid, via coenzyme A, is involved in the synthesis of some neurotransmitters, steroid hormones and vitamin D, and also contributes to fat and carbohydrate metabolism required for energy production. Deficiency of pantothenic acid is very rare as it is found in small amounts in all animal and plant foods. Foods particularly rich in pantothenic acid include liver and organ meats as well as most animal-origin foods, whole grains, legumes and most fruits and vegetables. When found in foods, most pantothenic acid is in the form of coenzyme A and acyl carrier proteins and must be converted into free pantothenic acid for absorption to take place, and because the active transport system for pantothenic acid uptake is saturable, absorption will be less efficient at higher concentrations of intake. After absorption, pantothenic acid is converted to the sulphur-containing compound pantetheine which is then reconverted back into coenzyme A. Studies have found that supplementing with pantothenic acid can be beneficial for the production of steroid hormones (12) which are important for our stress management systems. Adults should consume at least 6 mg daily from a range of food sources.

Vitamin B6 (pyridoxine)

While vitamin B6 exists in 6 forms, only the pyridoxal-5-phosphate form has cofactor activity required for approximately 100 enzymes that are important for the metabolism of neurotransmitters and other neuroprotective compounds. Vitamin B6 also plays a role in energy metabolism and is important in the synthesis of haemoglobin, the component of blood that binds and transports oxygen around the body. Additionally, vitamin B6 contributes to the normal function of the nervous and immune systems and helps maintain normal psychological function and hormonal activity. While rare, a number of inborn errors of vitamin B6 metabolism exist that can compromise the metabolism of vitamin B6 to pyridoxal-5-phosphate, usually manifesting in symptoms of epilepsy. (13) Vitamin B6 is present in a wide range of foods including meats, pulses, cereals, vegetables and fruit. In addition, vitamin B6 is also produced by bacteria in the colon. While most B vitamins can be taken in high amounts long term (any excess will simply flush out in the urine), taking supplementary B6 that provides >20 mg per day long term can lead to nausea, heartburn and tingling of the fingers and toes. In most cases, symptoms will cease once supplementation is stopped. Adults should aim to eat around 1.4 mg per day from whole food sources and if supplementing should not exceed 25 mg daily unless advised by a healthcare practitioner. Individuals who are particularly at risk of low B6 status and would most likely benefit from supplementation include those with impaired renal function, autoimmune disorders such as rheumatoid arthritis and people with alcohol dependence.

Vitamin B7 (biotin)

Biotin is a coenzyme necessary for the synthesis of fatty acids, amino acids and glucose from non-carbohydrate sources such as pyruvate and lactate. Biotin also plays an important role in maintaining normal hair and skin, and in the psychological and nervous system function. Cheese, organ meats, whole wheat and soybeans are good sources of biotin, as well as eggs, mushroom, leafy greens and legumes. As biotin is found in a wide range of foods, most people will have adequate biotin in the diet; however, while rare, signs of biotin deficiency include skin rashes, hair loss and brittle nails, reflecting biotin’s use in supplements that are often targeted specifically at hair, nail and skin health. Low biotin status may occur in pregnancy, in alcoholics and in individuals with digestive and/or absorption issues such as following gastrectomy (surgery to remove the stomach). These conditions require biotin supplementation. (14) The recommended daily intake is 50 μg, but intake in excess of this is absorbed efficiently without reaching saturation.

Vitamin B9 (folate)

Food folates are mainly present as polyglutamates that need to be enzymatically modified before absorption, and absorption of natural food-sourced folate is generally actually lower than the synthetic folic acid form that is widely found in fortified food and some supplements. However, neither folic acid nor food folate are biologically active and must be converted to 5-methyltetrahydrofolate (5-MTHF) through a multi-step process that is dependent on the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). Many people do not produce adequate or effective MTHFR, with significant effects. For example, if the body’s ability to reduce folic acid to 5-MTHF is exceeded (approximately >200 mg/day), unmetabolised folic acid may accumulate in the bloodstream. (15) While the health effects of circulating unmetabolised folic acid are currently unclear, it is generally accepted that the effects are undesirable. (3) Many supplement manufacturers are switching to folate (5-methyltetrahydrofolate) to avoid use of the synthetic folic acid. Folate, via its actions in the folate cycle, is vital for the formation of red blood cells, the recycling of homocysteine and psychological functioning and is best known for its role in preventing neural tube defects in newborns. As elevated homocysteine is a known risk factor for mood-related disorders and heart complications, and cognitive decline, increasing folate may be prudent to aid in the recycling of homocysteine. As with the other B vitamins, folate is found in high levels in liver as well as leafy green vegetables and legumes. Anyone consuming a diet rich in vegetables will be getting the recommended 400mcg per day of folate but women trying to conceive or in the early phases of pregnancy may need to supplement as requirements increase. Using the reduced form of folate, 5-methyltetrahydrofolate, overcomes bioavailability issues associated with standard folate and may be particularly effective, given the large number of individuals with inadequate or ineffective MTHFR. (16)

Vitamin B12 (cobalamin)

Vitamin B12 is obtained primarily from fish, meat and dairy products. Although B12 is found in fortified cereals, because it is not present in plants deficiency can occur in strict vegetarians and vegans. To be absorbed, ingested food-bound B12 must first be freed from its protein carrier via the act of peptic digestion, a process requiring adequate stomach acid. The ‘free’ cobalamin binds to intrinsic factor, a glycoprotein secreted by parietal cells within the stomach wall, and is absorbed via a carrier-mediated (saturable) pathway. The processes involved in B12’s uptake are compromised in certain conditions such as inflammatory bowel disease, in older individuals (>75 years) and also by certain drugs including: metformin (a drug used in the management of diabetes), proton pump inhibitors (antacids), angiotensin-converting enzyme (ACE) inhibitors (for the management of high blood pressure) and antihistamines, thereby increasing the risk of deficiency. (17)


B12 is used as a coenzyme for a number of reactions involved in the synthesis of haemoglobin (required for the transport of oxygen in red blood cells). Deficiency can cause weakness, fatigue, loss of appetite, constipation and anaemia. Low vitamin B12 status without full deficiency can have a number of neurological implications, including numbness of the hands and feet, balance loss, confusion, memory loss, and – in the advanced stages – depression and dementia. The recommended daily intake of 2.5μg can be achieved easily from animal products, particularly fish and beef. Vegetarians and vegans must source B12 from fortified foods or supplements. Uptake of B12 (bound to intrinsic factor) is mainly in the ileum by a process of ‘fractional absorption’ in which the absorption capability decreases as the oral load increases. Optimal uptake is therefore achieved with lower intakes and it is estimated that at intakes of around 1 mg, 50% is absorbed but that at 25 mg only 5% is absorbed. While some B12 can be absorbed by passive diffusion (thus unbound to intrinsic factor) only around 1% of dietary B12 is absorbed by this pathway. (18) 

Ingredient



Thiamine – vitamin B1 

(thiamine hydrochloride)








Riboflavin – vitamin B2 (riboflavin-5-phosphate)






Niacin – vitamin B3

(nicotinamide)




Pantothenic acid – vitamin B5

(calcium D pantothenate)







Pyridoxine - vitamin B6 (pyridoxal-5-phosphate)





Biotin – vitamin B7

(D-biotin)















Folate – vitamin B9 

([6S]-5-methyltetrahydrofolate,as Quatrefolic®)


















Vitamin B12

(methylcobalamin) 




Unique benefits of the form Igennus uses


Thiamine hydrochloride is highly water-soluble and absorbed by both diffusion and active transport mechanisms, whereafter it undergoes rapid metabolism to thiamine pyrophosphate.




As with many B-vitamins, riboflavin must be converted to its active form – riboflavin-5-phosphate – in order for it to be utilised by the body. As absorption of riboflavin occurs in the upper gastrointestinal tract, a compromised digestive system can adversely affect the body’s ability to convert riboflavin to riboflavin-5-phosphate. Our supplements deliver body-ready riboflavin-5-phosphate.



Niacin can induce side effects that include flushing and itching of the skin, and decreased insulin sensitivity. For this reason we use the nicotinamide form.




Calcium D pantothenate is the commercially available form of vitamin B5 and is frequently used in combination with other B vitamins in B-complex formulations



Vitamin B6 exists in 6 forms but only the pyridoxal-5-phosphate form has cofactor activity. Several inborn errors of B6 metabolism exist, which can compromise vitamin B metabolism to pyridoxal-5-phosphate – required as a co-factor for approximately 100 enzymes that are important in the metabolism of neurotransmitters and other neuroprotective compounds.



There are eight different forms of biotin, but only one of them – D-biotin – occurs naturally and is fully active.


Folic acid refers to the oxidised synthetic form of vitamin B9 that is used in many dietary supplements and in food fortification. Folate refers to the various tetrahydrofolate (THF) derivatives naturally found in food. Unlike natural folates, which are metabolised to THF in the mucosa of the small intestine, folic acid undergoes initial reduction and methylation in the liver, where conversion to the THF form requires dihydrofolate reductase. The low activity of this enzyme in the human liver, combined with high intake of folic acid, may result in unnatural levels of unmetabolised folic acid (UMFA) entering the bloodstream. There are increasing safety concerns surrounding high intake of folic acid, due to the presence of UMFA. 


The MTHFR gene is responsible for producing methylenetetrahydrofolate reductase, the enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate required for homocysteine breakdown.   Several mutations in the MTHFR exist that can compromise an individual’s capacity to produce 5-methyltetrahydrofolate and can lead to unhealthy levels of circulating homocysteine. 


Quatrefolic® provides the metabolically reduced folate form utilised and stored in the human body, as (6S)-5-methyltetrahydrofolate, and may benefit certain genetic defects that influence folate metabolism. Quatrefolic® overcomes issues related to MTHFR gene mutations as well as accumulation of unmetabolised folic acid (UMFA) arising from standard folic acid supplementation.


Methylcobalamin is the natural form of vitamin B12, whereas cyanocobalamin (the cheaper cyanide-containing form of vitamin B12 found in abundance in most vitamin B-complex supplements) is a synthetic source of vitamin B12.   Methylcobalamin is the specific form of B12 needed for nervous system health; unlike cyanocobalamin, methylcobalamin is better absorbed and is retained in higher amounts within tissues.


Table 1. Benefits of the forms of supplemental B vitamins used in Igennus products

Vitamin


Thiamine (B1)


Riboflavin (B2)


Niacin (B3) (as nicotinamide)


Pantothenic acid (B5) 


Vitamin B6 


Biotin (B7)


Folate (B9) 


Vitamin B12 

Reference Intake


1.1mg


1.4mg


16mg


6mg


1.4mg


50µg


200µg


2.5µg

Tolerable Upper Limit


n/a


n/a


16mg


n/a


25mg


n/a


1mg


n/a

Table 2. B Vitamins – Reference Intake and Tolerable Upper Limit


References:

  1. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015 Jan 10;14:6. 
  2. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Ann Rev Nutr. 2016 Jul 17;36:211-39. 
  3. Cho E, Zhang X, Townsend MK, Selhub J, Paul L, Rosner B, Fuchs CS, Willett WC, Giovannucci EL. Unmetabolized Folic Acid in Prediagnostic Plasma and the Risk of Colorectal Cancer. J Natl Cancer Inst. 2015 Sep 15;107(12):djv260. 
  4. Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol. 2012 Feb 4;12:4. doi: 10.1186/1472-6904-12-4. 
  5. Lonsdale D. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med. 2006 Mar;3(1):49-59. 
  6. Marashly ET & Bohlega SA. Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine. Front Neurol. 2017 Jul 20;8:333. 
  7. Saedisomeolia A, Ashoori M. Riboflavin in Human Health: A Review of Current Evidences. Adv Food Nutr Res. 2018;83:57-81. 
  8. Bhat KS. Nutritional states of thiamine, riboflavin, and pyridoxine in cataract patients. Nutr Rep Int 1987;36:685-692. 
  9. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. 2003 Jun;77(6):1352-60. Review. 
  10. Heemskerk MM, van den Berg SA, Pronk AC, van Klinken JB, Boon MR, Havekes LM, Rensen PC, van Dijk KW, van Harmelen V. Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B. Am J Physiol Endocrinol Metab. 2014 Apr 1;306(7):E808-13.  
  11. Bechgaard H, Jespersen S. GI absorption of niacin in humans. J Pharm Sci. 1977 Jun;66(6):871-2. 
  12. Jaroenporn S, Yamamoto T, Itabashi A, Nakamura K, Azumano I, Watanabe G, Taya K. Effects of pantothenic acid supplementation on adrenal steroid secretion from male rats. Biol Pharm Bull. 2008 Jun;31(6):1205-8. 
  13. Surtees R, Mills P, Clayton P. Inborn errors affecting vitamin B6 metabolism. Future Neurol 2006, 5:615 
  14. Zempleni J, Mock DM. Biotin biochemistry and human requirements. J Nutr Biochem. 1999 Mar;10(3):128-38 
  15. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997 Jun;65(6):1790-5. 
  16. Tsang BL, Devine OJ, Cordero AM, Marchetta CM, Mulinare J, Mersereau P, Guo J, Qi YP, Berry RJ, Rosenthal J, Crider KS, Hamner HC. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015 Jun;101(6):1286-94. 
  17. Romain M, Sviri S, Linton DM, Stav I, van Heerden PV. The role of Vitamin B12 in the critically ill--a review. Anaesth Intensive Care. 2016 Jul;44(4):447-52. Review. 
  18. efsa.europa.eu/sites/default/files/efsa_rep/blobserver.../ndatolerableuil.pdf  

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