Overview

Vitamin B6 (pyridoxine) is a water-soluble nutrient that cannot be made in the human body. You need to get B6 from the foods you eat or through nutritional supplements. This is a part of the B Vitamins group and is important for everyday functioning.

The functional (active) form of vitamin B6 is the Pyridoxal 5’ phosphate (PLP). PLP is a coenzyme (smaller molecules that help enzymes create a reaction in the body). The range of B6 in the blood is usually measured in terms of PLP levels.

Starting from the breaking down of carbohydrates, fats, and proteins to supporting brain health, PLP helps more than a hundred enzymes in the body to do their job right.

It is not surprising that B6 is considered a very important B vitamin. Here are some of the top benefits of maintaining right B6 levels in the blood.

The Story Behind Vitamin B6

It was only in the early 1900s that physicians and pathologists started working on the idea of inadequate nutrition leading to diseases. The idea that lack of nutrition can cause a variety of health conditions including death was intriguing to the great minds.

Scientists from the Merck Group of Pharma in the early 20th century played a great role in developing B Group vitamins on an industrial scale and this paved the way for the easy availability of B complex supplements to match growing needs in the community.

In 1934, Paul Gyorgy, an American biochemist and nutritionist was experimenting on rats, feeding them artificially created diets rich in already discovered B vitamins (B1 and B2).

He discovered that the rats developed skin allergies with the diet and when he fed them baker’s yeast, the condition disappeared. 

He then extracted a particular compound from the yeast that helped cure skin allergies and named it vitamin B6. Later, Gyorgy and his fellow scientists also ended up extracting B6 from wheat germ and fish.

Paul Gyorgy is also known for the discovery of vitamin B2 and biotin and was later awarded the National Medal of Science for his efforts.

Molecular aspects

When you obtain vitamin B6 through natural sources, fortified foods, or supplements, it enters the stomach and then moves to the small intestine. Jejunum and ileum are two parts of the small intestine and B6 is absorbed here.

The process of absorption is known as passive diffusion (the molecules flow easily with no effort from a region of high concentration to a region of low concentration). The absorbed molecules are acted upon by a protein enzyme known as alkaline phosphatase. The vitamin is then converted to PLP in the jejunum’s inner layer.

PLP is passed on to the tissues and it helps the various enzymes in the body work effectively.

The remains of B6 after it gets converted to PLP are sent out through the urine. One of the major products sent out is 4-pyridoxic acid. In fact, up to 60% of ingested B6 is sent out as 4-pyridoxic acid.

People whose bodies do not absorb the right amounts of vitamin B6 have negligible 4-pyridoxic acid in the urine, and this is a clear indication of B6 deficiency.

Did You Know?

Did you know that vitamin B6 is considered a complementary and alternative therapy for children diagnosed with autism?

From the time vitamin B6 was identified, there has been a group of scientists attempting to treat neurological disorders with these. The studies started in the 1950s for people with schizophrenia. They were treated with extra high doses of vitamin B6 and improvements were noted. 

The Autism Research Institute (ARI) noted that about 49% of children who were treated with a combination of vitamin B6 and magnesium supplements showed improvements.

The relationship between vitamin B6 and autism is still being analyzed globally. We will hopefully find solid results very soon. 

Recommended values

The Dietary recommended Intake (DRI) of vitamin B6 was set by the Food and Nutrition Board. The values depend on age and gender.

What Happens When You Take Excess Of Vitamin B6

While mildly excess doses of vitamin B6 don’t cause any adverse effects, when you consume very high oral doses of B6 supplements for an extended period of time, it can result in certain sensory, skin, and gastric impairments.

Severely high doses of B6 can result in:

Here is a table that shows the daily tolerable upper limits for vitamin B6 in the body. Consuming more B6 than the levels mentioned here will cause the above side effects.

What Happens When You Have Vitamin B6 Deficiency

Usually, a person will not be deficient in just vitamin B6. He/she will have lower concentrations of other B complex vitamins too. Mild vitamin B6 deficiency does not show a lot of symptoms. 

Severe deficiency or a prolonged period of deficiency will result in the following conditions.

In infants and younger children, lack of vitamin B6 is known to cause irritability and seizures. 

Non-genetic factors affecting Vitamin B6 levels

Genetic association

There are two genes that cause people to require more vitamin B6 than the usual recommended ranges. 

ALPL

The ALPL gene plays a role in breaking down vitamin B6 from complex to simpler forms. It produces enzymes that help in clearance of B6.

A particular variant (type) of the gene can cause 12-18% lowered vitamin B6 rates in the body. Individuals with this type are likely to require more vitamin B6 levels.

Compensate by eating vitamin B6 rich foods, consume oral B group supplements and choose fortified foods. Around 89% Africans, 52% Caucasians, and 44% Asians carry this type of gene.

MTR

The MTR gene is responsible for converting folate into sources usable by the body.

A particular type of the gene is said to result in reduced MTR activity and causes a 30% increase in the risk of developing colorectal cancer. These individuals are likely to require more vitamin B6 levels (about twice more than the DRI values) to bring down the risk.

Oral supplements help match increased B6 needs. Fortified foods also make a difference.

Around 31% of Africans, 17% Caucasians, and 13% Asians carry this type of gene.

Recommendations for healthy Vitamin B6 levels

Summary

  1. Vitamin B6 is a water-soluble nutrient available in food sources like poultry, red meat, legumes, grains, and fruits and vegetables. 
  2. Prolonged or extreme vitamin B6 deficiency can show out symptoms like dermatitis, lowered immunity levels, mouth ulcers, and neurological conditions like depression and confusion.
  3. While moderately excess amounts of vitamin B6 are relatively safe, extremely high doses can cause uncontrolled body movements, photosensitivity, and gastric issues.
  4. Some of the common causes of vitamin B6 deficiency are bad diet habits, excessive smoking, the presence of renal and autoimmune diseases, and the use of certain types of medications. 
  5. Some people are genetically designed to have lower absorption rates of vitamin B6 in the body. They will have to compensate with fortified foods and supplements.

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1265394/?page=1

https://pubmed.ncbi.nlm.nih.gov/23183295/

https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/vitamin-b-complex.html

https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

https://www.massgeneral.org/children/autism/lurie-center/vitamin-b6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357176/

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/alpl

Folate, also known as vitamin B9, is a water-soluble B vitamin. It is naturally found in many folate-containing foods like spinach, broccoli, avocados, and lentils.

Apart from natural sources, the synthetic form of folate, folic acid, is also sold as a supplement. This form is supposedly absorbed better by the body. 

Lucy Wills, a researcher, was the first one to identify folate and its function, in 1931. She demonstrated that anemia in pregnant women could be prevented/reversed with brewer's yeast. In the late 1930s, folate was isolated from brewer's yeast.

It was first extracted from spinach in 1941 - the term "folic" is from the Latin word 'Folium', which means leaf. 

Further, the crystalline form of folate was extracted in 1943, which was the basis of the synthesis of Aminopterin, a derivative of folic acid.

Aminopterin was the first-ever anticancer drug developed, and its clinical efficacy was proved in 1948. 

The Significance of Vitamin B9

The Vitamin D–Folate Hypothesis

Vitamin D and folate are linked by their disparate sensitivities to Ultra Violet Radiation (UVR). While UVR stimulates the production of Vitamin D in the skin, it degrades folate through oxidation.

The hypothesis suggests that skin pigmentation may have evolved to maintain a balance in the levels of these vitamins.

The increased pigmentation observed in high-UVR regions was attributed to the need for protecting folate levels, while the depigmentation is low-UVR regions was a result of facilitating adequate vitamin D levels. 

The VDR gene provides instructions for making a protein called Vitamin D Receptor, which allows the body to take in vitamin D. The different variants of the VDR genes are present in different frequencies across populations. 

For example, the common VDR variant Fok1 has a lower frequency in African populations compared to European/Asian populations, while the frequency of another variant, Cdx2, is highest in African populations and the lowest in Europeans.

The difference in the frequency of these alleles across different ethnic populations can be attributed to the different UV regimes. 

Several relationships are reported between UVR and folate metabolism genes. Two main enzymes involved in folate metabolism, serine hydroxymethyltransferase (SHMT) and methylenetetrahydrofolate reductase (MTHFR), have been studied to be UVR responsive.

For example, in regions where there’s a higher exposure to UVR, the frequency of a thermolabile MTHFR variant, C677T, is less. 

These findings collectively provide strong molecular support to the Vitamin D-Folate hypothesis and showcase the existence of interactions between UVR, skin type, and vitamin D and folate genes.

The Recommended Dietary Allowance (RDA) For Folate

Typically, the body has around 10-30 mg of folic acid stored in the liver, and 5-15 ng/mL in the blood. 

In order to understand the recommended dosage of folic acid, the following terms are important:

It is important to note that the bioavailability of folate depends on the source. Synthetic vitamin B9 (folic acid) is readily absorbed (about 85%) into the body, compared to folate from food sources (about 50%). Dietary Folate Equivalent (DFE) was developed to reflect the total amount of bioavailable folic acid.

1 mcg DFE = 1 mcg food folate = 0.6 mcg of fortified foods/supplements taken with foods = 0.5 mcg folic acid in the form of a supplement (taken on an empty stomach).

A healthy adult needs 400mcg DFE folate daily. Pregnant women need 600 mcg of folate per day to meet the requirements of the growing fetus as well.

Genetics And Folate status

MTYL1 Gene

MTYL1 gene is located on chromosome 2. 

It codes for myelin transcription factor 1, which is expressed in the neuronal tissues.

This transcription factor converts postnatal human fibroblasts into induced neuronal cells, thus playing a big role in cognitive function.

A variant in this gene is linked with serum folate levels

This gives an initial idea of an association between folate levels and depression and schizophrenia. 

rs12611820

A variation in this gene, with a C genotype, is reported to be linked to serum folate levels. In a GWAS study conducted, a single copy of the C allele was seen to decrease the serum folate levels by 0.169 units. 

MTLY1 gene (rs12611820) outcomes

MTHFR Gene

The MTHFR gene is located on chromosome 1. It codes for an enzyme called methylenetetrahydrofolate reductase, which plays a role in processing amino acids. This enzyme is involved in a chemical reaction that processes folate to its primary form (5-methyl tetrahydrofolate) found in the blood.

This compound is necessary for the multistep process that converts homocysteine to methionine.

In the normal functioning of the body, there is a balance between homocysteine and folate levels. However, when this balance is disturbed, it leads to health effects.

Mutations in the MTHFR gene have been associated with high homocysteine and low folate levels, both of which are harmful to the body.

rs1801133The most-studied variant of the MTHFR gene is 677T←C (rs1801133) in exon 5. The 677T variant has been studied to be less effective in the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.

Thus, the serum folate concentration is lower in individuals with the 677TT genotype than in those with 677CC or 677CT genotypes.

MTHFR gene (rs1801133) outcomes

Can Folate Deficiency Be Inherited?

Inherited folate deficiency, also called Hereditary folate malabsorption, is a disorder that interferes with the body’s ability to absorb folates from food. Infants with this condition have normal folate levels at birth; however, they begin to show signs of folate deficiency within the first few months of life. Feeding difficulties, diarrhea, and failure to thrive are common signs observed in infants with inherited folate deficiency. 

This condition is inherited in an autosomal recessive manner. 

Now, for the expression of a recessive trait, both parents must pass on their recessive versions of traits.

A random process selects the gene to be passed down to the next generation.

In the case of autosomal recessive conditions, there is a 25% chance of occurrence.

If just one parent passes it on, the child will remain healthy but acts as a carrier of the gene.

Carriers could potentially pass it on to the coming generations.

Inheritance Of Folate Deficiency: Autosomal Recessive

Folate/Folic Acid Deficiency

Folate deficiency is usually a result of poor diet, alcoholism, and malabsorptive disorders. Hence the prevalence of isolated folate deficiency is pretty rare; other nutritional deficiencies mostly accompany it.

What Are The Signs And Symptoms Of Folate Deficiency

Causes of folate deficiency

  1. An improper diet. Green leafy vegetables, fruits, yeast, and meats are sources of naturally available folate. If this is lacking in your diet, you may be at risk of developing anemia.
  2. Drinking too much alcohol
  3. Some digestive disorders, like celiac disease and Crohn’s disease, certain types of cancers, and severe kidney problems that require dialysis. 
  4. Some medications, like those used for seizures, may also cause this condition.
  5. Pregnancy can demand more folate in order to meet the requirements of the growing fetus as well. 
  6. A congenital condition, where a person has a genetic mutation that hinders the body from absorbing the natural form of folate.
  7. Changes in the digestive tract in the older age group (65 and above) can result in insufficient folate absorption.

Who’s at risk for folate inadequacy

  1. People with Alcoholism: Alcohol affects folate levels in the following ways
    1. interferes with folate absorption and hepatic uptake
    2. accelerates folate breakdown
    3. increases its renal excretion 
  2. People with certain medical conditions: People with malabsorptive disorders like celiac disease and inflammatory bowel disease may absorb less folate than people without these disorders
  3. Pregnant women: The folate requirements increase during pregnancy because of its role in DNA synthesis. This increased requirement may be difficult to meet through diet alone. Thus, prenatal vitamins containing adequate amounts of folic acid and other nutrients are recommended during pregnancy. 

Overdose and toxicity

It is rare to reach a toxicity level from consuming folate via natural food sources. An arbitrary upper limit for folic acid on a daily basis is 1000mcg. 

Dangers of folate toxicity

Folate-containing foods

Since vitamin B9 is water-soluble, it needs to be replenished in the body on a daily basis. There are a lot of sources of vitamin B9. 

Folate supplements

Folate is also available in the form of dietary supplements. Multivitamin supplements and B-complex tablets usually contain folic acid. These supplements are advised for individuals that have a mutation in the MTHFR gene.

It is recommended to take the active form of folic acid (L-methyl folate, or 5-MTHF). It is beneficial to have folic acid supplements daily to ensure optimal nutrient health for an individual. 

Summary

Folate is an important vitamin that helps in cell replication, production of RBCs, and the maintenance of healthy cells in the body.

It is a water-soluble vitamin and should be included in the daily diet for a healthy individual.

There are vast implications if an individual has folate deficiency, with symptoms ranging from mouth sores to life-threatening anemia.

Pregnant women should also be wary of the amount of folic acid in their diet, as it can heavily impact the health of the fetus. 

An individual can have inadequate folic levels because of an unbalanced diet, genetic variations, or other risk factors.

Folate deficient individuals can meet their requirements by adjusting their diet or taking supplements. When it comes to supplements, the dosage is an important factor.

Excess folate consumption can lead to folate toxicity the could result in a decline in cognition.

Thus, as always, it is recommended to consult a physician before starting any supplementation. 

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK499994/
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954959/
  3. https://pubmed.ncbi.nlm.nih.gov/22992775/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123605/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667971/

Overview

Vitamin B12 is one among the B vitamins and is also known as Cobalamin, since it contains the mineral called cobalt. This water-soluble vitamin cannot be made in the body and needs to be obtained from the food we eat. 

Vitamin B12 helps with the below functions in the body:

Vitamin B12 deficiency can cause irreversible damage to the body and is, unfortunately, an increasing problem in the countries around the world. There are several reasons why your body might be receiving less vitamin B12 than the recommended daily intake. We will talk about that in the coming sections.

The Story Behind Vitamin B12

The story behind vitamin B12 goes as far back as the 1850s and includes the efforts of many renowned pathologists, physicists, and scientists.

Thomas Addison was an English physicist working in the famous Guy’s Hospital in London. Addison was working on the different causes and effects of diseases and identified a condition called Pernicious anemia.

Pernicious anemia is characterized by abnormal and insufficient Red Blood Cells. This disease was considered fatal between the 1800s and early 1900s. 

It took almost 40 years to find a cure for pernicious anemia. George Hoyt Whipple, an American pathologist, had intensely analyzed the effects of food on the disease and concluded that a liver-based diet in dogs helped increase RBC count in the blood. This led to the identification of liver as a food-based treatment option for treating Pernicious anemia. 

While doctors knew this diet helped reverse the condition, they didn’t fully understand why.

It took another 30 years for scientists to successfully identify and remove a water-soluble compound from liver samples and confirm that this was what actually treated the anemia. This compound’s structure was defined in 1956 and was named ‘vitamin B12’. 

There were a total of five Nobel Prizes awarded to scientists around the world for the studies related to vitamin B12. We have these great minds to thank for bringing to the world’s notice one of the most important B vitamins.

Molecular Aspects- Getting Technical

Once you consume foods rich in Vitamin B12, gastric juices in the intestine help release the vitamin from the food. Once the vitamin is free, a particular protein called R-binder attaches itself to B12 and prevents the acids in the stomach from destroying the vitamin B12 molecule. 

Now, the R-binder protein takes B12 to its next destination, the intrinsic factor (IF). This is also a kind of protein produced in the stomach. 

From here, the B12 reaches an important carrier protein called Transcobalamin II. This helps circulate B12 to different parts of the body.

For the proper absorption and circulation of vitamin B12, the gastrointestinal tract and its help are vital. This is why people with gastric issues may have problems absorbing B12. 

Did You Know?

Did you know that your body stores enough quantities of vitamin B12 for future use? If you have been getting enough or more than the daily recommended values of vitamin B12, a certain amount keeps getting stored in the liver. This reserve can last for anywhere between 3 and 5 years! 

The body knows the importance of vitamin B12 and hence keeps a stock of it for your benefit.

If you have been consistently getting lesser vitamin B12 than what’s needed, your excess reserve is continuously used and you start getting signs of vitamin B12 deficiency only after a couple of years.

The rate at which the stored levels are depleted (turnover rate) depends on your body’s ability to get and absorb vitamin B12. Healthy individuals with normal absorption rates may have a lesser turnover rate than those with gastrointestinal issues or pernicious anemia.

Recommended values

The Dietary Reference Intake (DRI) is a reference for assessing the general needs of vitamin B12 levels in children and adults on an everyday basis.

What Does Excess Of Vitamin B12 Lead To?

 Excess of vitamin B12 does not cause toxicity in the body as fat-soluble vitamins do. 

Vitamin B12 that is ingested is used for everyday functioning and a part of it keeps getting stored in the liver as a reserve. The remaining doses are easily excreted out through urine. Hence it is not very easy to get an overdose when it comes to B12.

However, if you are on vitamin B12 shots, supplements, and a diet rich in red meat, poultry, and dairy products simultaneously, excess quantities of the vitamin may cause dizziness, nausea, and headaches in some individuals. 

What Are The Symptoms Of Vitamin B12 Deficiency?

When you are consuming lesser vitamin B12 than the DRI values, you are at risk of developing the below conditions.

Non-genetic Factors Affecting Vitamin B12 Levels

Genetic association

The FUT2 gene encodes a protein that helps a harmful bacteria called Helicobacter pylori attach itself to the digestive tract. This bacteria can inhibit the absorption of vitamin B12 in the body. Here is a list of FUT2 gene variants that can result in increased/ decreased levels of vitamin B12 in the body.

The TCN2 gene encodes a protein that helps in the final transportation of vitamin B12 from the blood to the cells in the body. A certain variant of the TCN2 gene in the Caucasian population is known to cause increased/decreased levels of B12 in the body.

Recommendations for healthy Vitamin B12 levels

Maintaining healthy vitamin B12 levels in the body is beneficial for overall health maintenance. It keeps you energetic, strong, and healthy. Here are expert recommendations on getting your daily dose of vitamin B12 right.

Summary

  1. Vitamin B12 is a water-soluble and essential  vitamin that cannot be made in the body. It is available from ingredients you eat, in fortified packaged foods, and in the form of oral supplements and vitamin B12 shots.
  2. Vitamin B12 deficiency can cause a variety of problems including neurological abnormalities, anemia, fatigue and tiredness, and memory issues. It is very difficult to have vitamin B12 overdose. Higher levels are removed from the body through urine.
  3. Non-genetically, factors like age, medications consumed, pregnancy and lactation, and a vegetarian/vegan lifestyle can increase your risk of being vitamin B12 deficient.
  4. Genetically, some people are not able to absorb vitamin B12 from foods and may have lesser levels than what is normal.
  5. A simple blood test will show your vitamin B12 levels. Genetic testing will let you understand if your body is likely to require more vitamin B12 than others. Getting these tests done will help you plan your diet and supplement needs. 

Reference

http://www.animalresearch.info/en/medical-advances/timeline/pernicious-anaemia/

https://ods.od.nih.gov/factsheets/VitaminB12-Consumer/

https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

https://www.ncbi.nlm.nih.gov/books/NBK114329/ https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/vitamin-b12

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