Methylation - Particularly as it Applies to Gout

Wayne has been looking into the association between MTHFR and gout. This may be a productive new avenue to explore and I'm going to put links and theory under this category on this page.
In VERY simple terms: The methylation cycle converts homocysteine into methionine which is then used to make the methyl donor SAMe. Once the methyl group has been donated, we are left with S Adenosine Homocysteine (SAH) which is then converted to homocysteine.

For many people (mostly of European descent) this cycle does not work properly due to several mutations in the MTHFR gene. The MTHFR mutations result in a reduction in the amount of the active form of folate L-F-MTHF which in turn inhibits the activity of the MTR gene and results in a build-up of homocysteine. This build-up of homocysteine can back feed to create more SAH which can “perhaps” lead to raised levels of uric acid.

It is worth noting that many people switching to a carnivore or zero carb diet will by default increase their consumption of foods containing methionine and hence could exasperate any existing issues with the methylation cycle and “potentially increase their risk of gout”.
See the 4-part Youtube series by Dr. Neil Rawlins for a good introduction into the MTHFR gene and its mutations.

The man-made substance Folic Acid is now added to many foods. However, for those with MTHFR mutations this is a disaster as Folic Acid can block the receptors for the active form of folate L-5-MTHF.
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Most people can successfully treat high homocysteine levels by taking L-5-MTHF supplements and Hydroxo or Methyl B12. Methylcobalamin (B12) is the other main input to the MTR gene.

See the work of Dr. Amy Yasko for more information on how to treat MTHFR issues. In his paper “Reversal of cognitive decline: A novel therapeutic program” Dr. Dale Bredesen recommends Methyl-B12, Methyl-Folate, P5P and if necessary TMG to treat high homocysteine levels.  

Wayne Richmond
Rad Komissar had this to say on Facebook the other day - adding a bit more information to the methylation puzzle...

Gilbert -- You make it sound like Phil has died in a tragic PKD plot twist. PKD is likely not going to kill him but it may cause some harm as it did for many who've gone on this journey including myself. Being that I have first-hand experience with the PKD I will just say listen to your body very carefully and if something goes awry you'll know it's the PKD. I also at first felt good on the PKD. Some people do fine on the PKD but it's only a small percentage of folks based on my observations. I'd recommend PKD only to those with cancer and epilepsy and maybe some autoimmune conditions.

  1. Most people cannot sustain 400g of meat per day. It's a terribly small amount of food. I lost 20lbs on PKD and would have continued losing had I not put a stop to it. I now eat 2lbs and feel a shit ton better like I did previous to the PKD. When you starve someone they are bound to get better and feel lighter overall but this is obviously unsustainable in the long run. It's like fasting but without the autophagy benefits -- might as well do intermittent fasting but eat till you are full on the refeeds.

  2. Organ meats are not good for everyone to consume indiscriminately no matter what ICMNI tries to convince you. Someone like me ended up irritable, depressed and anxious because of it -- the complete opposite of what I felt on the carnivore diet for 1.5 years without any organs whatsoever. My depression was healed within a week and a half of ZC and I never looked back. Then ICMNI rolled around with their "science". I knew that eating liver would cause me issues and it did. Still, I wanted to try it just to make sure. Now I know exactly what I should and should not touch.

    You see, those of us that are undermethylated, which is a much larger chunk of people than overmethylators and who also have a serotonin issue (depression/anxiety, etc) should under no circumstances consume liver and probably most of the other organ meats as well. Why? Because the liver contains a significant amount of folates. Folates are great at speeding up the methylation cycle and fixing it but at the same time folates act as selective serotonin reuptake promoters which stripes serotonin from the brain synopsis hence less serotonin than usual remains available in the synaptic space between the two nerves. We want more serotonin in the gaps not less for undermethylated depressives. For instance, autistics are usually all undermethylated and usually do not suffer from mood issues such as depression so for them it would actually be good to consume organ meats such as liver but I digress.

    I'm probably the only nerd or one of who understands these nuances. There is a reason why so many people are against eating liver and other organs, not to mention they don’t like the taste. Phil, you have nothing to worry about as far as organ meats are concerned because I'm pretty sure you are an overmethylator although your wife may not be and is most likely an undermethylator, however, if she does not have a history of mental issues there is no reason to worry for her either. Don't ask me how I know all this, I just do. You can do a histamine test to find out your methylation status for sure. Too much histamine means the person is undermethylated and too little an overmethylator. It's an inverse relationship.

    Overmethylated depressives actually have way too much serotonin in the brain and since folates will promote reuptake it will decrease the amount of serotonin in the synaptic gaps between the two nerves and level out the brain chemistry nicely which in return will take away depression, therefore, overmethylators should, in fact, consume liver or other organs high in folates. So the reality is undermethylators get depressed/anxious because of too little serotonin and overmethylators because of too much serotonin.

    Technically folates are great for fixing an undermethylators methylation but these positives get negated by how folates act in the brain as I explained above. Sometimes what's good for the body is not good for the brain and vice versa. LIkewise, undermethylators usually store more folates in the body and overmethylators don’t have enough. Those who have a normal methylation status have nothing to worry about and can eat pretty much anything without any issues. All these issues are directly connected to the famous MTHFR gene and should not be underestimated. I believe the smartest people in the world have the MTHFR gene/mutation and because of that are also prone to mental disorders such as anxiety and depression. I don't know what's better to be born a moron but have perfect health or the other way around.

  3. The other issue that most people experience with the PKD is the fat amount that they peddle. It's just way too much. Some of the most common symptoms that people report are GERD and diarrhea. 82% fat is just retarded high and completely unnecessary for most people. You also may not get enough nutrients which come with the protein because you’re not eating enough protein. 70-75% of fat is plenty for most people. Those that do not have metabolic damage can easily get away with 60-70% fat. An 80/20 ground beef patty is about 72% fat by calories -- just to give you an idea. I suggest each person find their own personal fat threshold and stay under it to avoid side effects. Seems like 80/20 ground beef would be a “perfect ratio” of fat to lean and is also a good starting point for experimentation. Likely not too little and not too much fat for the vast majority. Find your ideal ratio and you’re all set! 

  4. Listen to your body. After all, I'm just some guy from the internet. Hope this helps!

    If you'd like to learn more about the methylation cycle and what it does in the brain specifically as far as mood is concerned then I cannot recommend more a highly sought after researcher and pioneer in the field of nutrient therapy and methylation, Dr. William Walsh. Look up his work. I trust him because he's got no products to sell and he knows what he's talking about through many years of vigorous research and hands-on testing with thousands of people. And of course, the main reason why I know he is right is that I did his therapy for a whole year prior to ZC.

    There are other issues with PKD that are less important but I think I covered all the major hurdles that people report on this carnivore flavor. In the end, we must stick to what works for us personally and not follow trends or listen to “gurus”. Hope this helps! :)
Dr. William Walsh: Lab tests for mental health issues
More on Methylation
mthfr-gout-itou2009.pdf
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File Type: pdf
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Additionally, if there are aberrations or expressive genetic mutations  in the body’s methylation cycles (such as MTHFR, MTRR, SUOX, CBS), this can alter the rate of purine and uric acid biosynthesis. The pathway to purine biosynthesis is induced from 5, 10 methylene tetrahydrofolate. This folate metabolite is directly affected by multiple methylation reactions, involving many enzymes. Considering the high prevalence of methylation cycle dysfunction, one should always give attention to this factor when uric acid is elevated. Methylation dysfunction may be a core component of cardiovascular disease because of methylation’s role in homocysteine metabolism, glutathione formation and nitric oxide synthesis.
​Although folate occurs in naturally in some foods, and folic acid is used to fortify others, approximately 60 percent of the population in the United States have genetic variations that make them unable to utilize these nutrients. These variations do not allow the MTHFR enzyme to function properly so methylation of folate does not occur. Without this activation step, folate cannot be used by the body, resulting in negative health side effects and the possible inability to maintain a healthy mood.

This deficiency usually occurs because folic acid, the most common form of folate in supplements and fortified foods, must be converted to its active forms to be used by the body. The enzyme needed to convert folate to its active form, methylfolate, is called methylenetetrahydrofolate reductase (MTHFR). The problem lies in the fact that almost half of all people have genetic variations that reduce the ability of the MTHFR enzyme to make this conversion. Folate deficiencies are tied to a host of conditions.

For people with MTHFR gene variations, supplementing with the already activated form of folate is far more effective in providing this form of folate than introducing the pre-converted form to the body through typical folate supplements. L-Methylfolate supplements provide the active form of folate naturally present in the body and available for biological action.
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This image illustrates the folic acid activation cycle. The other forms of vitamin B9 are folic acid and folate. Folate is often called the natural form of vitamin B9, but it actually refers to a family of different compounds that occur naturally in some vegetables. Folic acid is the supplemental or "synthetic" form of vitamin B9 and is typically the first line of treatment for folate deficiency and related health conditions, such as high homocysteine and neural tube defects. Any folic acid we ingest must be metabolized (converted) into Dihydrofolate (DHF), Tetrahydrofolate (THF), and then finally into L-methylfolate to be used in the body. Once in this form it can be transported into cells, tissues and even across the blood-brain barrier. But issues can arise during metabolism for those with an enzyme issue, such as an MTHFR mutation.
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This is the 5mg one I'm using