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Mccoy:   choline though, might be a prob, at 57% the RDA, the only nutrient consistently below the RDA which I do not supplement


Michael Rae has argued for choline (phosphatidylcholine) supplementation by vegetarians:





( PC intake also increases phosphorous intake.)

Mccoy: so maybe the Hcyst hypothesis of increased CVD risk is just a matter of reverse causation. An effect rather than a cause.


Homocysteine is associated with a number of other diseases apart from CVD, but the issue of causality still remains:


The metabolism and significance of homocysteine in nutrition and health


Other pathologies

HHcy, an independent risk factor for vascular disease has been shown to occur in other related pathologies as well. Abdominal aortic aneurysm (AAA) is a condition where abdominal aorta fails to dilate normally and studies report an association between elevated plasma Hcy levels and AAA [74, 75]. Similarly, increased levels of Hcy has also been seen in hypothyroidism and this has been associated with increased risk of CVD [76, 77].


In cancer patients, elevated Hcy levels may be caused due to rapidly dividing tumor cells and thus high plasma Hcy, a risk factor for cancer is a potential tumor marker [78].


More recently, HHcy has been shown to promote hepatocellular carcinoma via an epigenetic mechanism involving cytochrome P450 (Cyp450) metabolism [79]. It has also been implicated to adversely affect intestinal vasculature resulting in a condition such as inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract [80].


[...]there are also interventional trials which support the notion that targeting to lower Hcy will lower related pathologies. In a randomized controlled trial by Smith and coworkers, it was shown that brain atrophy in cognitively impaired elderly declined with B vitamin supplementation and the rate of which was dependent on pre-existing plasma ω-3 fatty acids [102].


Another large randomized CSPPT (China Stroke Primary Prevention Trial) study conducted in Chinese adults with hypertension without a history of stroke or MI, showed that oral folic acid supplementation with enalapril significantly reduced the relative risk of first stroke by 21% [103]. Similarly, a duration-based reduction (29%) in stroke was demonstrated after 36 months of follow-up against less than 36 months in a meta-analysis of the effect of B vitamins on stroke [31].


Apart from several age-related pathologies, HHcy has also been shown to play a role in depression, migraine and retinal vein occlusion. High levels of Hcy have been considered to cause cerebral vascular disease and neurotransmitter deficiency resulting in depression of mood. High Hcy may result in diminished remethylation to methionine; critical for the synthesis of epinephrine...


Many of the studies that are cited showing no benefit from vitamin B supplementation suffer from serious shortcomings.


Why Do Homocysteine-Lowering B Vitamin and Antioxidant E Vitamin Supplementations Appear To Be Ineffective in the Prevention of Cardiovascular Diseases?
Cardiovascular Therapeutics 30 (2012)


[...]recent large, randomized clinical trials did not substantiate a beneficial effect of homocysteine-lowering B vitamin supplementation or vitamin E antioxidant therapies in reducing cardiovascular risk in humans. We analyzed eight B vitamin and four E vitamin trials from a critical point of view, and in this article we reviewed and commented on their results and focused on the contradictions found in them. We showed that the possible factors implicated in the failure of vitamin therapies included inappropriate designs.
The protocols neglected an essential fact: that the impact of some confounding factors, such as concomitant use of statins, acetylsalicylic acid, folic acid, and other drugs, might have led to bias and an inappropriate interpretation of the data. The cardiovascular protective and preventive effects of statins and aspirin might have reduced or abolished the possibility of observing a difference in the number of events between the vitamin and placebo groups for the clinical endpoints. We concluded that the vitamin preventive effect on cardiovascular disease may not be rejected in reference to the negative trial evidence.
It also should be taken into account that in all of the large vitamin trials the participants had advanced disease which had been progressing for several decades, whereas the intervention with supplemental B vitamins had only lasted for a period of 2–8 years.
Confounding Factors in Vitamin Trials

When examining the characteristics of the trials it appeared that the participants had concomitantly been using statins, aspirin, or other drugs both in the active (vitamin) and the placebo groups prior to and during the controlled period of the trials. Table 2 shows the medications that were taken by participants in both theactive and placebo groups of the trials.
In the NORVIT trial [53], “participants were given standard post-myocardial infarction therapy” consisting of acetylsalicylic acid and statins. In the WENBIT trial [56], a trial withhomocysteine-lowering vitamins after coronary angiography, almost the same numbers of participants used acetylsalicylic acid, clopidogrel, and statins both in the vitamin and placebo groups. In the HOPE [57] and HOPE-TOO [58] trials, aspirin and other antiplatelet agents as well a lipid lowering drugs were used both in the vitamin and placebo groups. In the PHS II study [60] aspirin use was indicated in 77.4% of participants, both in the active and placebo groups. Of the major cardiovascular events, 478belonged to the active group and 483 belonged to the placebogroup of aspirin users at the end of the trial. In the WAFACS trial [55] almost the same doses of aspirin, lipid-lowering drugs,multivitamins, and folic acid were indicated as baseline characteristics in both the active and placebo groups. Moreover, almost 50% of the patients—1263 from 2721 and 1323 from 2721 in the active and the placebo groups, respectively—had taken more than 432 µg/day folic acid by the end of the trial. In the HOST [54] and renal HOPE-2 [51] trials, the effect of lowering homocysteine levels on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease was investigated. The participants used lipid-lowering agents, aspirin or an antiplatelet agent,and beta-blockers as concomitant medications in the same proportions in both the placebo and active groups.
Statins, aspirin, and other drugs or vitamins may have obscured the potential beneficial effects of vitamin B and vitamin E substitution, and might have reduced or abolished the possibility of observing a difference in the number of events between the active and placebo groups for the clinical endpoints; therefore the results could not reflect the effects of vitamin substitution per se. Differences between the active and placebo groups could only have been shown if the benefits of vitamin substitution plus statin and aspirin were additive; however, this was not investigated in separate groups. Moreover, a folate intake of above 400 µg/day (e.g., in the WAFACS trial) may also cause bias of the results since an intake of this amount of folate induces almost maximal (90%) homocysteine lowering that can be reached by folate treatment [72].
From the large vitamin trials, no conclusions along the lines of “B vitamin supplements cannot currently be recommended for the prevention of CVD events” [75] or “vitamin E was associated with an increased risk of hemorrhagic stroke” [60] can be drawn because the results were determined from inappropriate trial settings...

[...]The positive arguments of numerous investigations favor the concept of B and E vitamins preventing cardiovascular disease. However, it is obvious that an assessment of the effects of vitamins on secondary prevention (i.e., omitting the use of aspirin, statins, or other medications) per se is difficult from an ethical point of view. Furthermore, most of the large vitamin trials were conducted for the aim of secondary prevention, and the conclusions that can be drawn from them cannot be extended over the primary prevention. We take the view that (1) the B- and E-vitamin prevention therapy can work in the primary prevention, and (2)the large vitamin trials did not have power to settle the debate on the effectiveness of vitamin substitution in the secondary prevention of the cardiovascular diseases
Edited by Sibiriak

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Mccoy:  But at the end the CVD risk seems to remain higher even if Hcyst level is lowered,


A recent and thorough meta-analysis comes to somewhat less pessimistic conclusion regarding folic acid supplementation/homocysteine reduction:


Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta‐Analysis of Randomized Controlled Trials

J Am Heart Assoc. 2016 Aug; 5(8): e003768.
PMCID: PMC5015297
Our findings, based on the most comprehensive and up‐to‐date evidence, provide support for a modest benefit of folic acid supplementation for the prevention of stroke. There was a 10% reduced risk of stroke and a 4% reduced risk of overall CVD with folic acid supplementation. A greater benefit for CVD was observed among participants without preexisting CVD or with lower plasma folate levels at baseline and in studies with a larger decrease in homocysteine levels. We did not observe any significant benefit or harm with folic acid supplementation for the risk of CHD.
Edited by Sibiriak

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Sibiriak, good exhaustive references!


What I'm going to do now, also after having examined Chris Masterjohn's suggestions in his 'testing nutritional status', (linked by Todd in another thread). 

  1. Take choline + betaine/TMG suppelements. here I only found choline bitrartrate in reasonable price (phosphatidylcholine is only 15% choline and comes at low dosages and high prices here). choline is a methyldonor which I only consume, according to cronometer, at 50% the RDA. A vegan should not be worried about excess turning not TMAOs, if I construed that correctly, because of the lack of TMAOs-fabricating gut bacteria.
  2. take precautionary moderate supplementation of B-complex vitamins, which are involved in the methylation  process or in the formation of methylfolate. Even though they are above the RDAs, who knows...

Chris masterjhon's words, from his 'testing nutritional status', which is a pretty good quick reference with a practical analytical index at the end.


The homocysteine levels associated
with optimal health are 5-9 micromoles per liter. If your homocysteine is elevated, it could
be due to a deficiency of one or more methyl donors (B12, folate, choline/betaine), a
deficiency of vitamin B6, which is needed for its catabolism, or a deficiency of any of the
B vitamins that enable the production of methylfolate (thiamin, riboflavin, niacin, B6).

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Mccoy:  A vegan should not be worried about excess turning not TMAOs, if I construed that correctly, because of the lack of TMAOs-fabricating gut bacteria.


That may not be  true.  In the following recent study,  vegans/vegetarians experienced a large increase in plasma TMAO following  choline supplementation.


Gut Microbe-Generated TMAO from Dietary Choline Is Prothrombotic in Subjects


Weifei Zhu, PhD,1 Wang Zeneng, PhD,1 W. H. Wilson Tang, MD,1,2 and Stanley L. Hazen, MD, PhD1,2
We prospectively recruited healthy vegans/vegetarians (n=8) and omnivores (n=10) with no preceding (1 month) history of antibiotics or probiotics. This is a single-center study approved by the Cleveland Clinic Institutional Review Board. After informed consent, subjects (46±5yo, 40% male, non-smokers without hypertension, diabetes or cardiovascular disease) were given oral choline supplementation (choline bisulfate 500mg twice daily, ~450mg total choline/day) for 2 months with monthly blood testing after overnight fast.
Both vegan/vegetarian and omnivore alike showed significant >10-fold increases in plasma TMAO levels at both 1 and 2 month periods (p<0.01 each; Figure 1A), with corresponding enhanced platelet aggregation responses to submaximal adenosine diphosphate (ADP, 5μM) following choline supplementation (Figure 1A). Moreover, a striking dose-dependent association was observed between plasma TMAO levels and platelet function (Figure 1B). Similarly, amongst all subjects in the study, a significant association was noted between change from baseline in TMAO level versus the change from baseline in platelet aggregation (Spearman rho=0.38, p=0.03).
These studies show for the first time a direct pro-thrombotic effect of dietary choline and elevated levels of the gut microbial metabolite TMAO in humans. They also suggest the platelet hyperresponsiveness mediated by elevated TMAO can be attenuated by low dose of aspirin. Importantly, they suggest that elevated levels of the gut microbe-generated metabolite TMAO may overcome the anti-platelet effects of low-dose aspirin – a hypothesis that warrants further investigation, particularly in subjects at high cardiovascular risk. An unanticipated finding was that low dose aspirin partially reduced choline supplement-dependent rise in TMAO. While the mechanism for this is unknown, aspirin has been reported to alter the composition of the gut microbial community5. Finally, aspirin use in primary prevention subjects has recently been debated. The present studies, coupled with published studies linking heightened TMAO levels with thrombotic event risk4, suggest studies are warranted to explore if low dose aspirin is beneficial amongst subjects with elevated TMAO and no clear contraindications to aspirin.
[science Daily News Release]

Researchers found:

  • Blood levels of TMAO rose more than 10 times after both 1 and 2 months of choline supplementation in both vegans/vegetarians and omnivores alike.
  • The tendency of platelets to form clots in a laboratory test rose with choline supplementation.
  • The ability of elevated TMAO levels to promote clot formation was reduced when subjects were also taking a daily baby aspirin (81 mg/day).

"Foods that raise TMAO may increase your risk for clotting and thrombotic events. Unless prescribed by your doctor, avoid supplements with choline. A Mediterranean or vegetarian diet is reported to help reduce TMAO," said Stanley L. Hazen, M.D., Ph.D., senior author of the study, chair of Cellular and Molecular Medicine, and section head of Preventive Cardiology & Rehabilitation at the Cleveland Clinic in Ohio.




[Medscape News Report]


"It's a fallacy to think if you're a vegetarian or vegan you can't have a high TMAO," Hazen clarified. "There's a ton of choline in gallbladder juice, so you're constantly feeding choline to your gut microbes, even when you eat a cucumber sandwich."


[...]The mean levels of TMAO in the blood increased from 2.6 µmol/L at baseline to 27 µmol/L and 29 µmol/L at 1 month and 2 months, respectively, in the vegans/vegetarians. The levels increased from 2.5 µmol/L at baseline to 36 µmol/L and 27 µmoL/L, respectively in the omnivores.


The patients' platelets showed enhanced aggregation with a submaximal stimulus (5-µmol/L adenosine diphosphate), and this hyperresponsiveness increased with increasing levels of TMAO.


In the second part of the study, after a washout period, the 10 omnivores were given 81-mg aspirin each evening for a month, followed by 2 months of choline supplements, during which time the subjects continued on aspirin.  This time, the degree of TMAO elevation and platelet hyperresponsiveness were each attenuated. Aspirin lowered TMAO by about 40%.


"These studies argue that if you have a high TMAO—which is a clinically available test—you're clearly at heightened risk for experiencing clotting," said Hazen. "So maybe that's a primary-prevention group that not only should use more global preventive efforts but also should be on a baby aspirin."





The situation may to be different with L-carnitine.


Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

Robert A. Koeth et al.

PMCID: PMC3650111



Vegans and vegetarians produce less TMAO from L-carnitine


The capacity to produce TMAO (native and d3-labeled) following L-carnitine ingestion was variable among individuals. A post-hoc nutritional survey performed amongst the volunteers suggested antecedent dietary habits (red meat consumption) may influence the capacity to generate TMAO from L-carnitine. To test this prospectively, we examined TMAO and d3-TMAO production following the same L-carnitine challenge, first in a long term (>5 years) vegan who consented to the carnitine challenge (including both steak and d3-(methyl)-carnitine consumption). Figure 2a illustrates results from carnitine challenge in this vegan volunteer. Also shown for comparison are data from a single representative omnivore with reported common (near daily) dietary consumption of red meat. Post-prandially the omnivore showed both an increase in TMAO and d3-TMAO levels in sequential plasma measurements (Fig. 2a), and in a 24 hour urine collection sample (Fig. 2b). In contrast, the vegan showed nominal plasma and urine TMAO levels at baseline, and virtually no capacity to generate TMAO or d3-TMAO in plasma after the carnitine challenge (Fig. 2a,b). The vegan subject also had lower fasting plasma levels of L-carnitine compared to the omnivorous subject (Supplementary Fig. 6).


To confirm and extend these findings we examined additional vegans/vegetarians (n=23) and omnivorous subjects (n=51). Fasting baseline TMAO levels were significantly lower among vegan/vegetarian subjects compared to omnivores (Fig. 2c). In a subset of these individuals an oral d3(methyl)-carnitine challenge (but with no steak) was performed, and confirmed that long term (all > 1 year) vegan/vegetarians have markedly reduced synthetic capacity to produce TMAO from oral carnitine (Fig. 2c,d). Interestingly, vegan/vegetarians challenged with d3-carnitine also had significantly more post-challenge plasma d3-carnitine compared to omnivorous subjects (Supplementary Fig. 7), a result that may reflect decreased intestinal microbial metabolism of carnitine prior to absorption.



But slog through this for additional insights:

Effect of Vegan Fecal Microbiota Transplantation on Carnitine‐ and Choline‐Derived Trimethylamine‐N‐Oxide Production and Vascular Inflammation in Patients With Metabolic Syndrome

J Am Heart Assoc. 2018 Apr 3; 7(7): e008342.
PMCID: PMC5907601  PMID: 29581220



Edited by Sibiriak

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Grapefruit juice, cruciferous vegetables, garlic, and red wine/resveratrol have been mentioned as foods which may reduce TMAO production.




And I ran across this study on pistachios, which may or not be relevant.


Effect of pistachio consumption on the modulation of urinary gut microbiota-related metabolites in prediabetic subjects.


Hernández-Alonso P et al.

J Nutr Biochem. 2017 July


Edited by Sibiriak

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Re. after reviewing the TMAO thread, choline and TMAO production. From what I grasped from different sources, podcasts and so on (I don't even remember which ones, but among them a panel of lipidologists, Dr. Greger, Masterjohn, others):


  1. The TMAO issue is still controversial, not accepted by all objective experts
  2. The TMA-producing gut bacteria are absent in vegan individuals, since they proliferate only when animal compounds are present in the GI tract. So, even by using supplements like choline salts, there is no way, if this assumption is right, that vegans or vegetarians can have a consequent presence in blood of TMAO. In this aspect, choline salts would even be safer than PC, since it seems that the latter can carry some pre-formed TMAO.

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I'm leaving last the most surprising results: the lipid panel


The weirdest thing is that, now that I'm a vegan, eating almost no cholesterol, my cholesterol is higher than the value I had as a lacto ovo. Since other people have observed this, I'm going to open a dedicated thread on the topic:



Edited by mccoy

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Re. low-normal blood Iron and hemoglobin. I'm looking up at the other parameters which suggest anemia, as reported in chris Masterjohn's cheat sheets on test labs:



On a complete blood count (CBC) ( LabCorp , Quest ) low hemoglobin , low mean
corpuscular hemoglobin (MCH) , and high red blood cell distribution width (RDW)
are indicators of iron deficiency anemia. Mean corpuscular volume (MCV) is likely to
be low (making the anemia microcytic), unless a deficiency of vitamin B12 or folate also




My MCV, MCH and RDW do not follow the above patterns, so I'm pretty positive I'm not borderline anemic, which would have annoyed me not little since I'm eating about 300% RDA of iron.

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I've been reviewing again all the material posted by Sibiriak on TMAOs and choline. It remains controversial, but controlled trials did point out that in vegans TMAOS are formed after 500 mg choline salts are assumed. That's bad news for those who wish to supplement, me included. I'm thinking about ditching the choline bitartrate wich was shipped to me just today, but maybe I'll just take 100 mg per day, only to increase a little my dietary choline. I'll try and increase the dietary sources as well, then I'm going to forget about it.

Increasing B12, taking some TMG supplements and folate supplements should obviate any methylation problems and eventually decrease homocysteine. 


And what about the pescatarians? Fish seems to produce huge amounts of TMAOs. Is Valter Longo totally wrong in suggesting fish three times a week?

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New bloodwork after 2 years, and some of the results have been a little unexpected.

fasting blood sugar is 89 mg/dL, and that's all right since I'm eating more sugars, especially simple ones since the previous analyses. AbA1C is 6.1%, a little on the high range. Must start to check my carbs intake in a while.

The lipid panel is discussed in another thread, but it reflects my increase in SAFAs from dairy products.

Ferritin is 64 ng/ml, twice the lower bound of the lab range: 30-350

Blood Iron is weird: 231ug/dl, above the upper bound of the lab range of 65-175. I really wonder why since I was expecting a low value, since I'm eating dairy products with no iron, less spinach and green vegetables than the previous time, less iron overall. Maybe the answer is iron from cacao powder? I really don't know, although it may be some sort of a spike.

Total PSA is good at 0.9 ng/dl, no prostate problems, I had a urological examination a few months ago and the only part left was the PSA. Good.

WBC is slightly lower than the lower bound of the lab range: 3.9 L10^3/uL.

RBC is 4.9 and all other relevant parameters are good.

Testosterone is normal-high: 21800 nmol/L, compared to the lab range for >50 years; 6680-25700. 

IGF-1 is unexpected. Since I'm eating lots of methionine ingesting abundant yogurt, I was fearing some high values with a concomitant possible higher cancer hazard. Nothing like that, my IGF-1 is normal- low ar 91 uU/ml. In theory, it should have been higher. This shows how individual situations may vary. Also, my IGF-1 is lower than the 140 value suggested by Valter Longo for all ages. I already eat enough protein and exercise, so I'm not sure I'm going to go for a higher value.

Last my homocysteine at 15.2 umol/L is still a little higher than the  upper bound of the lab range: 14.5, the issue noticed in my previous labs is persisting.


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