Vitamin B9

Folate, a water soluble B vitamin, plays a crucial role in various aspects of health and wellness including DNA synthesis, repair, and cell division.  Its synthetic form, folic acid, is widely used in dietary supplements and fortified foods. 

Adequate folate intake is essential, especially during pregnancy to prevent neural tube defects in the developing fetus. 

While folate naturally occurs in foods like leafy greens, fruits, and legumes, folic acid supplementation is recommended for pregnant women and individuals at risk of deficiency due to certain medical conditions or medications. 

Understanding the importance of folate and folic acid can help individuals make informed choices about their dietary and supplementation habits.

Overview of B Vitamin Family

The B vitamin family comprises a group of water-soluble vitamins that play critical roles in numerous physiological processes essential for human health. 

Comprising eight distinct vitamins, it includes riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12), these vitamins are intricately related and often function as coenzymes in various metabolic pathways. 

VItamin B12 is the only B vitamin that can be stored in the body, in the liver.  All other B vitamins are quickly excreted through the urine, therefore they require daily repletion.  

Individually, the B vitamins contribute to energy production, DNA synthesis, nervous system function, and red blood cell formation, among other vital functions. Collectively, the B vitamins are indispensable for maintaining overall health and well-being, underscoring their importance in supporting various physiological systems within the human body.

Folate (Vitamin B9)

What is Folate? 

Folate is a water-soluble B vitamin that serves as a crucial coenzyme in various biochemical reactions essential for DNA synthesis, repair, and methylation. 

Its active form, tetrahydrofolate (THF), acts as a carrier of one-carbon methylation units involved in the synthesis of nucleotides and amino acids. Natural folate primarily occurs in foods such as leafy greens, legumes, and fruits.  Synthetic folic acid is also available as a supplement.  

Folate deficiency can lead to various health complications, including anemia and neural tube defects, emphasizing the importance of adequate intake through diet or supplementation.

What is the Difference Between Folate and Folic Acid?

Folate and folic acid share similarities in their role as essential B vitamins crucial for cellular metabolism, particularly in DNA synthesis and methylation processes. Both compounds serve as coenzymes in one-carbon transfer reactions, facilitating the production of nucleotides and amino acids necessary for cell growth and repair. 

However, a notable difference lies in their chemical structures and sources. 

Folate refers to naturally occurring forms of the vitamin found in foods like leafy greens, legumes, and fruits, while folic acid represents the synthetic form commonly used in dietary supplements and fortified foods due to its higher stability and bioavailability. 

Within the body, dietary folate undergoes enzymatic conversion to THF through a series of steps involving dihydrofolate reductase. 

Upon ingestion, folic acid undergoes conversion in the liver to produce the biologically active form of folate, 5-methyltetrahydrofolate (5-MTHF), which can then participate in cellular processes. 

Despite these differences, both folate and folic acid play critical roles in maintaining overall health and preventing folate deficiency-related conditions such as anemia and neural tube defects.

Functions of Folate: What Does Folate Do in the Body?  [2., 10. 14.]

Vitamin B9 exerts a wide range of beneficial effects on human health, which are due to its role in methylation and DNA expression.  The active form of folate, 5-methyltetrahydrofolate, is responsible for its functions.  

As the active form of folate, 5-methyltetrahydrofolate (5MTHF) plays a vital role in numerous biochemical processes in the body.  It is the primary circulating form of folate; it serves as a methyl donor in the conversion of homocysteine to methionine, a crucial step in methylation reactions. 

5MTHF’s essential role in methylation pathways promotes DNA repair, gene expression, and neurotransmitter synthesis.  

Functions of folate include:

• DNA synthesis and repair
• The production of nucleotides and amino acids
• Facilitates one-carbon transfer reactions crucial for cellular metabolism
• Supports methylation processes, including the conversion of homocysteine to methionine
• Necessary for normal fetal development, particularly in preventing neural tube defects
• Plays a role in neurotransmitter synthesis, contributing to neurological function
• Involved in the formation of red blood cells and prevention of megaloblastic anemia
• Aids in the metabolism of histidine, serine, glycine, and other amino acids
• Required for the synthesis of S-adenosylmethionine (SAMe), a key methyl donor in various biochemical reactions

Recommended Dietary Allowance (RDA) for Folate

The RDA for adult men and women is 400 mcg/day.  [10.]

In pregnancy the RDA for folate is 600 mcg/day, and 500 mcg/day in lactation.  [10.]  The World Health Organization recommends 600 to 800 mcg of folic acid daily in pregnancy.

Sources of Folate [17.] 

Animal-based sources:

• Liver (beef, chicken, pork)
• Eggs

Plant-based sources:

• Dark green leafy vegetables such as spinach, kale, turnip greens, and romaine lettuce
• Legumes such as chickpeas, lentils, black beans, and kidney beans
• Asparagus
• Brussels sprouts
• Avocado
• Okra
• Broccoli
• Citrus fruits and juices, especially oranges
• Papaya
• Banana
• Strawberries
• Tomato juice
• Beets
• Fortified cereals and grain products, including bread, pasta, rice, and flour
• Sunflower seeds
• Peanuts

Folate Forms and Supplementation Indications

Folate Supplement Forms  [6.] 

Folate supplements are available in various forms, each with unique characteristics and bioavailability.  Folic acid, 5-methyltetrahydrofolate (5-MTHF), and folinic acid are the three commonly available supplemented forms of folate. 

Folic acid is the synthetic form commonly used in supplements and fortified foods, requiring enzymatic conversion to its active form, 5-MTHF, within the body.  It is commonly used in dietary supplements and fortified foods due to its stability and cost-effectiveness. 

5-MTHF is the bioactive form of folate and doesn't require enzymatic conversion, making it more readily available for absorption. 

Folinic acid, also known as 5-formyltetrahydrofolate, is another supplemental form that can directly enter the folate metabolic pathway without relying on specific enzymatic processes, making it useful for individuals with certain genetic variations or absorption issues.

Indications for Folate Supplementation [6., 10., 11.]

Preconception and Pregnancy

Adequate folate levels are necessary for prevention of neural tube defects (NTDs) during pregnancy.  Folate supports fetal development and growth.

‍Folate Deficiency and Megaloblastic Anemia

Folate is essential in the treatment and prevention of folate deficiency, which can lead to megaloblastic anemia and neurological complications.

It may also be prescribed to support individuals with malabsorption syndromes or those taking medications that interfere with folate metabolism, such as methotrexate.

High Homocysteine Levels  [8.]

Management of hyperhomocysteinemia, which is the buildup of homocysteine in the blood and is a risk factor for cardiovascular disease.  

Homocystinuria, a related disorder, is an inherited disorder of methionine metabolism that causes an abnormal buildup of homocysteine and related metabolites in the blood and urine.  Homocystinuria often requires high doses of folate to lower homocysteine levels.

Neurological and Mental Health

Folate may be given to support cognitive function and mental health, as folate plays a role in neurotransmitter synthesis and methylation processes.  It is also considered an adjunct therapy for certain psychiatric conditions including depression and schizophrenia, where folate levels may be compromised.

Testing Options for Folate Levels  [10.]

Blood Tests

Blood tests are used to assess folate levels in the body.  RBC folate is considered the most sensitive as it reflects tissue levels, although homocysteine levels are another indicator of folate levels.  

Testing options for folate status include:

Erythrocyte (RBC) Folate

Reflecting tissue folate stores, erythrocyte folate concentration indicates long-term folate status. A concentration of 305 nmol/L (140 ng/mL) is considered adequate, as values below this threshold have been associated with megaloblastic anemia and other signs of folate deficiency.

Plasma Homocysteine 

Elevated plasma homocysteine levels indicate insufficient folate to facilitate its conversion to methionine, with various cutoff values used to define elevated concentrations. Studies show an inverse relationship between folate intake and plasma homocysteine values, making it a sensitive indicator of folate status but not highly specific.

Serum Folate 

A concentration below 7 nmol/L (3 ng/mL) suggests negative folate balance, often occurring within weeks of folate deprivation. 

While serum folate reflects dietary intake, it may not differentiate between transient reductions in intake and chronic deficiency. However, repeated measures over time can track changes in folate status when interpreted alongside other indices.

Test Procedure and Preparation Guidelines

The procedure for testing folate levels typically involves obtaining blood samples.  A venipuncture is commonly required.  

Before undergoing folate testing, individuals may be instructed to fast for a certain period and avoid consuming folate-rich foods or supplements to prevent interference with the results.

It's essential to follow any preparation guidelines provided by the healthcare team to ensure accurate test results and to discuss any medications or supplements being taken that could affect biotin levels.

Interpretation of Folate Testing

While individual labs often report different reference ranges, one reference range for folate  testing is given as:  [4.]

Erythrocyte (RBC) Folate: 

Adults: 140-628 ng/mL or 317-1422 nmol/L

Children: Over 160 ng/mL or over 362 nmol/L

Plasma Folate: 

Adults - 2-20 ng/mL, 2-20 μg/L, or 4.5-45.3 nmol/L

Children - 5-21 ng/mL, 5-21 μg/L, or 11.3-47.6 nmol/L

Infants - 14-51 ng/mL, 14-51 μg/L, or 31.7-115.5 nmol/L

However, it is important to note that due to widespread supplementation of folic acid in the food supply, new reference ranges have been proposed.  [5.]

Homocysteine: [10.]

Reference ranges for homocysteine levels given by one lab differ.  Various researchers have employed different cutoff values to designate elevated homocysteine levels. 

The most frequently cited threshold for plasma homocysteine is greater than 16 μmol/L, although others, such as 14 μmol/L and 12 μmol/L have also been utilized. 

One group of researchers utilized a prediction model to establish a reference range of 4.9 to 11.7 μmol/L. Additionally, some researchers have suggested reference intervals tailored to specific age and gender groups.  

Clinical Significance of High Folate Levels [10.]

There is no reported toxicity level with folate from foods, including supplemented foods.

However, high folate levels can have clinical significance, particularly when they exceed the body's metabolic needs. Excessive folate intake can mask vitamin B12 deficiency, potentially leading to neurological damage that is irreversible and debilitating. 

High folate levels have been associated with various adverse effects, including mental changes, sleep disturbances, and gastrointestinal issues. 

While there's no clear evidence of folate-induced neurotoxicity in humans, concerns persist regarding the potential for decreased treatment effectiveness when high doses of folate are taken alongside certain medications. Additionally, while studies have not shown adverse reproductive effects of supplemental folate, investigations specifically designed to detect such effects are needed. 

Similarly, although some studies suggest a potential link between supplemental folate intake and cancer, the evidence remains inconclusive and may be confounded by other variables such as alcohol and smoking. 

Hypersensitivity reactions to folate supplementation have been reported, albeit rarely, emphasizing the need for caution. 

Overall, while folate is crucial for health, excessive intake warrants careful consideration due to potential adverse effects and interactions.

Clinical Significance of Low Folate Levels [6., 10., 11.]

Low folate levels carry significant potential health risks including:

Neural Tube Defects

Low folate levels during pregnancy are associated with an increased risk of neural tube defects (NTDs) in newborns, such as spina bifida and anencephaly. 

Adequate folate intake before and during early pregnancy is crucial for preventing these birth defects.

Developmental Abnormalities

Folate deficiency during fetal development can result in developmental abnormalities, such as facial deformities, cardiac defects, and limb malformations. Adequate folate intake is essential for normal embryonic development and organogenesis.

‍Megaloblastic Anemia 

Folate deficiency can lead to megaloblastic anemia, characterized by the production of large, immature red blood cells (megaloblasts). 

This condition results from impaired DNA synthesis in erythropoietic cells, leading to ineffective erythropoiesis and reduced red blood cell production.

Cardiovascular Disease 

Low folate levels are linked to an increased risk of cardiovascular disease (CVD) and related complications, including coronary artery disease, stroke, and venous thromboembolism. 

Folate plays a role in homocysteine metabolism, and inadequate folate levels can lead to elevated homocysteine levels, which are associated with cardiovascular risk.

Cognitive Impairment

Folate deficiency has been implicated in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease and dementia. 

Inadequate folate levels may impair methylation processes in the brain, leading to neuronal damage and cognitive impairment.

Mood Disorders 

Low folate levels have been associated with an increased risk of mood disorders, including depression and anxiety. 

Folate plays a role in neurotransmitter synthesis and regulation, and inadequate folate levels may disrupt neurotransmitter balance, contributing to mood disturbances.

Increased Cancer Risk 

Low folate levels have been linked to an increased risk of certain cancers including colorectal cancer, breast cancer, and cervical cancer. Folate is involved in DNA synthesis, repair, and methylation, and folate deficiency may lead to genomic instability and aberrant DNA methylation patterns implicated in carcinogenesis.

Natural Ways to Optimize B Vitamin Status

Dietary Sources of B Vitamins

Incorporate a variety of foods rich in B vitamins such as:

• Whole grains like brown rice, oats, quinoa, and barley
• Leafy greens such as spinach, kale, and Swiss chard
• Legumes including lentils, chickpeas, and black beans
• Nuts and seeds like almonds, sunflower seeds, and flaxseeds
• Lean meats such as chicken, turkey, and beef
• Dairy products like milk, yogurt, and cheese
• Eggs, particularly the yolk which contains B vitamins
• Seafood such as salmon, tuna, and mackerel which are rich in B12
• Include fortified foods like fortified cereals, bread, and plant-based milk alternatives to increase B vitamin intake.

Lifestyle Strategies to Optimize B Vitamin Status

• Consume a balanced diet rich in fruits, vegetables, whole grains, and lean proteins to ensure adequate B vitamin intake.
• Avoid excessive alcohol consumption as it can interfere with the absorption and utilization of B vitamins, particularly B1 (thiamine), folate and vitamin B6.  [9.] 
• Manage stress levels through relaxation techniques such as deep breathing exercises, meditation, yoga, or mindfulness practices, as chronic stress can deplete B vitamin stores.  [21.] 
• Get regular physical activity, which can help improve overall metabolism and enhance the body's utilization of B vitamins.  Increasing exercise increases vitamin B needs, so supplementing may be desirable in some individuals.  [13.] 

Medications That Lower Vitamin B Levels in the Body

Individuals taking the following medications may want to discuss their B vitamin needs with their healthcare provider:

• Metformin: Used to treat type 2 diabetes, metformin can reduce vitamin B12 absorption and increase the risk of deficiency over time.  [12., 15.]
• Proton pump inhibitors (PPIs): These medications, such as omeprazole and esomeprazole, are commonly used to treat acid reflux and peptic ulcers. Long-term use of PPIs can interfere with the absorption of vitamin B12.  [7., 15.]
• Histamine H2-receptor antagonists: Drugs like ranitidine and cimetidine, used to reduce stomach acid production, may also impair vitamin B12 absorption.  [15.]
• Anticonvulsants: Some antiepileptic drugs like phenytoin, phenobarbital, and primidone can lower levels of folate and vitamin B12 in the body.  [18.] 
• Chemotherapy drugs: Chemotherapy medications can affect the body's ability to absorb and utilize B vitamins, leading to deficiencies.  [3.] 
• Oral contraceptives: Some birth control pills can deplete levels of B vitamins, particularly folate and vitamin B6.  [20.] 
• Diuretics: Certain diuretic medications, including loop and thiazide diuretics, can increase urinary excretion of B vitamins, particularly vitamin B1 (thiamine) and folate.  [16., 19.]

It's important to consult with a healthcare professional if you're taking any of these medications to discuss potential nutrient deficiencies and appropriate supplementation, if needed.

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