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Methylation, MTHFR, and Thyroid Health

Published August 29 2016

Methylation is a process which is very important to our overall health.  It is necessary when it comes to protein synthesis, detoxification, the formation of neurotransmitters, the regulation of hormones, and it has numerous other functions.  While some people reading this are familiar with methylation, I realize that many are unfamiliar with this process, and so what I plan on doing in this article is to explain what methylation is, expand on how it’s important to our health, and also explain how methylation relates to thyroid health.

The reason why I decided to discuss this topic is because many people have problems with methylation.  Methylation problems are common in people with hypothyroidism and Hashimoto’s Thyroiditis, and it also is an issue in many people with hyperthyroidism and Graves’ Disease.   I’m not going to discuss the complex biochemical processes involved with methylation in this article, as the primary goal is to discuss the importance of methylation and how it relates to thyroid health.

So what is methylation?  On every organic compound there is something called a methyl group.  This consists of one carbon atom, and three hydrogen atoms.  And methylation involves the donation of a methyl group.  But why is this important?  Methylation is necessary for most of the body’s systems.  It is involved in the repair of DNA, it helps to prevent the overproduction of homocysteine, and it’s important when it comes to detoxification.  If someone has problems with methylation, and many people do, then they will have a greater risk of developing certain chronic health conditions.  And so one of the goals is to make sure you do things to help support proper methylation.

There are numerous factors which can affect methylation, but the following are five important ones:

1. Genetics.  Genetics is without question a factor when it comes to methylation.  There is strong support that genetic variants regulate methylation, which in turn regulates gene expression (1) [1].   A growing number of human diseases have been found to be associated with aberrant DNA methylation (2) [2].  However, as I’m about to discuss, lifestyle and environment can be big factors as well.

2. Diet.  There is no question that diet plays a big role in proper methylation.  Studies to date suggest that certain dietary components may alter genomic and gene-specific DNA methylation levels in systemic and target tissues, affecting genomic stability and transcription of tumor suppressors and oncogenes (3) [3]. In other words, what you eat can affect the expression of genes.  With regards to methylation, folate is one of the more important nutrients to consider.  Most data and supportive evidence exist for folate, a key nutritional factor in one-carbon metabolism that supplies the methyl units for DNA methylation (3) [3].  Other nutrients play an important role in methylation as well, such vitamin B6 and B12, magnesium, and zinc.   Of course you need to eat well to get sufficient folate and other nutrients important for methylation, and if someone has a methylation defect then in addition to eating well, nutritional supplementation might be necessary.

3. Problems with the gut.  If someone has problems with the gut then this can affect methylation.  For example, if someone has a leaky gut or small intestinal bacterial overgrowth (SIBO), then they might not absorb certain nutrients required for proper methylation.  Similarly, if someone has low HCL levels then this too will affect the breakdown of nutrients, and can in turn affect methylation.

4. Environmental Toxins.  Numerous environmental toxins can have a negative effect on methylation.  There is evidence that pesticides may modify gene promoter DNA methylation levels, which in turn suggests that epigenetic mechanisms may contribute to pesticide-induced carcinogenesis (4) [4].  The toxins from cigarette smoke can also affect methylation (5) (6) [5].  I came across a study which showed that lead exposure might have a negative effect on methylation (7) [6].  Xenoestrogens such as bisphenol A (BPA) can affect DNA methylation (8) [7].  And numerous other chemicals can affect methylation as well, which is why it’s important to minimize your exposure to these toxins, and do things to help eliminate them from your body.

However, while one’s toxic load can be a factor, certain genetic polymorphisms can affect the detoxification pathways.  For example, having a catechol-o-methyltransferase (COMT) polymorphism can lead to the reduced detoxification of catecholamines (i.e. epinephrine) and estrogen.  A polymorphism of the CYP3A4 gene is can affect the detoxification of certain drugs and hormones.  Both the MTHFR and GSTM1 genes play a role in arsenic metabolism, and polymorphisms of these genes may play a role in arsenic-induced cancer (9) [8].

5. Medications.  Numerous medications might also have a negative effect on methylation.  For example, certain drugs will disrupt folate metabolism.  These include aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim and triamterene. Other drugs which can produce low serum and tissue concentrations of folate include anticonvulsants, antituberculosis drugs, and oral contraceptives (10) [9].  Folate is just one nutrient involved in methylation, but the metabolism of other nutrients which are important to methylation can also be disrupted when taking certain medications.  As another example, it is well known that Metformin, which is commonly taken by people with diabetes, can result in a vitamin B12 deficiency (11) [10] (12) [11], which is also important for proper methylation.

Homocysteine and Thyroid Health

Homocysteine is a sulfur amino acid, and its metabolism requires folate, vitamin B6, and vitamin B12 (13) [12].  So it shouldn’t come as a surprise that plasma homocysteine concentration is inversely related to the intake and plasma levels of folate, vitamin B6, and vitamin B12 (13) [12].  In other words, having a deficiency of any of these three vitamins can lead to an increase in homocysteine.  Elevated homocysteine levels have been associated with conditions such as increased total and cardiovascular mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer’s disease, increased incidence of bone fracture, and a higher prevalence of chronic heart failure (13) [12].

There does seem to be an association between high homocysteine levels and hypothyroidism (14) [13].  Hypothyroidism is associated with increased cardiovascular morbidity (15) [14], and this can be due to an increase in homocysteine commonly found in these patients.  Taking synthetic or natural thyroid hormone might not completely normalize homocysteine levels in people with hypothyroidism (15) [14], and if this is the case then other factors which affect homocysteine need to be addressed.

MTHFR and Thyroid Health

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that is vital for re-methylation of homocysteine to methionine.  Riboflavin (vitamin B2) is the precursor for flavin adenine dinucleotide (FAD), which is the cofactor for MTHFR (16) [15].  It has been shown that thyroxine regulates the conversion of riboflavin to riboflavin mononucleotide and FAD in laboratory animals (17) [16].  As a result, it is common for people with hypothyroidism to have problems converting riboflavin to FAD, which in turn will result in deficient MTHFR activity (18) [17].  But as I mentioned earlier, giving thyroid hormone to these patients doesn’t seem to have much of an effect on high homocysteine levels, whereas correcting a deficiency involving folate, vitamin B6, and/or vitamin B12 does seem to help in many cases.  Trimethylglycine can also help to lower homocysteine levels (19) [18] (20) [19].

Although not all of my patients with thyroid and autoimmune thyroid conditions obtain genetic testing, for those who do, it is very common for them to have an MTHFR polymorphism.  Although I’m sure some people reading this are familiar with genetic polymorphisms, many probably don’t know what these are.  A polymorphism is a common genetic defect.  There are many other genetic polymorphisms one can have besides the MTHFR defect, and I’ll discuss some of these in a future article.

With regards to MTHFR and thyroid autoimmunity, one study involving 50 patients who were diagnosed with Hashimoto’s Thyroiditis found that 15 of these patients had MTHFR mutations (21) [20].  Another study involving 199 patients with Graves’ Disease looked at the association between MTHFR polymorphisms and Graves’ Disease, and actually showed evidence that the MTHFR mutation (C677T) protects women from developing Graves’ Disease (22) [21].  This isn’t the case with everyone, as I’ve had numerous women patients with Graves’ Disease who tested positive for an MTHFR polymorphism.  Another study looked into the associations between factors regulating DNA methylation and the prognosis of autoimmune thyroid disease.  They concluded that MTHFR +677 C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of autoimmune thyroid disease (23) [22], although the study did show that the DNMT1+32204GG genotype and the MTRR+66AA genotype may correlate with autoimmune thyroid disease.  In other words, having an MTHFR polymorphism apparently won’t directly trigger the development of an autoimmune thyroid condition, or have a positive or negative effect on the prognosis of those people with autoimmune thyroid conditions.

More About The MTHFR Polymorphism

As I have been discussing, genetics plays a big role in all of this, as the MTHFR gene is responsible for producing MTHFR.  MTHFR is an enzyme which helps to break folic acid down and convert it into 5-methyltetrahydrofolate, which in turn is necessary to remethylate homocysteine to methionine.  Methionine is an amino acid and is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids.  Methionine is converted to s-adenosylmethionine (SAMe), which serves as he principle biological a methyl donor (24) [23].  SAMe helps to regulate many of the enzyme reactions, and so decreased levels of SAMe can lead to numerous health issues.

As I’ve already mentioned, it’s very common to have a polymorphism of the MTHFR gene.  This polymorphism affects the methylation process, and since MTHFR is responsible for breaking down folate, having an MTHFR polymorphism can lead to high homocysteine levels, which as I mentioned earlier can lead to numerous health conditions. This also affects the conversion of homocysteine into glutathione, which is an antioxidant that plays a very important role in detoxification.  But this isn’t just about homocysteine, as folate is necessary for the synthesis of neurotransmitters such as serotonin, epinephrine, and dopamine (25) [24].  As a result, if someone has an MTHFR polymorphism, this will affect the breakdown of folic acid into 5-methyltetrahydrofolate, which in turn will lead to a decrease in neurotransmitters.  In fact, a study I came across showed that depressed individuals with low serum folate tend not to respond well when taking selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (25) [24].  The same study mentions how correcting the insufficiency by taking folate along with the SSRI will have a greater impact on the person’s depression.

C677T vs. A1298C Defect

There are different combinations of MTHFR polymorphisms.  First of all, one can be homozygous or heterozygous.  If someone is homozygous for MTHFR C677T this means that they inherited a copy of the gene from each parent.  The same is true for someone who is homozygous for MTHFR A1298C.  On the other hand, if someone is heterozygous for MTHFR C677T or A1298C then this means that they inherited one copy of the defective gene, and inherited a normal gene from the other parent.  **If someone has a homozygous C677T polymorphism then this means that the MTHFR enzyme is working at only approximately 30% effectiveness, compared to approximately 70% effectiveness for those who have a heterozygous C677T polymorphism.

Should Everyone Get Tested For The MTHFR Polymorphism?

Some people will want to consider testing to see if they have an MTHFR polymorphism.  Dr. Ben Lynch is a naturopathic doctor who focuses on methylation and MTHFR polymorphisms.  He recommends for just about everyone to get tested to determine if they have an MTHFR polymorphism.  Some healthcare professionals will only test the homocysteine levels, and if this looks okay they will assume that there isn’t a problem with MTHFR.  However, it’s important to keep in mind is that not everyone who has an MTHFR defect will have elevated homocysteine levels.  And so while I do think it’s a good idea to test the homocysteine levels, along with certain nutrients affected by an MTHFR defect (RBC folate, vitamin B6, vitamin B12), these values can be normal even in the presence of an MTHFR polymorphism.

With regards to folate, you want to avoid taking supplements that include folic acid.  Folic acid is synthetically made, and as I mentioned earlier, unmetabolized folic acid can cause a lot of health problems.  This is especially true with those who have an MTHFR polymorphism, as they will have difficulty converting folic acid into methylfolate.  So when supplementing you want to take biologically active forms of folate.  In addition, it’s important to keep in mind that many processed foods are enriched with folic acid, which can also cause problems.  Once again, Dr. Lynch talks about this in great detail in some of his articles and videos.

Testing For An MTHFR Polymorphism

There is testing available to assess the methylation capacity in your body.  As I mentioned earlier, you can test to see if you have an MTHFR polymorphism.  Many conventional labs now offer this type of testing.  Another option is to order a genetic panel through the company 23andme, and then use a service such as Genetic Genie, Nutrahacker, or MTHFR support to interpret the results.  This not only can help determine if you have an MTHFR defect, but this testing can reveal other genetic polymorphisms as well.

Another option is to evaluate some of the nutrients involved in methylation.  One of the common nutrient markers is methylmalonic acid.  If this is elevated then this usually means there is a vitamin B12 deficiency, although there could be other reasons behind this.  You can also test for RBC folate.  Other markers to test include urinary formiminogluatmate and urinary xanthurenate, which are included in some organic acids tests.  You can also obtain a methylation panel through a company such as Doctor’s Data or Metametrix.

How Can One Improve Methylation?

There are numerous things you can do to help improve methylation.  From a dietary standpoint, one of the most important things you can do is to make sure you are eating plenty of leafy green vegetables in order to get enough folate.  I would try to eat at least a couple of servings per day of foods such as spinach, kale, Swiss chard, and watercress.  For those who have a hypothyroid condition, I realize that some of these are classified as goitrogenic foods, but for most people, eating one or two servings per day isn’t going to cause a problem.  The other B vitamins are also important, and with regards to methylation, vitamin B6 and B12 are essential, and so eating foods such as fish and eggs can help with this, along with beef, lamb, and poultry.  Unlike vitamin B12, there are some good plant sources of vitamin B6 such as spinach and sweet potatoes, and certain fruits such as bananas and avocados.  Refined foods tend to deplete the B vitamins, and so you want to minimize your consumption of these.  Drinking a lot of alcohol can also lead to a deficiency of the B vitamins, as can prolonged, chronic stress.

As I also mentioned in this article, gut problems, environmental toxins, and taking certain medications can also interfere with methylation.  While all of the factors I mentioned are important, eating well and correcting any gut issues are in my opinion the two main priorities.  But it’s also important to consider the impact of environmental  toxins, as well as certain prescription medications.

However, if someone has an MTHFR polymorphism, or another type of genetic polymorphism, then supplementation very well might be required.  Methylation is a very advanced topic, and while I’m admittedly not an expert on genetic polymorphisms, I will expand on this in the future as I continue to increase my knowledge on the topic.  In the meantime, for more information I would visit Dr. Ben Lynch’s website, which is www.seekinghealth.org [25].  Another excellent resource is the this article [26] from the Stop the Thyroid Madness website, as this article lists some of the different combinations of MTHFR polymorphisms.

Hopefully you have a better understanding of methylation and how it relates to thyroid health.  Regardless of what condition someone has, it is important to eat well, manage stress, minimize one’s exposure to environmental toxins, etc.  However, one needs to keep in mind that if they have a genetic polymorphism such as one affecting MTHFR, this can’t be corrected.  With that being said, if you are aware that you have such a defect then you can take the proper precautions in order to improve methylation.