57 replies to this topic

[Ukko]

Dude, wow your methylation paths are super mutated. You have no less than three strong double mutations in the TMG/choline based methylation shortcut path using BHMT. You will need a lot of TMG and it still might not work really well. Then you also have three strong double mutations on MTR and MTRR out together. The MTR one means that on theory your methylation should be supercharged but it usea a ton of B12. But then you strong double mutations on MTRR mean that you are making very little methyl B12. Likely have symptoms of megaloblastic anemia also and low dopamine. What you need is a little methylfolate....a ton of B12 5mg but maybe even 10mg and the prodigious amounts of TMG that you are already taking. Try that and Hcy should fall notably. Also keep the NAC, taurine and B6.

[ta5]

Thanks for your input Ukko.

 

I didn't know I would be using B12 faster because of my mutations. That's good to know. 

 

When I was taking 2.5mg per day methylcobalamin, my B12 was tested to be >2000 pg/ml, not just above the reference range, but above the amount they measure. So, I lowered it to 1.25mg, and tested 1195 pg/ml which is still above the ref range. Even so, I raised the dose to 1.67mg per day. My level should be around 1460 pg/ml now. Do you think I need more than that?

 

 

 

Update:

I had my Cystatin C tested and it was 0.49 mg/L, reference range [0.53-0.95]. Even though it's below the ref range, I'm guessing it's good. It's high levels of Cystatin C that are associated with increased homocysteine. So, I think my kidneys are fine.

[albedo]

Ta5, Ukko

 

Very good point about cystatin C. I understand it has been associated to hyperhomocysteinemia and is a sensitive marker for chronic kidney disease. Typically it is ordered when your doctor is not satisfied with results of other tests, such as a creatinine or creatinine clearance. I understand an high level of cystatin C in the blood corresponds to a decreased glomerular filtration rate (GFR) and hence to kidney dysfunction. I read (forgot the reference) that since cystatin C is produced throughout the body at a constant rate and removed and broken down by the kidneys, it should remain at a steady level in the blood if the kidneys are working efficiently and the GFR is normal. I have it in the higher part of the reference range (at 0.87 in the ref. range 0.53 - 1.01). Unfortunately I do not have a long historic of values to check for stability but was 0.85 one year before so I guess I am doing fine.

[resveratrol_guy]

For the record, I managed to lower my homocysteine from 22.6 to 8.7, despite heavy niacin supplementation. Details are in this post, point #9.

 

[tunt01]

For the record, I managed to lower my homocysteine from 22.6 to 8.7, despite heavy niacin supplementation. Details are in this post, point #9.

 

 

Do you have any serum blood values for B12 or folate that show the relationship between your change in supplement intake vs. the change in homocysteine?  

 

I'm curious because I added 100 mcg B12 (1/10th your dose), my B12 values went up 95 pg/mL but my homocysteine actually went up a couple points.  It wasn't a monumental shift, and maybe due to other issues.  but it was kind of a WTF moment when I was going through some bloodwork.

 

BTW - Thanks for your continued input on various matters.

[resveratrol_guy]

Do you have any serum blood values for B12 or folate that show the relationship between your change in supplement intake vs. the change in homocysteine?  

 

I'm curious because I added 100 mcg B12 (1/10th your dose), my B12 values went up 95 pg/mL but my homocysteine actually went up a couple points.  It wasn't a monumental shift, and maybe due to other issues.  but it was kind of a WTF moment when I was going through some bloodwork.

 

BTW - Thanks for your continued input on various matters.

 

My pleasure, prophets. Anonymous data sharing is the only way forward, unless one has time to wait for the FDA.

 

I did not measure plasma B12 or folate recently. That's because I'm forced by my doctor's insurance encumbrances to be very selective about what I test. Even after I showed severely elevated homocysteine, I was still not allowed to test those related molecules.

 

What I can say is that, given my history of egg consumption and health gut flora maintenance (which helps us absorb B12), plus tests several years ago showing consistently normal plasma B12, I mostly suspect a genetic problem with folate metabolism. So I seem to be incompetent at extracting it from green leafy vegetables.

 

Ideally, I would like to cease methylfolate supplementation because it's progrowth. But compared to the threat of dementia from folate defficiency, I'll settle for the growth hazard because I can combat it in plenty of other ways. (It bears repeating: do not take any form of folate on an empty stomach. In theory, you could end up with a rapidly fatal digestive tumor. Mix with fibrous food. For that matter, don't inhale it when you empty the capsule. Better paranoid, than dead.) Too bad I can't test homocysteine often enough to titrate the optimal dose.

 

So the only advice I can offer is to (1) find out from your doctor what you can test and how often without setting off insurance alarms and (2) keep your methylcobalamin and methylfolate doses constant between tests so you can learn what matters.

Edited by resveratrol_guy, 01 April 2016 - 08:49 PM.

[aribadabar]

 

...I mostly suspect a genetic problem with folate metabolism. So I seem to be incompetent at extracting it from green leafy vegetables.

 

Ideally, I would like to cease methylfolate supplementation because it's progrowth. But compared to the threat of dementia from folate defficiency, I'll settle for the growth hazard because I can combat it in plenty of other ways. (It bears repeating: do not take any form of folate on an empty stomach. In theory, you could end up with a rapidly fatal digestive tumor. Mix with fibrous food. For that matter, don't inhale it when you empty the capsule. Better paranoid, than dead.) 

 

If you supposedly suffer from genetic mutation that inhibits folate absorption then this means that you are not getting enough.

The theoretical cancer risk is if you OVERDOSE folate which , given the impaired folate nurtigenomic profile, seems as a non-issue (within reasonable methylfolate supplementation (~<1mg/d)).

How much 5-MTHF are you taking that makes you concerned about its intake?

 

I am also curious what is the risk of accidental inhalation of MTHF? Would you point us to some references on the subject?

 

Thanks!

[resveratrol_guy]

 

If you supposedly suffer from genetic mutation that inhibits folate absorption then this means that you are not getting enough.

The theoretical cancer risk is if you OVERDOSE folate which , given the impaired folate nurtigenomic profile, seems as a non-issue (within reasonable methylfolate supplementation (~<1mg/d)).

How much 5-MTHF are you taking that makes you concerned about its intake?

 

I am also curious what is the risk of accidental inhalation of MTHF? Would you point us to some references on the subject?

 

Thanks!

 

I'm only taking 400 ug of Quatrefolic ((6S)-5-methyltetrahydrofolic acid glucosamine salt) every 2 days, so I guess my dose is reasonable in your view. However, this is not 5-MTHF, strictly speaking, so perhaps there's a bioavailability difference that matters here.

 

The inhalation risk is: (1) fostering cell growth in the lungs (yikes!) and (2) probably worse, inhaling the crystalline silica present in some supplements (but not my Jarrow capsules), which can result in silicosis and lung cancer. Bryan_S brought #2 to my attention long ago, and I've been wary of it ever since.

[aribadabar]

 

 

If you supposedly suffer from genetic mutation that inhibits folate absorption then this means that you are not getting enough.

The theoretical cancer risk is if you OVERDOSE folate which , given the impaired folate nurtigenomic profile, seems as a non-issue (within reasonable methylfolate supplementation (~<1mg/d)).

How much 5-MTHF are you taking that makes you concerned about its intake?

 

I am also curious what is the risk of accidental inhalation of MTHF? Would you point us to some references on the subject?

 

Thanks!

 

I'm only taking 400 ug of Quatrefolic ((6S)-5-methyltetrahydrofolic acid glucosamine salt) every 2 days, so I guess my dose is reasonable in your view. However, this is not 5-MTHF, strictly speaking, so perhaps there's a bioavailability difference that matters here.

 

The inhalation risk is: (1) fostering cell growth in the lungs (yikes!) and (2) probably worse, inhaling the crystalline silica present in some supplements (but not my Jarrow capsules), which can result in silicosis and lung cancer. Bryan_S brought #2 to my attention long ago, and I've been wary of it ever since.

 

 

FWIW, I am homozygous for MTHFR (rs1801133) which suggest 30% efficiency in folate absoption.

I now take every morning, on an empty stomach, 800mcg Quatrefolic + some veggie greens during the day thinking if I need ~400mcg folate daily then I really need to ingest 400/0.3=1333mcg total to reach that. I figure the Quatrefolic + the greens combo brings me close to this target.

The empty stomach intake was due to the (previous) SAMe (now TMG) co-ingestion which is suggested to be taken first thing in the morning.

 

Also, I read in several MHTFR websites that 5-MTHF(methylfolate) needs to be combined with cobalamin (methyl/hydroxo/adenosine) as well as the other B vitamins so my power methylation boost combo of activated B forms consists of the already mentioned 800mcg Quatrefolic (activated B9) + 1000mcg sublingual Methyl- or hydroxoB12 (alternating) +25mg P5P (coenzymated B6) + 20mg Cocarboxylase ( activated B1) + 500mg TMG ( which replaced SAMe due to cost).

 

Not that I "feel" anything objectively at these doses but I reckon it won't hurt in light of my impaired genetic configuration.

 

If I go over 2000 mcg methylB12 sublingually I feel some "buzz" which dissipates within 30-40 min. I don't see an issue with occasional high-dose B12 supplementation specially in the context of the virtually vegan diet I practice.

I never tried >800mcg Quatrefolic due to the cancer risk already mentioned so can't say if there is any "feeling" from larger dosing.

 

What is your take on the need for supplementation of riboflavin (B2) in light of the MTHFR mutation?

Edited by aribadabar, 02 April 2016 - 06:15 PM.

[resveratrol_guy]

FWIW, I am homozygous for MTHFR (rs1801133) which suggest 30% efficiency in folate absoption.

I now take every morning, on an empty stomach, 800mcg Quatrefolic + some veggie greens during the day thinking if I need ~400mcg folate daily then I really need to ingest 400/0.3=1333mcg total to reach that. I figure the Quatrefolic + the greens combo brings me close to this target.

The empty stomach intake was due to the (previous) SAMe (now TMG) co-ingestion which is suggested to be taken first thing in the morning.

 

Also, I read in several MHTFR websites that 5-MTHF(methylfolate) needs to be combined with cobalamin (methyl/hydroxo/adenosine) as well as the other B vitamins so my power methylation boost combo of activated B forms consists of the already mentioned 800mcg Quatrefolic (activated B9) + 1000mcg sublingual Methyl- or hydroxoB12 (alternating) +25mg P5P (coenzymated B6) + 20mg Cocarboxylase ( activated B1) + 500mg TMG ( which replaced SAMe due to cost).

 

Not that I "feel" anything objectively at these doses but I reckon it won't hurt in light of my impaired genetic configuration.

 

If I go over 2000 mcg methylB12 sublingually I feel some "buzz" which dissipates within 30-40 min. I don't see an issue with occasional high-dose B12 supplementation specially in the context of the virtually vegan diet I practice.

I never tried >800mcg Quatrefolic due to the cancer risk already mentioned so can't say if there is any "feeling" from larger dosing.

 

What is your take on the need for supplementation of riboflavin (B2) in light of the MTHFR mutation?

 

 

Thanks for mentioning all those other supplements, which may be useful to others with worse mutations. Apart from methylcobalamin, I don't take them. If anything, I'd like to get my methylfolate intake down, although it's hard to know the right amount, given the difficulty of getting blood tests approved.

 

Sorry I'm no expert on MTHFR, so I don't have any opinion on B2.
 

[albedo]

 

FWIW, I am homozygous for MTHFR (rs1801133) which suggest 30% efficiency in folate absoption.

...

What is your take on the need for supplementation of riboflavin (B2) in light of the MTHFR mutation?

 

 

...

Sorry I'm no expert on MTHFR, so I don't have any opinion on B2.
 

 

 

I just put in the personalized nutrition thread a post on the beneficial effect of B2 for high homocysteine related risks when being homozygous for MTHFR C677T SNP. You might wish to check the references therein just in case you have not seen them already.

 

[Progression]

Where are the sources that says that iron and heavy weightlifting increases homocystein levels?

 

 

My homocystein levels are currently at 8.

 

 

I am taking vitamin b12 daily and now I have also started taking 400 mcg of folic acid. I am also thinking of trying vitamin b6 and b2.

 

My homocystein levels has increased in the past year, even though I have taken vitamin b12 (regularlry over some months and then I quit) and a multivitamin pretty regularly.

I drink about two-three cups of coffe every day.

 

Any thoughs on what could cause elavated homocystein levels?

 

In the evening I am also drinking caffein free coffe because it contains melatonin. Is it coffe or caffein that leads to increased homocystein levels?

 

Thanks for answering.

Edited by Progression, 21 July 2016 - 09:13 AM.

[resveratrol_guy]

I've been there, Progression. What fixed mine (22 -> 8) was methylfolate (400 mcg every other day) and methylcobalamin (1 mg every day). Note that these are not the same as folic acid and cyanocobalamin, respectively.

 

Also, be careful with multivitamins. If they contain a Cu(2+) salt such as copper sulphate, you could be increasing your chances of developing Alzheimer's.

 

I have no evidence for any connection between iron, weightlifting, or caffeine, and homocysteine.

[Tom Andre F. (ex shinobi)]

Do we know how such mutations can happen ?

[resveratrol_guy]

Do we know how such mutations can happen ?

 

I think the mutations relating to homocysteine and folate (MTHFR and others) happened a long time ago due to random replication errors. They're still in the gene pool because they're not so morbid as to prevent reproduction, and perhaps confer some unknown benefits. Personally, my folate metabolism is impaired (says 23AndMe), which is why I think methylfolate is most helpful for me, although methylcobalamin might be more effective for others with different mutations.

[Tom Andre F. (ex shinobi)]

 

Do we know how such mutations can happen ?

 

I think the mutations relating to homocysteine and folate (MTHFR and others) happened a long time ago due to random replication errors. They're still in the gene pool because they're not so morbid as to prevent reproduction, and perhaps confer some unknown benefits. Personally, my folate metabolism is impaired (says 23AndMe), which is why I think methylfolate is most helpful for me, although methylcobalamin might be more effective for others with different mutations.

 

 

Thanks a lot resveratrol_guy ! Its really informative. I always thought it was the same for many visible changes such as baldness sensitivity (linked to heart disease) etc.

 

Im not familiar however with genetics and you mention 23andme,I think I should have a look into this and make a test for myself.

[Progression]

Where are the sources that says that iron and heavy weightlifting increases homocystein levels?

 

 

Thanks for answering.

 

Anyone?

[ta5]

Exercise

Iron

[albedo]

Thank you Ta5. Another reason for me to watch iron!

[Oleic]

I really need some help here guys. Ive been taking 400mcg of folic acid, vitamin b6  8,4 ug and vitamin b12 18 ug. Also tried vitamin b2 riboflavin 2,25 mg sometimes. However, over a 3 month period my homocystein levels increased from 8,1 to 8,8.

I am thinking that it might be something that I do that makes the homocystein increase? Could it bee some of the following that is causing the increase:

 

Supplement with Thymus and Fenugreek. There is a supplement that from the paramcy (non description) that contains these.

 

I also consume a lot of spices in the morning.

Coffeinfree coffe

Taurin.

 

Compared to a couple of years ago I only had a small increase in homocystein levels over a 6 month period.

 

I really appreciate answers on this one

 

 

 

Edited by Oleic, 22 September 2016 - 01:07 PM.

[pamojja]

Ive been taking 400mcg of folic acid, vitamin b6  8,4 ug and vitamin b12 18 ug. Also tried vitamin b2 riboflavin 2,25 mg sometimes. However, over a 3 month period my homocystein levels increased from 8,1 to 8,8.

I am thinking that it might be something that I do that makes the homocystein increase?

 

A 0,7 µmol / L may not mean much more than a temporary insignificant increase. In my case saw it between 14.1 and 6.4. I do take 3 g/d of niacin against Lp(a), and to counter it's effect on my homocysteine I had to slowly titrate up methylfolate and B12 to 2 mg/d, B6 at 160 mg, B2 at 120mg and betain at 2.4 g/d.

 

Therefore you've room there, and could slowly increase your doses, but replace folic acid with methylfolate.
 

[Oleic]

 

Ive been taking 400mcg of folic acid, vitamin b6  8,4 ug and vitamin b12 18 ug. Also tried vitamin b2 riboflavin 2,25 mg sometimes. However, over a 3 month period my homocystein levels increased from 8,1 to 8,8.

I am thinking that it might be something that I do that makes the homocystein increase?

 

A 0,7 µmol / L may not mean much more than a temporary insignificant increase. In my case saw it between 14.1 and 6.4. I do take 3 g/d of niacin against Lp(a), and to counter it's effect on my homocysteine I had to slowly titrate up methylfolate and B12 to 2 mg/d, B6 at 160 mg, B2 at 120mg and betain at 2.4 g/d.

 

Therefore you've room there, and could slowly increase your doses, but replace folic acid with methylfolate.
 

 

 

Thank you for answering However, I doubt that is just a insigificant increase. As my results should have gone done given that I began taking vitamin b1, folic acid and vitamin b6.

Anymore input on my situation guys?

[pamojja]

Thank you for answering However, I doubt that is just a insigificant increase. As my results should have gone done given that I began taking vitamin b1, folic acid and vitamin b6.
 
Anymore input on my situation guys?

 

Well, it looks to me, compared to testing an unresponsive homcysteine and much wider fluctuations since 8 years. You can take a look at my labs, and supplements taken during this time in this spreadsheet:

 

https://docs.google....OcN4/edit#gid=4

 

However, it hasn't been updated with my 2016 results and final improvements. Folic acid at higher doses does simply nothing in that department for me. The most likely reason is that about half the population carry a mthfr gene mutation which hinders the conversion from synthetic folic acid to active folate. On top of that folic acid intake can block the uptake of active folate. But read that would occur at higher doses, starting from 1mg per day.

[Darryl]

Genetic predispositions to elevated Hcy don't increase vascular risk.

 

Lewis et al, 2005. Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. BMJ, 331(7524), p.1053.

Clarke et al, 2012. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med, 9(2), p.e1001177.

Van Meurs, et al, 2013. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nut, 98(3), pp.668-676.

 

B vitamin interventions lower Hcy, but don't reduce vascular risk, with the exception of a barely significant reduction in stroke risk (but not severity).

 

Toole et al, 2004. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA, 291(5), pp.565-575.

Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators, 2006. Homocysteine lowering with folic acid and B vitamins in vascular disease. NEJM, 2006(354), pp.1567-1577.

Bønaa et al, 2006. Homocysteine lowering and cardiovascular events after acute myocardial infarction. NEJM, 354(15), pp.1578-1588.

Jamison et al, 2007. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA, 298(10), pp.1163-1170.

Mann et al, 2008. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease—results of the renal Hope-2 study. Nephrology Dialysis Transplantation, 23(2), pp.645-653.

Albert et al, 2008. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA, 299(17), pp.2027-2036.

Ebbing et al, 2008. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA,300(7), pp.795-804.

Saposnik et al, 2009. Homocysteine-lowering therapy and stroke risk, severity, and disability additional findings from the HOPE 2 trial. Stroke, 40(4), pp.1365-1372.

Huang et al 2012. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clinical Nutrition, 31(4), pp.448-454.

 

There's also an association of elevated Hcy with cognitive aging, but there, as well, vitamin interventions have no effect:

 

Clarke et al, 2014. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nut, 100(2), pp.657-666.

 

Excess methionine intake, which elevates Hcy, is atherogenic independent from its effects on Hcy.

 

Troen et al, 2003. The atherogenic effect of excess methionine intake. PNAS, 100(25), pp.15089-15094.

 

This is corroborated in human epidemiology.

 

Virtanen et al, 2006. High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutrition, metabolism and cardiovascular diseases, 16(2), pp.113-120.

 

My interpretation: the association of elevated Hcy with vascular risk in the general population is a coincident marker of diets with high methionine intake (high protein, esp. animal protein, diets), but Hcy doesn't play a causal role.

 

 

 

Edited by Darryl, 25 September 2016 - 09:12 PM.

[pamojja]

My interpretation: the association of elevated Hcy with vascular risk in the general population was a coincident marker of diets with high methionine intake (high protein, esp. animal protein, diets), but Hcy doesn't play a causal role.

 

Here a differentiated and contrarian view about 'high' methionine intake:

 

https://selfhacked.c...ne-restriction/
 

Have been vegetarian most my live, increasing amino-acids only improved my PAD.

Edited by pamojja, 25 September 2016 - 08:49 PM.

[RWhigham]

Moderator's Note - This post is wrong, the author made a correction in the next post.

 

No use trying to push homocysteine lower than "normal"

 

Metabolic processes that use SAMe produce S-adenosyl homocysteine which hydrolyses to homocysteine.

Methionine is converted to SAMe by an enzyme. SAMe is used as a methyl donor in at least 40 essential metabolic processes. https://en.wikipedia...osyl_methionine

 

"Whereas SAMe is produced and used in nearly all tissues, the transsulfuration and remethylation of homocysteine by BHMT are tissue specific, existing primarily in the liver and kidney." http://jn.nutrition..../137/2/311.full

 

So, homocysteine has to travel (from cells all over the body) to the liver and kidneys for disposal.

I don't see how extra vitamins can change this.

 

"Remethylation" refers to the methyl-folate conversion back to methionine.

"Transsulfuration" refers to the B6 conversion to cysteine. "Cysteine can be further metabolized into other important biological compounds such as glutathione" http://jn.nutrition..../137/2/311.full

Edited by YOLF, 15 December 2016 - 03:20 PM.

[RWhigham]

 

No use trying to push homocysteine lower than "normal"

 

Metabolic processes that use SAMe produce S-adenosyl homocysteine which hydrolyses to homocysteine.

Methionine is converted to SAMe by an enzyme. SAMe is used as a methyl donor in at least 40 essential metabolic processes. https://en.wikipedia...osyl_methionine

 

"Whereas SAMe is produced and used in nearly all tissues, the transsulfuration and remethylation of homocysteine by BHMT are tissue specific, existing primarily in the liver and kidney." http://jn.nutrition..../137/2/311.full

 

So, homocysteine has to travel (from cells all over the body) to the liver and kidneys for disposal.

I don't see how extra vitamins can change this.

 

Wrong!  On closer reading of the article:

 

(1) There is a folate-independent remethylation pathway (called BHMT in the article) from homocysteine to methionine in the liver and kidneys. (It can utilize betaine)

 

(2) There is also a transsulfuration pathway (called CBS in the article) from homocysteine to cysteine in the liver and kidneys.  

 

(3) There is a 3rd pathway not restricted to liver and kidneys. It uses folate and a B12-dependant enzyme to convert homocysteine to methionine.  This pathway can be compromised by an MTHFR genetic defect, or by folate or B12 deficiency.

 

 

Edited by RWhigham, 09 December 2016 - 11:22 PM.

[Oleic]

Interesting article RWhigham