The Problem With Blood Tests For Folate

MTHFR mutations change the efficiency with which your body activates folate, so it makes sense to test folate levels, right? Right?

Sadly, blood tests for folate have one big fatal flaw, making them both innaccurate and functionally useless, and the most common folate levels that we see on the blood tests of people with MTHFR might surprise you.

What do Blood Tests for Folate Actually Test?

This test measures the total of all types of folate in the serum, which is the fluid part of blood, excluding red blood cells. This includes the active form of folate, 5-MTHF, but also includes inactive forms like folic acid and unmetabolized folic acid. Because inactive forms of folate are included, this test is really only useful in reverse, and only some of the time.

If you see a high result on your folate test, it is easy to assume that means you have great levels of folate and you're healthy and ready. Unfortunately, it is more likely to mean that you have high levels of unmetabolized folic acid, or UMFA, and you have a problem that could be an MTHFR gene variance, toxic levels of synthetic folic acid intake, or a deficiency in the cofactors needed to activate folate (riboflavin and others).

High folate levels usually mean you have UMFA indicates an overload of unprocessed synthetic folic acid, which has been shown to impair the conversion to active folate. Having high levels of UMFA is actually a bad sign for folate activity, but high levels of UMFA still show up as "folate" on this blood test.

Why Blood Tests for Folate are Inaccurate and Useless.

Testing for all forms of folate, including those that are either useless or harmful including UMFA, or unmetabolized folic acid, gives you absolutely no information about functional levels of folate that are being used by your body.

Research generally has shown poor correlation between test results and actual folate-deficient disease states including microcytic anemia, dementia, pregnancy complications having to do with folate deficiency, and neuropsychiatric disorders.

Normal Range for Folate in Blood Tests

The blood test for folate generally only has a bottom range, with no safe upper limit specified. Typically a "normal result" is 4 mcg/L or more.

Certainly, if your blood folate tests below 4 mcg, then you have a folate deficiency and should immediately begin eating foods high in natural folate like dark green leafy vegetables, beans, lentils, and avocados. You could also supplement with a small dose of the active form of folate, 5-LMTHF. Sadly, a "normal" looking folate level can't be trusted.

While an upper range isn't specified, I often see folate of 12 mcg/L or more in people with the MTHFR mutation, and if the person is undiagnosed, blood folate >12 mcg is a good warning sign that the person should be tested for MTHFR gene mutations.

High Folate Levels in Blood Test And Why That Could Mean You Have MTHFR

Having high folate in a blood test looks like a good thing. Hey! I've got extra-great folate, I"m super healthy. Clinically, however, people with the MTHFR mutation frequently have high blood folate levels, even as they are having symptoms of low folate. This is due to unmetabolized folic acid backing up in the blood because it is unable to be converted to the active form because of the MTHFR deficiency. In fact, UMFA in the blood makes the MTHFR enzyme function more slowly.

In general, if you see blood folate >12 mcg (three times the low-folate indicator), then it is important to test for MTHFR mutations.

Other Tests for Folate Status

Other tests for folate status include:

• RBC folate - not often used, inaccurate, and poorly researched. Also tests all forms of folate so possibly not useful.

• Homocysteine - this inflammatory amino acid is one of the most useful tests for people with MTHFR and/or functional folate deficiency.

• 5-MTHF - there is a test specifically for the active form of folate, but most doctors are unfamiliar with and unwilling to order this test.

RBC Folate Blood Test

RBC folate is a measure of how much folate is in the red blood cells, not the serum (which is what the usual folate test is measuring). This test is used far less frequently than the serum folate test. Red blood cells have a roughly 6 - 8 week lifespan and so can indicate folate status over that period of time. In theory red blood cells should contain active folate only, but this tests shows a high coefficient of variation, meaning that performing the test multiple times on the same sample is likely going to yield widely different results. In short, the test isn't accurate or reliable.

Homocysteine Test To Indicate Folate Levels

Blood tests for homocysteine are most frequently used as a marker for heart disease risk. Homocysteine is an amino acid that is typically low in healthy blood, but which builds up if there is a deficiency of folate, B12, or a problem in the related genes. Homocysteine is a byproduct of methionine metabolism. Your body converts the amino acid methionine to homocysteine, and then uses vitamin B12, folate, and vitamin B6 to break down the homocysteine and either recycle it back to methionine, or convert it into other useful substances.

High homocysteine can indicate a deficiency in any of these three B vitamins (B6 (pyridoxine), B9 (folate), or B12 (cobalamin)). It can also indicate a genetic mutation in one of the genes directly involved in breaking down homocysteine including the MTHFR gene, MTR gene, or MTRR gene.

This test is obviously non-specific, and high homocysteine is a risk factor in many diseases. It is considered an independent risk factor for cardiovascular disease, stroke, infertility, complications in pregnancy, dementia, and many other conditions. It is also being considered as a novel tumor marker in various types of cancer. So while this tests doesn't directly indicate folate levels, it can show a functional folate deficiency, but is limited because it isn't specific to folate.

Homocysteine is one of the most valuable screening tests for MTHFR, general nutritional and inflammatory status, and long-term disease risk, so ask your doctor to include it in your annual bloodwork every year.

Symptoms of Folate Deficiency

The first symptom of folate deficiency is tiredness or fatigue, but many other symptoms can indicate a problem. Symptoms include:

• Fatigue

• Shortness of breath

• Dizziness

• Tender, red tongue

• Mouth sores or mouth ulcers

• Memory loss

• Difficulty concentrating

• Muscle weakness

• Depression

• Diarrhea

Complications of Folate Deficiency

Folate deficiency is a serious issue and has been linked to:

• Infertility

• Certain cancers

• Cardiovascular disease

• Depression

• Dementia

• Alzheimer's disease

• Decreased Cognitive Function.

• Neural tube defects in babies born to folate deficient mothers.

  
  

It is no surprise that these are also all complications associated with the MTHFR mutation, which slows down the conversion of inactive forms of folate to the active form.

References:

Gilfix BM. Utility of measuring serum or red blood cell folate in the era of folate fortification of flour. Clinical Biochemistry. 2014 May;47(7-8):533-8.

De Bruyn E, Gulbis B, Cotton F. Serum and red blood cell folate testing for folate deficiency: new features? European Journal of Haematology. 2014 Apr;92(4):354-9.

Clifford AJ, Noceti EM, Block-Joy A, Block T, Block G. Erythrocyte folate and its response to folic acid supplementation is assay dependent in women. Journal of Nutrition. 2005 Jan;135(1):137-43.