Fortification can never replace real, whole foods and all the natural co-nutrients that go hand in hand.  You are lying to yourself, or letting somebody lie to you if you believe that processed, fortified food consumption can lead to health and prevention.  Let them continue their studies on isolated nutrients.  Meanwhile, let’s get on in the knowledge that health is an intricate web that starts with real, whole foods–not isolated supplements and fortification.

Today we will continue our discussion of how folic acid (used in fortified foods and vitamins) is different from folates found in real food.  Our continuation is going to get a bit technical, and I’m sorry.  But I think this could be a very valuable read and lead for somebody who has had a standard medical work-up that is normal yet is still struggling with particular health issues nobody can explain to them.  Listing only a sampling of problems possibly related to folate metabolism disorders:  depression, schizophrenia, bipolar disorder, Down’s Syndrome, stroke, Alzheimer’s Disease, Parkinson’s Disease.  autism,  migraine, and infertility, both male and female. (1)  Please note that there seems to be mostly correlation and not hard and fast causation.  Still.  Blows the mind that eating your greens and avoiding synthetic folic acid could play a role in these and other conditions.

Folate or folic acid?  Terminology reminder.

Remember from the last post that they are both types of vitamin B-9.  The term folic acid (which is not naturally occurring) should be reserved for discussion of the synthetic form of vitamin B-9.  The term folate usually refers to forms of vitamin B-9 which occur naturally, particularly in foods.  BUT many times the terms “folic acid” and “folate” are just lumped together simply as “folates,” with “folate” just being a generic term.

My nutshell overview.

My blog posts are a story of what I am learning from alternative health exploration, trying to align it with my conventional health training.  Posts are not intended for diagnosis or self-treatment.  Don’t use them that way.

What I am taking away from my research on folic acid versus natural folates is:

1. For some people, folic acid may be fine and does not appear to disrupt their overall folate biochemistry.
2. However, in today’s processed food world where everything seems supplemented with folic acid, even these people whose chemistry is suitable for using folic acid may be getting folic acid levels which are too high.  And folic acid as it is is unusable.  It is possible, although not yet definitively proven, that there are detrimental effects to unmetabolized folic acid in circulation.  If you’re interested, you should definitely keep an eye on studies relating to this.  They are popping up the last several years.  Excess folic acid binds preferentially over active folates in reactions, and it could downregulate intestinal folate uptake receptors, so a person absorbs less food folates.
3. Unfortunately, many people unknowingly have defects in the enzymes needed to process folic acid!  Despite having enough circulating folic acid, these people are functioning with a “folate” deficiency because they cannot convert folic acid to necessary forms of “folate” adequately.  This can lead to high levels of an amino acid called homocysteine.  High homocysteine levels create all kinds of problems in the body.  Folate metabolism disorders are moderately new discoveries in the medical field and so this is not common knowledge.  I think if more doctors were aware of this, there would be less use of folic acid for supplementation (and more use of another type of biological folate to be discussed later).
4. Better than folic acid is to eat real food rich in folates.  Real food folates are absorbed in forms which are already suited to be used in our body’s folate pathways. To get enough through diet, folate-rich foods must be eaten in abundance nearly every day of the week.  Indulge (yep, indulge!) in foods like lentils, beans, sunflower seeds, broccoli, spinach, asparagus, collard greens, Romaine lettuce, avocado, oranges, orange juice, and mangoes.  And of course, liver.  No supplement can ever give you the benefits of real food.  Eat real food.  Shun processed food.
5. If you cannot eat enough folate-rich foods or supplementation is needed, then there are vitamins with the biologically occurring forms of folate which can be used which may offer benefits over the standard folic acid.

Continuing on from the previous post…

 

1. Folic acid is better absorbed from the gastrointestinal tract than natural forms of folate.  Yes.  True.  But it requires more processing by the body to be used in cellular pathways.

Studies show that folic acid is actually better absorbed from the gastrointestinal tract than folate from foods.  Somewhere around 80-100% of folic acid is consistently absorbed (more is absorbed on an empty stomach).   A highly variable 50-90% of natural food folate is absorbed. (2)  Folic acid’s reliably better absorption sounds like a positive thing, right?!  Let’s see.  Let’s look beyond absorption.

Processing of folates found naturally in foods:

Food-based folates usually come with these “tails”  attached on their structures which have to be hacked off in the lumen of the GI tract before entering cells.  The “tails” are made up of strings of glutamates called polyglutamate tails, and enzymes in the brush border of the intestine cut off all but one of the glutamates.  Once the tail is hacked off and only one glutamate is left intact, the natural forms of folate can be transported by transporters into the GI cells to be used and also sent off to the liver–then off to the rest of the body.  These dietary monoglutamates are commonly 5-methyltetrahydrofolate (5-MTHF) and 5-formyltetrahydrofolate (5-FTHF). Monoglutamates are readily funneled into the folate pathways of the body!  Off they go!

Can glitches happen?  Of course!  If the GI tract is damaged, like in celiac disease or inflammatory bowel disease, then the enzymes can’t take off the tails of the natural folates and they cannot be abosrbed by the transporters.  Or if there are defects in the transporters to move the monoglutamate folates into the GI cells.  I have denoted these potential glitch points by underlining the affected area in the figure.

Processing of Folic Acid:

Folic acid can enter the GI cell as is.  It doesn’t have to have its tail cut like natural folates, so it is more bioavailable.  However, on the flip side, once it is absorbed, folic acid must be acted on by special enzymes inside the GI or liver cell to get it to a usable state.  The natural food folates, once abosrbed are mostly in a highly usable state–when the natural folate makes it into the GI cell, it is already teed up for action and ready to go.  Folic acid, on the other hand, is not and can get hung up in the system.  It is absorbed as folic acid into the GI cells where it can stay or get shuttled to the liver.  In both places, it must be acted on by a series of enzymes to get it to the usable 5-MTHF we mentioned already.  Let’s look at glitch points for folic acid.

One possible glitch is that the ingested amount of folic acid can overcome the ability of the GI and liver cells to act on it, and it will then go straight into circulation unchanged.  So there is free, unusable folic acid circulating.  Usually the kidney will take care of excess folic acid, but too much can overwhelm the kidney’s ability to get rid of it.  This can easily happen in a person who eats processed foods, like enriched bread and cereals, and also takes a multi-vitamin with folic acid.

Another glitch is that some people lack properly functioning enzymes in the pathway needed to get folic acid converted to its usable form.  So if you take in too much AND you have enzyme issues, you can really get some build-up of folic acid.  People can have deficient dihydrofolate reductase (DHFR) and deficient 5, 10-methyl tetrahydrofolate reductase (MTHFR).  (I will go into a little more detail on MTHFR deficiency later, but it is a huge topic beyond the scope of these two posts.)  In addition, to optimally convert folic acid to the much desired MTHF there must be adequate vitamin B-6 (pyridoxine) and vitamin B-2 (riboflavin) in the body.  So other vitamin deficiencies can block folic acid utilization.

So you can see there are more roadblocks in folic acid use than there is in the natural folate use.  There are concerns that this excess folic acid floating around may modify health risks, like allowing cancer to progress; masking or negatively impacting vitamin B12 deficiency neurologic symptoms; altered immune function;and increased obesity, insulin resistance, and asthma in children whose moms supplemented folic acid during pregnancy. (3, 4)

2.  Genetic variations which interfere with folate metabolism occur fairly commonly.  In the United States, up to 60% of people have folate metabolism deficiencies. Folic acid metabolism will be more problematic for these people than naturally occurring folates.(5)

I hope you can hang with all the acronyms and terminology as I try to break this down to understandable language.  One reason that folic acid is a concern is due to the fact that a pretty significant number of people lack full functionality of an enzyme called 5, 10-methylenetetrahydrofolate reductase.  It has several ways to name it, so don’t be confused; 5, 10-MTHFR can be shortened to MTHFR.  These people aren’t so good at creating natural, productive forms of folate out of folic acid!  The enzyme MTHFR is needed to get folic acid to the active form.  (That’s not all it does, but due to scope issues, we’ll stop there.)  Although some people have a severe form of MTHFR deficiency and are very sick, some people have milder forms that cause more of a non-specific health picture not readily attributable to MTHFR deficiency.  So unless a person is aware of it or their doctor is really on top of things, it can be neglected.

MTHFR (5,10-methylenetetrahydrofolate reductase) deficiency:  There is a gene called the MTHFR gene.  We all have two genes, one from mom and one from dad.  The genes code for an enzyme which kindly has the same name as the gene, the MTHFR enzyme.  The MTHFR enzyme helps make active, usable forms of folate for the body, particularly 5-methyltetrahydrofolate–see schematic diagram shown in previous section.  5-methyltetrahydrofolate goes by many names, too:   5-MTHF, L-methylfolate, [6s]-5-MTHF, L-MTHF, MTHF or L-5-MTHF.  Regardless, it is a highly usable and active form of folate, which is what we get when we eat food folates, and which we have to make when we ingest folic acid.

Whole, real food (not processed, enriched grain foods) usually contains 5-MTHF, but folic acid has to be turned into it!  If an MTHFR gene produces a faulty enzyme, then the person can’t use the folic acid that is being consumed to make the needed folate derivatives for cellular pathways.  Usually this doesn’t occur in an all or none fashion.  It depends on the defective error (because many have been identified, although two are much more common than others–the C677T and the A1298C)) and if you got just one defective gene from either your mom and dad–or if you got defective ones from mom AND dad.  Usually a person produces some enzyme that is still active, but maybe only at 70% or 40% its normal activity level.  Up to 60% of the US population has one copy of a gene (heterozygotes) that does not make MTHFR properly.  Up to 25% of certain US populations have two copies of a gene (homozygotes), which dramatically interferes with MTHFR production and function and folate/folic acid metabolism.  (6)

Many conditions are beginning to be associated with MTHFR genetic polymorphisms.  These include, but are not limited to, conditions like high homocysteine, risk of cardiovascular disease, increased blood clots, neural tube defects (like spina bifida or anencephaly), glaucoma, psychiatric disorders (schizophrenia, bipolar, and depression), cancers, and preeclampsia (high blood pressure in pregnancy).

 3.  “Okay.  I see some of the issues with folic acid.  But my doctor still wants me to take it.  What are people doing for supplementation?”  Well, besides folic acid, a physiologic version of a folate involved in cellular pathways is available.  It is L-methylfolate.  You will recognize it as the 5-MTHF discussed above. 

Technically, if you’re taking L-methylfolate (5-MTHF) in a supplement form, it is synthetic too (like folic acid).  However, the difference is that L-methylfolate directly enters the folate metabolic pathways and doesn’t require precursor steps to be used, like folic acid does.  L-methylfolate is the main folate in human circulation.  Taking a folate form which doesn’t need converted first like folic acid is likely important for people with 5-MTHFR issues, DHFR issues and with aging.

I’ve already talked about L-methylfolate above and how it can go by many names.  No matter what name it goes by, just know that it is the main folate from food ingestion.  So whatever claim is made for Deplin and Metafolin (marketing names) can be first and foremost said about L-methylfolate from food.  An exception would be in those people with damaged small intestinal tracts who can’t de-glutamate food folates.  I have listed the many names for L-methylfolate (and probably still missed some).  Unfortunately, it is important to know whether the L-methylfolate is an isomer that is naturally made by the body.  That’s where the “s” and “L” that you see below comes into play.  This takes you back to chemistry and how structures can have the same formulas, but how they are put together spatially is different.  To be active, methylfolate needs to be denoted by an “L” or “s.”  You may need to call the manufacturer to find this little piece of information out.  Should things really be this difficult?  (No.  But they are.)

• L-methylfolate
• Methylfolate
• Methyltetrahydrofolate
• MTHF
• L-MTHF
• 5-MTHF
• [6s]-5-MTHF
• [6s]-5-methyltetrahydrofolic acid
• L-5-MTHF
• Deplin (Prescription form, usually prescribed in depression along with an anti-depressant.  It is simply L-methylfolate in higher doses.  L-methylfolate, unlike unmetabolized folic acid, can cross the blood brain barrier and be utilized in neurotransmitter production.)  (7)
• Metafolin (This is a trade name.  It is used certain OTC products.  It is the calcium salt of [6s]-5-methyltetrahdrofolic acid.  My vitamin B complex vitamin and multi-vitamin have Metafolin in it.)
• …and other name variations I missed!

Closing

That’s it.  I know I left things out.  There was a lot to learn and cover.  Some readers actually know they have folate metabolism disorders and can provide critical feedback to us about what I have written about my understanding of folic acid, folate, and enzyme deficiency disorders.  It was good to research this topic and finally see what all the hubbub was about regarding folic acid and MTHFR deficiencies.  (If you kind of get this post, you’re set up for understanding methylation disorders.) I don’t know if I have one of these disorders or not, but overall I’m feeling well.  I will continue with eating greens nearly daily, broccoli, and liver.  If supplementation seems indicated, then I will use a biological folate rather than folic acid.

Regards–

Terri

Sources and Citations:

Lots of good reading here!  Although I noticed some of the links look like they won’t work in all my copying and pasting.  Try using Google Chrome to search these links.  If you just act like you’re going to copy it and then choose “Search Google for…” then you can use Google to get you to the site.  If that fails, let me know in the comments, and I’ll comment back with the active link.

1. Hickey, Curry, Toriello.  ACMG Practice Guideline:  lack of evidence for MTHFR polymorphism testing.  Genetics in Medicine (2013).  Volume: 15, 153–156. doi:10.1038/gim.2012.165 (Link)

2.  Overview of folic acid/folate.  Project Healthy Children.  http://projecthealthychildren.org/wp-content/uploads/2012/03/2012-06-19-PHC-Folic-Acid-FINAL-FINAL.pdf

3.  Smith, Kim, and Refsum.  Is folic acid good for everyone? Am J Clin Nutr March 2008 vol. 87 no. 3 517-533.  (http://ajcn.nutrition.org/content/87/3/517.full)                  

4.  Tam, O’Connor, and Koren.  Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation.  Obstetrics and Gynecology International.  Volume 2012 (2012)       

5.  Greenberg and Bell.  Multivitamin Supplementation During Pregnancy:  Emphasis on Folic Acid and l-Methylfolate.  Rev Obstet Gynecol. 2011; 4(3-4): 126–127.  (Link)

 6.  Greenberg, Bell, Guan, and Yu.  Folic Acid Supplementation and Pregnancy:  More Than Just Neural Tube Defect Prevention.  Rev Obstet Gynecol. 2011 Summer; 4(2): 52–59.  (Link)

7.  http://www.deplin.com/

8.  https://tspace.library.utoronto.ca/bitstream/1807/30137/1/Lakoff_Alanna_D_201006_MSc_thesis.pdf

9.  http://www.hindawi.com/journals/ogi/2012/485179/

10.  http://www.fao.org/docrep/004/y2809e/y2809e0a.htm

11.  Prinz-Langenohl, Bramswig, Tobolski, Smulders, Smith, Finglas, Pietrzik.  [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C –>polymorphism of methylenetetrahydrofolate reductase.  Br J Pharmacol. Dec 2009; 158(8): 2014–2021.  (Link)

12.  Smith, David.  Folic acid fortification:  the good, the bad, and the puzzle of vitamin B-12.  Am J Clin Nutr. January 2007 vol. 85 no. 1 3-5.

13.  Ueland and Rozen.  MTHFR Polymorphisms and disease. 2005.  Eureka.com.

Click to access Ueland_9781587063978.pdf