Your “MTHFR” Is Just A Riboflavin Deficiency

charlie

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Boom! The pieces are coming together. :ss2

By Chris Masterjohn Phd
This originally went out on my email newsletter, but by popular demand I'm sharing it here. Many people asked me to post it so they could share it, so here it is.

If you're not on my newsletter yet, you can sign up here.

I just got done doing a TON of research into riboflavin. I recorded a podcast on it with Alex Leaf of Examine.Com, where I focused on the basic science and Alex focused on the outcomes of supplementation studies. You can find that here.

One of the fascinating things we stumbled on is the possibility that the famous MTHFR polymorphisms — variations in the gene that uses riboflavin to make the methyl group of methylfolate — only decrease MTHFR activity because most people in whom the activity has been measured have mediocre riboflavin status.
Alex found some key studies supporting this and blogged about them here.
Here are the key findings:
  • Using experiments in bacteria, where the part of the MTHFR enzyme that binds riboflavin is similar to humans and other animals, the reason that the polymorphisms decrease enzyme activity is because they make the enzyme bind to riboflavin more weakly. At low riboflavin concentrations, the enzyme has poorer activity. However, at high enough riboflavin concentrations, enzymatic activity is restored to normal.
  • In humans who have the MTHFR C667T polymorphism, all of the elevated homocysteine is concentrated among people who have poor riboflavin status.
  • 1.6 milligrams of riboflavin per day decreases homocysteine, and this decrease is highly concentrated among people with the C677T MTHFR polymorphisms who also have poor riboflavin status. In them, 1.6 milligrams of riboflavin decreases homocysteine a whopping 40%!
And how many people have poor riboflavin status? It's generally assumed that riboflavin deficiency is rare in the developed world. Only 10% of Americans consume less than the RDA and clinical deficiency is rarely reported. But rarely does anyone study whether people have biochemical evidence of poor riboflavin status. A recent study in the UK found that a whopping 75% of boys, 87% of girls, and 41% of adults had blood markers of poor riboflavin status.
Why?
Because the best source of riboflavin is liver, and we don't eat liver any more. Because the next best sources of riboflavin are heart, kidney, and almonds. We don't eat heart or kidney and few people make large amounts of almonds a daily staple. The next best sources are red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. But you have to eat lots of these foods to get enough riboflavin and most people don't. They are either demonized (red meat, cheese, and in some circles eggs) or they are used once or twice a week at most (salmon) or as minor portions of dishes (everything else in the list, if they are used at all). And while some people do load up on red meat and cheese, often the rest of their diet is rather terrible because they are not health-conscious.

Another reason might be that poor magnesium status and any kind of problem with energy metabolism — like hypothyroidism, adrenal stress, or insulin resistance — hurts riboflavin retention. So we have worse food selection riding on top of poor metabolic health and poor magnesium status. Less riboflavin is coming in, and more is going out. We're left with a double-whammy on our riboflavin status.

If suboptimal riboflavin status is truly widespread, and if that is the reason why the C667T and the A1298C polymorphisms lower MTHFR activity, it suggests that riboflavin should really be central to our thinking of how to deal with methylation issues.

But it also helps explain something else: why almost everyone has at least one of these genetic variations. Only about 10-15% of the population doesn't have either one! In fact, they are combined in such a way that there is almost an even spread across the population. There are six possible combinations of the different MTHFR alleles, producing a continuous gradation of MTHFR activity from 100% of full activity in the best case to 25% of full activity in the worst. Roughly 15% or so of people fall into each one of the six combinations, leading to an even spread of MTHFR activity across the population.

This distribution is compatible with a tradeoff, as if both low methylfolate and high methylfolate levels had equal advantages and disadvantages. That's conceivable.

But if these variations in enzyme activity are just a result of having crappy riboflavin status, then another explanation emerges: from an evolutionary perspective, these variations proliferated because they just didn't matter. Our ancestors had better riboflavin status than we did. They ate more riboflavin. They ate more magnesium and peed out less of it. They held on to their riboflavin better because they had better magnesium status and better metabolic health. They could get away with MTHFRs that didn't bind riboflavin as tightly because they had so much riboflavin around.

So, what do we do about this?
First, I have revised my MTHFR protocol. My MTHFR protocol is laid out on my Start Here for Methylation page. While that page has always mentioned riboflavin, until now it had given riboflavin a back-seat consideration. I have now moved riboflavin to the driver's seat. The first point in the MTHFR protocol is to aim for 3 milligrams of riboflavin per day.

Here's how I suggest doing that:
On one or two days a week, eat four ounces of liver, ideally from beef, bison, or lamb. On the other days, consume one “liver equivalent,” mixed and matched from the following foods. These foods supply 1/2 of a liver equivalent: kidney, heart, and almonds. These foods provide 1/6 of a liver equivalent: red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. On days that you cannot meet the food requirement for a liver equivalent, take a low-dose riboflavin supplement or B complex providing 3-5 milligrams of riboflavin. For example, you could use a half a dropper of this liquid riboflavin supplement.

It's important to note that endurance exercise, weight loss, high-fat diets, and sunlight exposure all increase your riboflavin requirement substantially. If two or more of these apply to you and you have low MTHFR activity, your riboflavin requirement could be closer to 5 milligrams per day.

It's also important to note that we don't know yet just how close to maximal the extra riboflavin can get your MTHFR working. It might be the case that enough riboflavin completely normalizes the MTHFR enzyme.
Since we don't know for sure, my recommendation isn't to get extra riboflavin and then forget everything else. Rather, I recommend getting enough riboflavin first and foremost, and then still engaging the rest of the protocol by increasing choline, getting enough folate and protein, and considering supplementation with creatine and either collagen or glycine on an as-needed basis.

Think how different this is than trying to make up for low MTHFR activity by taking extra methylfolate. One methylfolate molecule goes into your body, stays inside your cells for 200 days, and every day has 18,000 methyl groups added to it using MTHFR. If you have a 75% decrease in that, you're losing 13,500 of those recycling events. You can't take 13,500 times the normal dose of methylfolate. I have no idea what it would do but I know it's not safe. Methylfolate is one of the primary normal food forms of folate, and I think it's great. You need to get enough folate, so getting normal, reasonable doses of methylfolate into your diet makes complete sense. But adding more to make up for low MTHFR activity is ludicrous.

Doubling your riboflavin intake from 1.5 mg to 3 mg may normalize MTHFR activity, or get close. You help the enzyme work right, and then those 13,500 lost recycling events are suddenly recovered.
Taking riboflavin to support the enzyme is high-impact. Loading up on methylfolate is not.
This is why it's really important to understand the biochemistry and to delve into the biochemical literature.
In addition to revising my MTHFR protocol on the Start Here for Methylation page, I have updated it in Testing Nutritional Status: The Ultimate Cheat Sheet as well.

By the way, I just released version 1.2 of the Cheat Sheet yesterday. The niacin and riboflavin sections have been completely overhauled, and it is now available in four formats instead of three: in addition to the traditional PDF, Kindle book, and iBook, I now have it as a Printer-Friendly PDF, where the hyperlinks are replaced by page number references, so you can flip through it as easily as you can click through the digital versions.

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RealNeat

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Thanks for the reminder @charlie. I had listened to this podcast before and forgot about it. Liver is such a powerhouse. I take 90% Liver braunshweiger from Thousand Hills in small doses almost every day so it seems I just have to up some other key foods and Im at 3mg B2. Are you fruitarian now? How do you match your 3mg if you follow this?
 
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charlie

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redsun

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Thanks for the reminder @charlie. I had listened to this podcast before and forgot about it. Liver is such a powerhouse. I take 90% Liver braunshweiger from Thousand Hills in small doses almost every day so it seems I just have to up some other key foods and Im at 3mg B2. Are you fruitarian now? How do you match your 3mg if you follow this?

Adding off of what charlie suggested eggs and milk are also very food sources. Eggs are definitely a good option for those who dont do dairy or organs.
 

Terma

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B2/R5P was always a hot topic and supplement on the phoenixrising forums (above the other vitamins for some) and my personal experiences were that R5P could have in circumstances dramatic though temporary effects on my brain, but it is important enough in enough pathways it's hard to say exactly why. It is also used in choline oxidase that forms betaine from choline (that one is sometimes less desirable). It's certainly interesting that R5P is a common point between the PR and RP forums since one embraced methylation while the other ran away from it. (Chris is late to the party?)
 
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Ihor

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Maybe there is something on the way to the synthesis of FAD and FMN from simple riboflavin through the riboflavin kinase enzyme, where the cofactors are zinc, magnesium, copper, calcium and ATP? It seems not so simple.

riboflavine.jpg

http://smpdb.ca/view/SMP0000070
 
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charlie

charlie

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Maybe there is something on the way to the synthesis of FAD and FMN from simple riboflavin through the riboflavin kinase enzyme, where the cofactors are zinc, magnesium, copper, calcium and ATP? It seems not so simple.
Gotta get those co-factors! Thank you for reminding us!
 

Ihor

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@charlie And it is also interesting that apparently the enzymes for the conversion of FAD and FMN will be almost completely regulated by thyroid T3 and T4.

"Riboflavin metabolism in the hypothyroid human adult"

It had been shown that thyroxine regulates the conversion of riboflavin to riboflavin mononucleotide and flavin adenine dinucleotide (FAD) in laboratory animals. In the hypothyroid rat, the flavin adenine dinucleotide level of the liver decreases to levels observed in riboflavin deficiency. We have shown that in six hypothyroid human adults, the activity of erythrocyte glutathione reductase, an accessible FAD-containing enzyme, is decreased to levels observed during riboflavin deficiency. Thyroxine therapy resulted in normal levels of this enzyme while the subjects were on a controlled dietary regimen. This demonstrates that thyroid hormone regulates the enzymatic conversion of riboflavin to its active coenzyme forms in the human adult."
Riboflavin metabolism in the hypothyroid human adult. - PubMed - NCBI



"Concentrations of riboflavin and related organic acids in children with protein-energy malnutrition"
Background: Riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) concentrations have been little studied in cases of malnutrition.

Objective: Our objective was to investigate the effects of malnutrition on riboflavin status and riboflavin's relation with thyroid hormones and concentrations of urinary organic acids.


Conclusions: Children in group S had low triiodothyronine concentrations and low conversion of plasma riboflavin into its cofactors, leading to a plasma FAD deficiency. Plasma FAD was not correlated with urinary dicarboxylic acid concentrations.
It seems that B2 looks more independent from other vitamins such as B6, B9 and B12 which require B2 to be activated. I wonder if there will be an indicator of the effective absorption of riboflavin by the body, the degree of yellowness of urine after taking it?
 

erho

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When I read about this, I wonder why Chris doesnt mention milk more? Does anyone know?
My daily intake of three quarts of skim milk comes out to over 5mg of riboflavin/day. Does it have anything to do with bioavailability? Otherwise I find the standard Peat-advise of milk covering this.
 

jmojo

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Masterjohn seems to be against R5P and prefers regular old riboflavin as a supplement. He seems to think that regular riboflavin is better utilized for most people as R5P can be poorly absorbed in people with intestinal issues. It's over my head in terms of understanding the details there but he got me thinking about it.
 

Amazoniac

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- MTHFR? Vitamin C Can Boost Your Folate by 50% | Alison Vickery
Lucock M, Yates Z, Boyd L, Naylor C, Choi JH, Ng X, Skinner V, Wai R, Kho J, Tang S, Roach P, Veysey M. Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status. Eur J Nutr. 2013 Mar;52(2):569-82. doi: 10.1007/s00394-012-0359-8. Epub 2012 Apr 21. PubMed PMID: 22527288.

Verlinde PH, Oey I, Hendrickx ME, Van Loey AM, Temme EH. L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men. Eur J Clin Nutr. 2008 Oct;62(10):1224-30. Epub 2007 Jul 11. PubMed PMID: 17622258.

Aylett SB, Neergheen V, Hargreaves IP, Eaton S, Land JM, Rahman S, Heales SJ. Levels of 5-methyltetrahydrofolate and ascorbic acid in cerebrospinal fluid are correlated: implications for the accelerated degradation of folate by reactive oxygen species. Neurochem Int. 2013 Dec;63(8):750-5. doi: 10.1016/j.neuint.2013.10.002. Epub 2013 Oct 15. PubMed PMID: 24140430.
 

Mito

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Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype.

Abstract
DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.
Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype. - PubMed - NCBI
 

nomoreketones

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Listening to the podcast now. Seems that producing ATP from fat requires twice the Riboflavin as producing ATP from carbs. Could that be why I did so crappy on Keto? On Keto I was so tired all day long that I wanted to just lay in bed all day.

Also I still have some exercise intolerance issues. Maybe Riboflavin deficiency could be one of the culprits.
 

redsun

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Listening to the podcast now. Seems that producing ATP from fat requires twice the Riboflavin as producing ATP from carbs. Could that be why I did so crappy on Keto? On Keto I was so tired all day long that I wanted to just lay in bed all day.

Also I still have some exercise intolerance issues. Maybe Riboflavin deficiency could be one of the culprits.
The thing is you would get even more riboflavin on a diet high in animal products but because keto limits carbs to 50g a day you can only have a few servings of dairy in the form of milk, yogurt. Cheese and other dairy products lose most of their riboflavin. The only major animal source you can eat daily is eggs but you need to eat quite a few. You get some from meat as well. Liver cannot be eaten frequently for other reasons. Greens provide some as well, but then theres the issue with eating such a high volume of greens.

Most do crappy on keto unless they are very sedentary because fat is a poor fuel for a more active lifestyle. The body is constantly starved of glucose and everything suffers, especially exercise tolerance, physical endurance, resistance to stress.
 

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