MTHFR and Folic Acid “Build Up”: What You Need to Know

Concerns about folate deficiency, especially before and during pregnancy are quite well known, and with doctors recommending folate supplementation to avoid neural tube defects, poor pregnancy outcomes, anemia, and cancer. Getting proper folate in the diet is important for our overall health.

Folic acid, as opposed to folate that our body produces, refers to the synthesized compound that is found in cheap dietary supplements and fortified foods.

Normally, folic acid is converted in the liver to the usable form known as methyltetrahydrofolate (MTHF), but when this mechanism is lacking certain enzymes, is overwhelmed, or is too slow, folic acid can build up in the serum as unmetabolized folic acid (UMFA). 

Folic acid supplements, particularly in high doses can mask the symptoms of pernicious anemia which is a vitamin B12 deficiency that dampens the bone marrow’s ability to make blood cells. This should be kept in mind – it’s important to check that your dosage is not too high.

Concerns surrounding the effect of too much folic acid have been acknowledged, however, the problem of un-metabolized folic acid appears to be more concerning in populations with certain MTHFR genetic variations.

An estimated 60% of US adults “have MTHFR”

MTHFR (methylenetetrahydrofolate reductase) is the enzyme produced by the MTHFR gene. It’s required for metabolizing folate and breaking down the amino acid homocysteine.

Up to 60 % of the U.S. population have an MTHFR genetic enzyme variant that, for the most part, goes unnoticed by the individual. In individuals with two copies of the MTHFR variant, the ability to convert folic acid into active MTHF is challenging. 

Two main MTHFR gene variants are currently being studied: 

• C677T
• A1298C 

These variants are surprisingly common. It has been estimated that in America, about 25% of Hispanics and 10-15% of Caucasians have two copies of C677T variant. Less is known about the population distribution of the A1298C variant, and research is ongoing in this regard, however its presence is still not a cause for concern.

According to these stats, there is a significant proportion of the population possessing the C677T variant, meaning that there is some amount of change in the DNA sequence that makes up the MTHFR gene in a big proportion of the population. 

Recent observations suggest that patients with the C677T MTHFR genotype may have higher folate requirements than individuals with a normal genotype.

UMFA syndrome and folic acid metabolism

Those with two copies of the MTHFR polymorphism (homozygous) cannot properly convert folic acid into a usable form. Studies suggest that this defective metabolism may cause folic acid to accumulate in high concentrations. This is referred to as UMFA.

One study found that un-metabolized folic acid was detected in 78% of fasting plasma samples from healthy participants who were not taking folic acid supplements. The authors indicate that this was due to increased consumption of fortified foods, as opposed to more natural forms of food containing folate. It could also be a result of a large proportion of these individuals having the homozygous MTHFR variant.

Instead of folic acid as a supplement, the active form known as 5-MTHF is a better option since it bypasses the defective MTHFR enzyme, providing the body with the final active product. Individuals affected by the MTHFR homozygous mutation should modify their diet and decrease their intake of fortified wheat flour and folic acid supplements. 

Do individuals with variants in MTHFR respond differently to folic acid?

More than 20% of people with MTHFR variations are thought to be affected, although there is no such thing as MTHFR symptoms. Additionally, different variants may have slightly different responses to folic acid supplementation. 

The C677T variation results in a 35% reduction in activity for heterozygotes individuals (those with single mutations) and a 70% reduction in activity for homozygous individuals (those with double mutations). However, it was shown that individuals with the MTHFR 677TT genotype who take folic acid have an average amount of folate in their blood that is roughly 16% lower than people with the MTHFR CC677 genotype.

In a study looking at 932 subjects given various doses of folic acid, it was revealed that despite the dose of folic acid administered, the authors observed that blood folic acid concentrations were highest in 677CC homozygous, lower in the 677CT heterozygous, and lowest in the 677TT homozygous.

These results confirmed that individuals with the MTHFR 677TT genotype have increased requirements compared to those with the CC and CT genotypes, and should supplement with 5-MTHF.

Folate Supplementation with MTHFR

As mentioned previously, 5-MHTF is the predominant micronutrient form of folate (not folic acid) that circulates in plasma and is required for important biological processes.

Unlike folic acid, 5-MTHF can cross the blood-brain barrier and does not mask pernicious anemia or vitamin B12 deficiency in the way that folic acid does. It is also readily available to transport in the blood stream and can be safely taken in high doses. 5-MTHF supplementation has been shown to effectively improve folate biomarkers in young women during early pregnancy and can prevent neural tube defects.

If you wish to naturally increase your folate intake, the best foods with high folate content can be found in the following:

• Beef Liver: 215 micrograms 
• Spinach: 131 micrograms 
• Black-Eyed Peas: 105 micrograms
• Fortified Rice: 90 micrograms 
• Asparagus: 89 micrograms 
• Enriched Spaghetti: 83 micrograms 
• Brussels Sprouts: 78 micrograms 
• Romaine Lettuce: 64 micrograms 
• Avocado: 59 micrograms 
• Broccoli: 52 micrograms

MTHF supplements

The most biologically active folate supplements are those that include:

• (6S)-5-methyltetrahydrofolic acid, monosodium salt or L-methylfolate 
• (6S)-5-methyl-tetrahydrofolic acid, calcium salt or L-methylfolate
• (6S)-5-methyltetrahydrofolate or (6S)-5-MTHF

Be sure to also read my recent post on methylfolate side effects.