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High S-adenosyl homocysteine but low homocysteine - please help me understand!

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by andocobo, Nov 7, 2015.

  1. andocobo

    andocobo

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    Hi everyone,
    I'm just hoping for some advice / bounce ideas around with some knowledgable people, any input is welcome! :)

    I've spent the last few days researching some test results I got recently - the tests found I have high S-adenosyl homocysteine (SAH), moderately high SAMe, low homocysteine and high glycine. The actual values are:

    SAH: 37 nmol/L
    SAMe: 140 nmol/L
    Homocysteine: <2 umol/L (didn't specify an exact value, just less than 2)
    Glycine: 424 umol/L
    Methionine: 23 umol/L (normal but will discuss later)

    I also had tetrahydrofolate, folinic acid and 5-methyl tetrahydrofalte tested, they were all within the normal ranges, values below:

    Tetrahydrofolate: 4.8 nmol/L
    Folinic acid: 25.0 nmol/L
    5MTHF: 9.3 nmol/L

    I also found I was heterozygous for MTHFR C677T, which may explain the slightly lowish 5MTHF.

    Below is my interpretation of these results, I'd love to find out what others think.

    I'm thinking there is an issue S-adenosylhomocysteine hydrolase (SAHH) enzyme (which I believe is coded for on the AHCY gene). This seems like it could explain the low homocysteine and high SAH & SAMe. Basically, my theory is that methylation is being inhibited by the buildup of SAH caused by the underactive SAHH enzyme, i think the underactive enzyme is also causing the deficit of homocysteine. It seems as though any homocysteine that is being made is being effectively recycled / or transsulfurated, so potentially there are no significant problems in those pathways.

    I believe my methionine level is normal because I have been on a vegan diet for the past 2 years or so which would be low methionine, also low in creatine and choline which I think may now be causing me problems.

    My tentative plan for treating improving this is:
    1. ensure low methionine diet,
    2. supplement with creatine and phosphatidylcholine to ease pressure on the SAMe methylation donation stage, and
    3. take L-Cysteine to boost the transsulfuration pathway.
    This is based on treatments I've read about for some poor people who were born with extremely reduced AHCY activity and suffered terrible symptoms, they were improved somewhat improved using this treatment (I've attached the study to this post). There don't seem be any ways to boost this enzyme directly, although I do note it has NAD+ as a cofactor, so Niacinamide may help???

    Here's the passage from the study which discusses the treatment:
    "The therapy included restricted methionine intake with supplementation of phosphatidylcholine, creatine and cysteine, which is a logical approach considering hypermethioninemia and possible inhibition of MTs, including PEMT. "

    Any ideas or suggestions or anything are very welcome!

    Thanks :)
     

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  2. Gondwanaland

    Gondwanaland Senior Member

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    I suppose vitamin B3 should help to raise homcysteine, never looked into it specifically since my Hcy has always been on the high side, and so has my husband's.

    If you are going to try it, be sure to buy both forms Niacin and Nicotinamide.

    I made the mistake of buying Nicotinamide only and feel the worse taking it since it slows liver phase I and it took me several months to find out that Niacin was the form my body preferred. My huband OTOH does better on Nicotinamide.
     
  3. andocobo

    andocobo

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    Thanks @Gondwanaland,
    I remember taking niacin once and I had the most intense flush thing, felt like I was gonna spontaneously combust hahaha! I've actually got the Thorne Basic B supplement which has most of the B vitamins and has a mix of niacin and niacinamide.

    I don't really know if the B3 will increase the homocysteine, so I'm also going to supplement with cysteine as I assume that would also be low because of the low homocysteine. Also I'm thinking the high glycine may(?) be related to the lack of cysteine, causing less glycine to be turned into glutathione and thus build up - totally just speculation at this point though :)
     
  4. vaarmen

    vaarmen

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    I know this is old but hope andocobo is still around to respond.

    I am Homozygous for all the AHCY mutations that Genetic Genie tests from 23andMe and suspect having low AHCY activity. I have not had SAMe/SAH test done yet as I am not in the US currently and the local market does not offer the test.

    I have problems understanding how underactive AHCY could cause hypermethioninemia, though. Say AHCY does not work then SAH is not converted to homocysteine. But does this cause hypermethioninemia? The methionine in the blood comes from dietary protein which is not dependent on AHCY, so I would really appreciate if someone could explain the AHCY-> Methionine hypothesis.

    I am also attaching my Genetic Genie pdf
     

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  5. Valentijn

    Valentijn The Diabolic Logic

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    The AHCY variants reported by Yasko and Genetic Genie have no impact.
     
  6. vaarmen

    vaarmen

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    Thanks for the input Valentijn. May I ask where your information comes from and how sure you are in the statement?
    Do the Yasko/Genie variants have any other impact at all? Why are they included by Genie and Yasko?

    Thanks in advance for your contribution!
     
  7. Valentijn

    Valentijn The Diabolic Logic

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    From reading the research. There's none showing that the AHCY variants can cause any problems.

    Some do. Yasko probably includes them to create a market to sell her supplements to. Genetic Genie merely reports the SNPs as Yasko does.
     
  8. andocobo

    andocobo

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    Thanks for the info Valentijn. Do you have any ideas on what could cause the elevated SAH and very low homocysteine my results showed if the AHCY mutations are irrelevant? You think purine metabolism might be an issue? Excess adenosine etc.? Or is it more likely to be a CBS issue do you think? Any info is appreciated! :) Thanks
     
  9. Valentijn

    Valentijn The Diabolic Logic

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    Were you on any supplements when you got those results?

    Maybe @alicec has some ideas ...
     
  10. andocobo

    andocobo

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    Thanks @Valentijn - those tests were done a while ago, but from memory I'd been off any supplements for a while so they wouldn't invalidate any test results.
     
  11. alicec

    alicec Senior Member

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    How abnormal are the results - ie what is the normal range?

    I don't know much about this enzyme but did a quick google.

    Apart from the very rare polymorphisms found in the Croatian studies, which are valuable for showing what happens when this enzyme goes seriously wrong, I found one study of more common polymorphisms which might have some effect.

    Two non-synonomous codon changes, rs13043752 and rs41301825, were found to result in a slight but significant decrease in enzyme activity. I don't know if these are tested by 23andme but it would be worth browsing raw data for them.

    Note these are not the SNPs which Yasko claims are relevant. There is no study of them that I have found so who knows why she plucked them out of the air.

    There are also some studies in the paper looking at effects of SNPs in flanking regions which affect expression of the protein. These could be worth studying in more detail and again checking if 23andme looks at them.

    I'm sorry I don't have the energy to work these out more closely for you - am going through a bad patch at the moment.

    So its possible there could be a genetic component to the results.

    Alternatively, one other thing that drives AHCY activity in the direction of homocysteine formation is removal of adenosine by adenosine deaminase. Things which feedback and inhibit this reaction would in turn inhibit AHCY.
     
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  12. alicec

    alicec Senior Member

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    It results in decreased breakdown of methionine.
     
  13. andocobo

    andocobo

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    Thank you so much @alicec for taking the time to contribute this while you're feeling so unwell - it looks very useful! I will look at it more closely later today.

    My SAH and homocysteine levels were:
    SAH: 37 nmol/L (upper limit of normal for this lab was 22 nmol/L)
    Homocysteine: <2 umol/L (didn't specify an exact value, just less than 2, I think lower normal range is around 4)

    Yes I have been looking into the adenosine pathway, I have tested low multiple times for a few immunoglobulins which the doctor thought might indicate some underlying immunodeficiency, but that line of investigation kinda just petered out. I wonder if an increase in adenosine from decreased activity of adenosine deaminase might explain both the low immunoglobulins and the high SAH.

    Again, thanks for your effort to help me out, I look forward to reading those links for provided!
     
  14. Valentijn

    Valentijn The Diabolic Logic

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    The conversion between homocysteine and SAH is done by S-adenosyl-L-homocysteine hydrolase, which requires NAD+, a form of niacin (B3). Have your B3 levels ever been tested, or have you tried supplementing it?
     
  15. andocobo

    andocobo

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    I've not had my B3 levels tested, but I have tried supplementing with NAD briefly, made me feel kinda weird in the head, weirder than normal, worse brain fog. I stopped after a few days, I think i was worried it might be doing some kinda damage, maybe slowing down other parts of the methylation cycle or something.

    I've tried taking regular niacin too, it gave me a huge, powerful and scary flush (I wasn't aware of the flushing phenomenon at the time). I've still got the NAD, I might try taking it again and see what happens.

    Do you know anything about how NAD might worsen brain fog etc? Also are you aware of any research that shows supplementing with NAD can increase SAHH activity?

    Thanks again!
     

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