Gallbladder Disease- the Connection Between MTHFR, Methylation, and Digestion

These are my notes for a post and video done by Dr Andrew Rostenberg, DC which can be found here.

While there doesn't seem to be a direct relationship between poor methylation and poor digestion, the two often occur together, which can be caused by the effects of poor methylation on the functioning of the liver and gallbladder, resulting in the gallbladder not being able to perform it's important role in proper digestion and detoxification. He says that the gallbladder is the most methylation-sensitive organ in the body. The liver needs the enzymes involved in methylation to make bile, which is made from cholesterol. If you can't make adequate bile, you can't excrete fats out of your body. There are some things that hinder the release of bile, which include "High stress lifestyles, low stomach acid, estrogen dominance, toxin and pesticide exposure can all stop the bile from being released. All these things hurt our methylation cycle, which in turn hurts the gallbladder."

Bile is critical for proper digestion of fats.  It is an emulsifier and a detergent so it breaks fat up into smaller pieces which can then be absorbed.  If there isn't enough bile, deficiencies of fat-soluble vitamins can occur.  Bile also works like soap in that it "rinses out" particles of food and bacteria from the walls of the small intestines, the same way that detergent rinses these things off of your dishes.  If this process doesn't work properly than bacteria can grow too high up in the intestines and cause SIBO.  If insufficient bile is excreted it can also lead to leaky gut.  Without adequate gallbladder function,  there are more cracks and spaces between the cells lining the gut.  The gallbladder concentrates the toxins and junk that the liver is trying to get rid of, so if it gets emptied less and less frequently and fully problems can occur.  The liver is trying to get rid of things like pesticides, flame retardants, heavy metals, food additives, and medications.  A major part of detoxification is simply producing bile when we eat.  Bile is also important for clearing excess estrogen so hormonal balance can also be affected.

Poor methylation means poor detoxification.  If methylation, sulfation, and glutathione aren't working well (oxalate can reduce sulfation even more) the body switches to an alternative pathway called UGT (glucoronidation), in which things are detoxified by being "stuck" to glucose.  Unfortunately this results in thick and sticky bile which can hinder it's function and even keep it from leaving the gallbladder.   The bile should have a relatively thin consistency, like that of dish detergent, rather than the more molasses-like thickness that it can take on when a lot of sugar is used for detox.  There is research showing that giving taurine and sulfur to mice with thick bile corrected the problem.  Estrogen must also be detoxed via the bile, so increased estrogen levels (such as pregnancy) or the taking of birth control pills and/or hormone replacement therapy can exacerbate this problem.  This also explains why gallbladder disease seems to occur more often during pregnancy.

Choline (as phosphatidyl choline) removes excess cholesterol but if the gallbladder isn't working right it may not be able to do this, so in some cases high cholesterol is simply the result of the gallbladder being unable to remove it.  Phosphatidyl choline also protects the gut lining from irritation caused by bile in the GI tract.  Without enough phosphatidyl choline fat cannot be removed from the liver which then leads to liver disease.

This is what he has to say about correcting the problem "So the way we prevent this is through optimizing methylation by increasing taurine, phosphatidylcholine, folate, B12, and TMG. Taurine is produced by the methyl cycle, and when taurine is given to rats with gallbladder sludge, their bile gets slippery again and rescues their liver from damage.5 The methylation genes PEMT and BHMT are found in the liver and they make choline phospholipids which are necessary to keep the bile flowing. Choline protects the liver and gallbladder against damage from the detergent action of bile and it promotes movement of cholesterol into the bile so it can be removed from the body. When we run out of choline, cholesterol and fat literally get stuck in our liver and muscles, leading to fatty liver disease and muscle damage."  (On an interesting and possibly related note, I recently read a theory that suggests that insulin-resistance and diabetes may be caused by bits of fat being inside the cells and "mucking up" the insulin receptors.  At the bottom of this post is a more detailed list of the supplements that Dr Rostenberg recommends.

Dr Richard Deth on Autism, Methylation, and Dopamine

This interview with Dr Richard Deth Ph.D was available to watch free online for one day and is part of a package deal available from The Autism Intensive, an expert interview series.  These are my notes from the interview.

Dr Deth's lab was the first to identify the D4 dopamine receptor, which has unusual structural features and properties related to methylation.  When dopamine stimulates this receptor it causes methylation of the phospholipids in the membrane.  He got involved in autism research when Dr Martha Herbert, an autism expert from Harvard Medical School, saw this research and told him that this was of interest to the autism community. 

What is methylation?  The word “methyl” refers to a single carbon atom that can be transferred from one molecule to another.  The molecule that receives the carbon atom is said to have been “methylated”.  Methylation is a process that is so common that it affects nearly every aspect of cellular metabolism and function.  It seems that poor methylation is a fundamental issue in autism.  Kids with autism tent to have low levels of methyl donors, and many respond well to supplementation with methyl B12 (mB12).  Of the 6 types of B12 in the body, methyl B12 is the active form for methylation.  Post-mortem studies have found that the levels of B12 are low in the brains of people with autism.  In order to address this, cells need to have access to enough B12 and also have enough glutathione that they can convert B12 to its active form (too much oxidative stress inhibits this process).  This way the cell can decide what is the best form and how much of different forms to make.  There is an assay now that can measure the levels of the 6 forms of B12 in the body, but brain levels can only be measured post-mortem. 

Post-mortem studies have found levels of mB12 in the brains of kids with autism at about 25% of what they should be.  This suggests that there is a problem with the transport systems that bring B12 into the brain, which is a poorly understood process.  B12, along with many other nutrients and products in the blood, is brought into the brain through a structure called the Choroid Plexus.  These structures, one in each of the 4 ventricles of the brain, are part of the blood-brain barrier (BBB) and selectively transport certain nutrients and other things from the blood into the cerebrospinal fluid (CSF).  There are certain proteins that attach to B12 and other things and actively carry them across the BBB.  Dr Deth is currently studying this process to understand better how this process works.  

Dr Deth's research directly shows that heavy metals such as mercury and lead interfere with methylation, which has led to him testifying in front of congress on the issue of vaccine safety, as well as testifying as an expert witness in the federal vaccine court.  He says that since then, the science has further validated this hypothesis and has fleshed out much of the specific details of how this interference occurs.  In particular the growing field of epigenetics has shed a lot of light on this connection.  Epigenetics is the study of how genes are turned on and off to regulate biological function and development, and this regulation of gene activity is controlled by methylation.  Epigenetics is the mechanism that orchestrates development, from the moment of conception throughout our lives, including development of the brain.  So if something interferes with methylation it can profoundly interfere with the process of development.  

Epigenetics is what links the environment and exposures that we get to our genetic expression.  Environmental factors impinge on anti oxidant status, which then impinges on methylation, and methylation *is* development.  Environmental factors include mercury, lead, RoundUp, pesticides, etc.  Genes influence a person's risk of being harmed by these environmental factors, but the genes themselves are not the "cause" of the autism (in most cases).  Among many researchers there is a predetermined certainty that autism must be genetic so they keep looking for the genes over and over despite the lack of results.  Sample sizes of 10,000 genomes have not turned up any consistent findings, and these researchers then say they just need a larger sample size- maybe 50,000 genomes.  Yet you can look at 30 to 50 kids with autism and measure their glutathione levels and find marked differences in these kids.  This finding (of low glutathione) happens all over the world, wherever autistic kids are studied.  What are the factors leading to the low glutathione, which then causes poor methylation and epigenetic problems during development?  

Understanding of autism causality is moving away from a “single agent” hypothesis to a complex interplay between susceptibility to injury and exposure to multiple contributing factors.  Early theories that mercury and thimerosal were involved are still true, and pointed to a mechanism of causality that is very complex and which has been validated and is now better understood.  Now that we know the mechanism, we can see how other factors also come into play.  When gluten and casein are digested, they result in peptides with opiate activity, and research has shown that these peptides interfere with the uptake of cysteine from the GI tract.  Cysteine is necessary for cells to produce glutathione- availability of cysteine is what determines how much glutathione is made.  This results in oxidative stress and damage to the DNA, via poor methylation.  

What is oxidative stress?  Oxidation is the ability to use electrons that we get from food to make energy.  As we metabolize nutrients in our food, our mitochondria use the process of oxidation to make ATP, which is our source of energy.  They do this by converting oxygen to water.  About 3 to 5 percent of the oxygen molecules that go through this process, instead of becoming water, become other oxygen species and are able to oxidize other biological molecules that we don’t want to be oxidized.  ReDox balance is a balance between oxidation molecules and anti-oxidant molecules.  Oxidative stress is the condition of having too many oxidizing molecules and not enough anti-oxidant molecules.  Oxidation damages various proteins and even DNA.  In 2008, Dr Deth published a paper called “The Redox Methylation Hypothesis of Autism”, in which he laid out the connections between the pathways that make anti-oxidants and the pathways that support methylation.  In response to oxidative stress, the body can down regulate methylation to restore balance.  Methylation can help to heal some of the damage to DNA via changing gene expression, but this is not always enough.  Autism is a spectrum because when methylation goes wrong, it affects so many areas of the body, and we each have our own genetic variability so we will each show this damage a bit differently.  Each person must receive treatment tailored to them as an individual. 

The dopamine D4 receptor is critical for attention.  Dopamine and D4 receptors can synchronize different neural networks that might otherwise not be synchronized together, and to tune their frequency of activity.  Frequency is how fast the neurons are firing.  Higher frequencies are more metabolically demanding.  When you are attending to something, dopamine and the D4 receptor make the circuits involved in what you are paying attention to shift to a higher frequency, the gamma frequency, which is 30-80 hz.  The D4 receptors are located in certain cells in the brain called parvalbumin expressing GABAergic interneurons.  Those cells develop post-nataly as the individual's capacity for attention develops.  By 4 to 5 months of age babies begin to be able to pay attention to things.  Problems with methylation could affect attention through this process.  Certain mutations in the gene for the D4 receptor is the biggest risk for developing ADHD.  When asked if this connection between the parvalbumin expressing intern neurons and the ability to pay attention could suggest that people of higher intelligence are more at risk for developing autism,  Dr Deth explains that once you correct the underlying metabolic problems in autism the person's actual intelligence can become revealed.  He goes on to explain his theory that people who are at the highest risk form environmental induced neurodevelopmental injury are people whose genes are poised for intelligence, but intelligence in the brain is a risky undertaking, making the cells are more vulnerable.  It’s a trade-off.  These are more likely to suffer from an environmental injury.  The parvoalbumin cells are the most sensitive cells because their high firing rate means that they have a high metabolic rate, which means that they create more damaging oxidative byproducts (also called reactive oxygen species).  (My thoughts here- this also means that these cells are more dependent on mitochondrial function so may be more sensitive to mito dysfunction).

Dr Deth has written a book called Molecular Origins of Human Attention in which the role of dopamine and D4 receptors is more fully explained.

Additional papers by Dr Deth that discuss methylation and redox imbalance in autism:

How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis.

"Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks."

Autism: a redox/methylation disorder.

"While autism is still a mysterious developmental disorder, expansion of research efforts over the past 10 to 15 years has yielded a number of important clues implicating both genetic and environmental factors. We can now assert with a measure of confidence that contemporary autism reflects the combined impact of multiple environmental factors on the processes that regulate development in genetically vulnerable individuals. Since epigenetic regulation of gene expression is acknowledged as the most critical factor in development and DNA methylation (the addition of a carbon atom at discrete locations) is the fundamental event for epigenetic regulation, dysfunctional methylation can be considered as a likely cause of autism. Since methylation activity is highly sensitive to oxidative stress (an abnormal redox state) and many environmental factors promote oxidative stress, we have proposed a redox/methylation hypothesis for autism causation. The narrative herein describes the evolution of this hypothesis, which is essentially a series of linked discoveries about how the brain uniquely relies on oxidation and methylation to guide its development and to carry out its cognitive functions."

Methylation and Hormone Balance

These are my notes for a podcast interview with Andrew Rostenberg DC about how methylation plays into balancing hormones.

What does methylation mean?

Think of methylation as a verb, it's an action that occurs in your cells and is at the foundation of our biochemistry.  We are carbon based organisms.  Simply put, methylation is the movement of a carbon atom from point A to point B. You can think of it like a banking system, in which money flows to where it is need.  Imagine though, if there were a crisis and the banks close, and you can't withdraw or deposit money when needed.  If you imagine that carbon atoms are the money in this example, this is like poor methylation.  Methylation ability is at it's foundation based in our genetics and in which SNPs (which stands for single nucleotide polymorphisms, which are common genetic variations) we carry.  It also is affected by epigenetic changes as well as the process that regulates epigenetic changes. Epigenetics is about choice, not predetermined outcomes.  We are born with the ability to heal, it's about giving our body back these abilities.

Hormone balancing and the methylation cycle....

In his practice, he sees mostly women with estrogen dominance, which presents as heavy periods, PMS, early menopause onset, irregular cycles, and having gallbladder disease and removal.  He says the gallbladder is a "fatty trash can" that the body uses to get rid of toxic metals, xenobiotics, birth control pills, and hormones, among other things.  When someone has had their gallbladder removed, it indicates that they have been a poor methylator for a significant amount of time, and they've been exposed to an elevated level of toxins.  Taurine pathways have a big effect on gallbladder function.  Also, where your body stores fat depends on hormone levels.  Large hips and butt compared to upper body indicates estrogen dominance.  There are two different forms of estrogens, the ones we make and the ones we are exposed to.  Most petrochemicals that people have made act as estrogen in the body and are much stronger than our natural ones (these are called xenoestrogens).  This is also not just a female problem, men can have high estrogen as well. Aromatase (sp?) is the process by which the body converts testosterone into estrogen.  When insulin goes up, sex hormone binding goes down.  Inflammation increases this as well.

What are the most important SNPs for hormone balance, and why?  

COMT is the main enzyme that will break down estrogen.  Estrogen has 3 different forms, 2 are carcinogenic and inflammatory.  COMT helps the body minimize those forms.  A SNP in this gene can slow down the clearance of estrogen and diverts it from the safer pathway through the liver into a more inflammatory pathway.  Another major one is PENT which is responsible for making choline inside of the body.  It makes phosphatidylcholine, which is one of the primary components of the cell membrane in white matter (so it support the nervous system).  Choline is the body's main storage area for methyl groups and when the body needs more methyl groups it pulls the choline out of the cell membranes and breaks it down.  This results in demyelination in diseases such as MS.  In a recent research study, women on a low choline diet (no red meat, no egg yolks, no soy lecithin, maybe more?) developed signs of fatty liver syndrome and other signs of choline deficiency.  A healthy body makes choline when there is not enough in the diet, but most of these women were found to have the PENT SNP.  Other SNPS were found to have an even more profound affect on fatty liver disease.

What kind of health problems are you likely to see in a patient who has hormone imbalance issues due to poor methylation if it is not addressed?  

We are sicker now, as an animal on earth, than we ever have been.  We've had these SNPs in our genes for a long time, so what has changed?  Our environment is polluted, especially with petrochemicals.  High exposure to hormones from birth control pills, pesticides, other toxins rob your body of methyl "currency"- depletes the "bank account" to protect us.  Low methyl groups means inflammation.  The process by which the liver excretes toxins into the gallbladder, in order to get them out of the body, depends on the methylation cycle and the biochemicals taurine and glutathione (glutathione is itself a product if methylation so is already low in poor methylators).  The liver is especially dependent on methylation.  In low methylation status, the bile in the gallbladder becomes thick and "sludgy" and forms stones, bile production decreases, so when you eat you don't have enough bile to absorb the fat soluble nutrients that are so crucial to health such as vitamins A, B, E and K, omega 3s, choline, and other fats are just harder to absorb.  Estrogen is very hard on the gallbladder.  Estrogen is also deeply involved in autoimmune disease. 

Problems you see in estrogen dominant women also include anemia from the heavy bleeding, estrogen thickens the blood and makes it more prone to clotting, which can even cause stroke (birth control pills can also do this).  Estrogen sensitive cancers (including uterine, breast, ovarian, and also prostate) also demonstrate estrogen dominance.  The prostate is the analog of the uterus and prostate cancer is the result of too much estrogen in a man.  A study published in the BMJ showed that in parts of the world, as women began to use the birth control pill (BCP), the rates of prostate cancer in men went up concomitantly.  The more women on the BCP meant more estrogen being excreted in urine, which went into the water supply.

There are also risks from having not enough estrogen.  There is an optimal amount to have in the body.  Women who are deficient in estrogen have a higher risk of stroke, heart attack and other cardiovascular disease.  The adrenal glands are supposed to kick in at menopause and compensate for the reduction in estrogen, but many women develop adrenal fatigue during their menstruating years and so the adrenals aren't able to step up the way they need to.

Connections with mito dysfunction...

The cells in the stomach that produce stomach acid are some of the most energy-hungry cells in the body.  Toxin buildup in the body, which results from low methylation, damages the mitochondria so cells are not able to make as much energy to do their jobs.  This creates a vicious cycle in which toxicity creates a situation in which the body can't absorb the nutrients that it needs to heal itself, from impaired bile function and reduced stomach acid.  Stomach acid levels are critical to break down proteins, and especially to absorb minerals from our diets (which is one of the reasons that chronic antacid use depletes the body of minerals such as calcium).  This is also a significant cause of anemia as adequate stomach acid is necessary for proper iron absorption. 

How does methylation of hormones affect the brain, and is there a relationship with neurotransmitters?

Estrogen has a huge impact on neurotransmitters.  He says drinking coffee can cause estrogen dominance because it is detoxed through the same pathway (but possibly only in people with certain SNPs?).  He mentions that people under stress can use starches to try to increase dopamine levels.  This topic was mostly glossed over and I will find another podcast to fill in this area.


How is stress related to methylation hormone imbalance?  

While adrenal stress isn't technically under the methylation umbrella, the constant stress that people tend to contribute to issues that relate to methylation, such as blood sugar imbalance and digestive trouble.  Adrenal stress pushes blood from our organs into our muscles.  Things like digestion, detoxification, tissue repair, get put on hold chronically.  It also reduces brain function and memory formation. 

Miscellaneous tidbits that came up during the questions include...

Common causes of anemia include malabsorption problems such as celiac disease, chronic infections including viruses and especially bacteria (who take the iron for themselves), low levels of stomach acid, untreated hypothyroidism, because a thyroid component is needed to uptake iron from the gut into ferritin.  Also vitamin C is crucial for iron absorption. 

For patients with vertigo and dizziness, aldosterone and anti-diuretic hormone are important to consider, especially the aldosterone and renin cycle.  Low aldosterone can relate to other adrenal issues, including POTS.  Adaptogens help the brain communicate with the adrenals rather than helping the adrenals function directly.  caution should be exercised with licorice and yucca however, as both can be very estrogenic. 

Taurine is a membrane stabilizer.  Seizures come from destabilization.  Regular seizures are very stressful to the body so really tax the adrenals.  Heart arrhythmia is the same mechanism- an unstable membrane of heart muscle. 


11 beta hydroxy steroid deficiency or mutation is related to PCOS.  It is what inactivates or activates cortisol.  Excessive cortisol can cause POTS.  Fat cells promote cortisol levels WAY more than non fat cells.

PCOS is an anovulatory cycle, which means no progesterone is made in the second half of the cycle, which puts a lot of strain on the adrenals. 

Estrogen can break down into certain metabolites, one is protective and 2 are destructive.  Iodine helps the body convert the dangerous forms back into estrogen.  Estrogen dominance can cause thyroid problems.

Saliva hormone testing should be collected on day 19-21 from the beginning of the cycle.

Stress pushes cholesterol to be made into cortisol instead of other hormones.  Stress causes us to "burn the furniture", meaning break down tissues in the body for protein for the liver to then turn into blood sugar, rather than burning fat, which breaks down muscle, builds fat, which then further increases the cortisol level in a vicious cycle.

Estrogen dominance is the ratio between estrogen and progesterone, which can be very high estrogen and normal progesterone or low estrogen but much lower progesterone.

Dr Ben Lynch on MTHFR Genetic Variance and Methylation

These are my notes for Dr Ben Lynch's presentation about MTHFR and methylation (which can be viewed here). The first 30 minutes of this presentation covered the basics of methylation, and my notes for that part can be found here.


-Disorders related to under-methylation, which therefore can also be associated with MTHFR, include: Autism, MS, Fibromyalgia, Diabetes, Parkinson's, Chronic Fatigue Syndrome, Alcoholism and other addictive problems, ADHD, Insomnia, Alzheimer's, Cancer, Allergies, Bipolar, Schizophrenia, Depression, Anxiety, Neural Tube Defects including Spina Bifida, Cleft Palate, frequent miscarriages, Infertility, Tongue Tie, Tethered Spinal Cord, Chiari Malformation, Pulmonary Embolisms, Atherosclerosis, Immune Deficiency, Chronic Viral Infection, Congenital Heart Defects, Chemical Sensitivity, Thyroid Dysfunction, Neuropathy, Down's Syndrome, and mercury poisoning.
-In his list of who to screen for MTHFR variants, in addition to people based on the list of disorders above, there is also people with cervical dysplasia, elevated cobalamin, cardiovascular risk, and newborns and people hoping to conceive.
-MTHFR is very common.  The frequency varies tremendously between different ethnic groups and in different locations.  The two groups with the highest rates appear to be Mexicans and people from southern Italy.  Rates of neural tube defects tend to correlate to rates of MTHFR (except in the case of southern Italy).
-Testing looks for the two common variants, called C667T (what Roo has) and A1298C.  There are at least 40 other variants that are known, but not tested for.


Problems associated with C677T variant, also know as A222V or rs1801133 include-


Cardiovascular function, Homocysteine regulation, DNA regulation, glutathione production, and low methylfolate levels.  1 copy of this variant results in a 40% loss of function of the MTHFR enzyme, 2 copies results in a 70% decrease.  Normal is having two Cs at this spot on the gene, not a T.

 Problems associated with A1298C variant, also known as E429A or rs1801131 include-

Neurological issues, regulation of neurotransmitters, low BH4 levels, and elevation of nitric oxide.  These people may not have deficiencies in methylfolate levels, it appears that this variant may cause issues via production of biopterin.   Normal is having two As at this spot, not a C.

Metabolism of Folic Acid and Folate

Folic acid is the non-natural form of this nutrient that is added to fortified foods.  It is converted by an enzyme called DHFR into the next form along the pathway (dihydrafolate or DHF), which is a slow process.  If folic acid is consumed at a faster rate than the conversion takes place, unmetabolized folic acid builds up in the system which leads to lower levels of NK (natural killer) cells.  Dr Lynch suggests that this is the mechanism for why folic acid can lead to cancer, by suppressing NK cells, which are critical in fighting cancerous cells at the very beginning before they become large tumors.

The end product of the chain of transformations is 5-MTHF.  This nutrient can be purchased from Thorne and is also available in uncooked leafy greens.  Nutrients that are needed to make methylfolate (other than simply eating it straight from leafy greens) are vitamins B2 and B6.  These vitamins are necessary cofactors, so even people who do not have a genetic variation and produce a fully functioning enzyme will still be deficient in methylfolate if they do not have adequate B2 and B6.

For 5-MTHF to be used, there needs to be adequate cobalamin levels for the methyl group from the 5-MTHF to go to to make methylB12.  Cobalamin levels must be adequate for the 5-MTHF to be used.  That is very important as many doctors will address low methylfolate levels without making sure enough cobalamin is present for the 5-MTHF to do anything.  Once the methyl group is transferred to the cobalamin to make mB12, it enters the methionine- homocysteine cycle that results in the production of SAM-e which is the body's primary methyl donor.  In this way, sufficient methylation capacity is dependent on the functioning of the MTHFR enzyme as well as the list of cofactors (B2, B6, B12, magnesium, etc).  Additionally, the SAM-e then is converted to homocysteine, which is then converted to glutathione, which is the body's primary anti-oxidant and a person's glutathione level is largely what determines their susceptibility to metal toxicity (mercury in particular). 

The above describes the impact of the C677T variant because it impacts the amount of folate that is converted to methylfolate.  The A1298C leads to different issues because it seems to impact the production of BH4 (tetrahydrabiopterin).  C677T also affects BH4 levels because methylfolate is needed for the DHFR enzyme to convert BH2 to BH4.  Because the mechanism is different, associated symptoms are also different with the 1298 variant.  Issues associated with 1298 tend to have more to do with neurological and mental health issues, addictions, chronic pain such as fibromyalgia, and nerve pain.  BH4 is needed to convert tyrosine into dopamine, tryptophan into serotonin, and arginine into nitrous oxide and citramine. 

Methods for Lowering Homocyteine

One common result of an MTHFR mutation is elevated homocysteine levels.  Vitamin B6 supports the conversion of homocysteine to glutathione, which is really important so this is an excellent way to lower it.  MethylB12 will convert homocysteine to methionine.  Betaine (also called TMG) is very effective at converting homocysteine to methionine as well.  TMG is very similar to DMG, and the two are often confused, although for some reason he says that DMG inhibits this conversion while TMG supports it (he also says that giving HCl supplements inhibits the body from producing HCl itself, which is not consistent with mine and many other people's experiences.  Giving HCl tends to lead to a person actually making enough on their own).  Beets are an excellent food source of betaine.  Lastly, riboflavin (B2) also supports the breakdown of excessive homocysteine.

He says not to supplement with glutathione directly because it shuts down the CBS pathway (which is how homocysteine is converted to glutathione).  If the CBS enzyme is defeicent, which is also common, then glutathione will already be low (this is very common in kids with autism).  Under functioning CBS also results in elevated ammonia, which is problematic for several reasons including that coping with the excess ammonia strains the body's ability to balance neurotransmitters. 

A Few Notes About Testing Homocysteine Levels

Most labs do not test properly for homocysteine levels, according to both Dr Lynch and the American Pathology Association.  He says home tests are not accurate and should not be used.  COnsumption of high methionine foods can give false results on the test.  The patient needs to fast for 12 hours prior to having blood drawn.  The sample must be put on ice immediately, or the red blood cells need to be spun out right away. 

Drugs to Avoid When MTHFR is present

There is a really long list, so I will just list the ones here that I recognize or seem relevant (if you want to see the whole list it's at 1:02 in the presentation).  Antacids should be avoided because they deplete B12.  Nitrous Oxide inactivates MS (methionine synthase, an important enzyme) and needs to be avoided.  This can actually be quite dangerous, even fatal.  Oral contraceptives deplete folate.  Metformin decreases B12 absorption.  Methotrexate and Bactrim reduce the function of important enzymes.

Supplements and Drugs to Address MTHFR

Of the prescription forms of methylfolate, Dr Lynch's favorite is Metanx.  He says that Deplin, which ranges from 7.5 mg to 15 mg, is so high that it can cause many problems.  He generally does not prefer meds to address MTHFR.

As for supplements, there are many options that are on the market and it is confusing.  Choose one that either has an L at the beginning of the name (as in L-methylfolate), a 6S (such as (6s)-5-methylfolate), Quatrefolic, or Metafolin.  Avoid forms that begin with an R- (racemic forms, they inhibit absorption of the L-form).  Companies are not allowed to put more than 1,000 mcg of L-methylfolate per serving into their products if it is on it's own, or 800 mcg if in a combo formula. 

Supps to take to support MTHFR include: L-methylfolate, methylB12 and/or hydroxyB12 (methyl- if the person under methylates, hydroxy- if they over methylate), vitamin E, Krill Oil (better for crossing BBB), Fish Oil, sylimarin (from milk thistle, if oxalate sensitive avoid this), selenium, zinc, glutathione (start low), a strong probiotic (a healthy gut spares the methylation cycle a lot of work), multivitamin with complete B complex and minerals, vitamin D3, vitamin C, electrolytes, magnesium, adaptogens (ashwaghanda is good), potassium. 

Protocol to Support MTHFR

The most important thing is to address lifestyle issues to reduce the strain on the body and the methylation pathway.  Eat Paleo or GAPS (he recommends people read "The Paleo Solution" by Rob Wolf), reduce toxic exposures, get enough sleep, digestion must be in good shape so that gut is healthy and nutrients can be absorbed, should be having several formed bowel movements per day, try to remove medications that are folic acid antagonists, make sure no folic acid or niacin in supps, test for MTHFR.  Specific supps with doses for each MTHFR SNP is at 1:20 in the presentation.  Potassium can help reduce side effects from methylcobalamin or methylfolate (due to alkalinizing?).  If symptoms are due to over-methylation, give 50 mg of niacin (timed release) to slow down excessive methylation.  To avoid pushing methylation too far to cause over-methylation, start low and work up slowly.