Saturday, July 03, 2010

Folate and homocysteine

Anna (many thanks) supplied me with a copy of the paper with a title which suggested that homocysteine was a stimulator of sulphate incorporation in to cartilage comparable to ILGF-1 (somatomedin/sulphation factor in those days). They were looking at concentrations of homocysteine comparable to those seen in children with the genetic lack of the enzyme cystathione synthetase, around 10mg/dl. That's VERY high, about 10 times the level in the blood of a normal person.

At this concentration there are undoubtedly marked skeletal deformities in children with homocysteinuria, presumably due to elevated homocysteine mimicing ILGF1 in their growing bones. As normal children appear to develop GAG containing arteriosclerosis at an early age then the ability of markedly elevated homocysteine to produces excessive GAG incorporation in to cartilage might very well be expected to increase the incorporation of GAG in to arterial plaque from physiological amounts to pathological amounts. That doesn't seem controversial to me.

The question is then whether homocysteine, at the concentrations seen in the plasma of the genetically more normal general population, drives arteriosclerosis. And, much more interesting, whether lowering homocysteine prevents cardiovascular disease in this population.

The vast majority of the work on homocysteine was done by Kilmer McCully and is covered by his book The Homocysteine Revolution. I think it's reasonable to summarise his approach to diet and cardiovascular health as to "eat Food". Food, with a capital F, denotes sources of B6, B12 and folate, three of the main factors for the metabolism of homocysteine. Needless to say there is a marked de-emphasis of sucrose and white flour consumption. But there is also a de-emephasis on white fat. Obviously there is not a whole lot of B6, B12 or folate in lard or beef dripping. When you take this line of thought to its logical conclusion you end up with a diet containing lots of fruit, vegetables, fresh whole grains and good quality lean meat. It's not exactly the Optimal Diet, in fact the term that comes to mind is "Ornish" plus meat. Would this work? Who knows? As far as I am aware Ornish has never tested his diet ideas. But the concept of whole food, freshly prepared, makes a lot of sense provided you don't mind the auto immune diseases from gluten and have not already broken you liver with decades of the SAD to allow blood glucose of spike to 200mg/dl after a bowl of whole meal pasta.

For folks too lazy to cook or juice some leaves, how about a B12/folate/B6 pill? Well the Norwegians have checked it and the initial problem is that it doesn't work for CVD, though it drops homocysteine nicely. The paper is from 2009. You can read the full text if you would like the to know their proposed mechanisms for the failure of vitamin induced reductions of homocysteine to prevent CVD events, but here's the executive summary:

"All the above mechanisms partly explain why clinical trials on Hcy lowering, such as the VISP, NORVIT, or HOPE-2 and possibly others to be conducted, failed to report any improvement in CVD risk and clinical outcome. Maybe more efficient ways to target Hcy metabolism, other than vitamin supplementation, should be examined. Focusing on increasing Hcy renal clearance or reducing asymmetric dimethylarginine levels would be potentially useful. In addition, other strategies able to increase intracellular 5-MTHF should be developed, to achieve the maximum regulation of intracellular Hcy metabolism."

The problems with vitamin treatment for elevated homocysteine in CVD have continued to in 2010. There has also been a follow on report on cancer and all cause mortality, a 2010 paper from the Norway studies, which does not make the lowering of homocysteine by using B vitamins look too helpful.

The increase in all cause mortality is a very interesting finding. You could argue that, in people without genetic homocysteinuria, that there might be some benefit from homocysteine at around 13micromol/l which is lost by lowering it to 9micromol/l, assuming you are eating a diet which has already established your heart disease. Or, equally, you could argue that taking vitamin B12 and folate, in the form of a vitamin supplement, is bad for you. Perhaps 0.8mg of synthetic drug grade folic acid is not quite the same as eating a few leaves. Quite a lot of leaves in fact.

The later idea is interesting as the WHEL intervention study, with it's significantly increased vegetable (and so probably folate) intake, didn't actually kill anyone beyond the death rate in the control group. Mind you, it didn't help anyone either but then eating leaves for health is a bit of a weird idea to me.....

So there's the choice. Is B12/folate supplementation bad for you? Or is homocystene helpful in small amounts and damaging in large amounts? A bit like oxygen.


EDIT there has been a similar report from Oxford with similar trends but with no statistical significance. The Oxford study used 0.4mg folic acid and the placebo group will have been eating UK breakfast cereals which are folate supplemented. Norway does not supplement it's food supply with folate so compared 0.8mg folate with zero supplementary folate level for the placebo group. There looks to be a dose response rate to folic acid toxiciy, if that's what the driver is for the problems. Heartwire produced a nice summary slide.

I realise that none of the changes are statistically significant but every parameter was worse in the folic acid/B12 group. The Norway study is in a better position to find significant effects and p does drop below 0.05. The Norway study is also much less likely to be drug money influenced. Tends to be convincing.


Drs. Cynthia and David said...

Came across this podcast with Dr. J. David Spence He discusses the role of homocysteine as a clotting factor and says that it helps prevent stroke but not MIs since these occur by different mechanisms (he says MI is due to ruptured plaque and the thrombosis is secondary). He also discusses the widespread deficiency of "metabolic" B12 among the elderly (as opposed to mere serum levels), leading to stroke, deep vein thromboses, neuropathy, and dementia. Not as interesting as the ILGF-1 theory, but enjoyable listening anyway.


Stan Bleszynski said...

Hi Peter,

Very interesting, thanks for pointing out those new studies.

I have a nagging suspicion that since cholesterol is the symptom not the cause, Lp(a) likewise, so seems homocysteine may be! Therefore attempts at lowering it with drugs vitamins or herbs may make it worse rather than better, exactly like with statins.

The easiest most logical explanation is that the body increases homocysteine, cholesterol etc because it needs to, rather than being a mad "animal" conspiring to kill itself.

Medicine has wrapped itself in a knot because they started with the wrong basic premise and they refused to question it (in public).


Peter said...

Cynthia, yes, I think we do have a use for homocysteine. If vWD really is protective against CVD it's at the cost of bleeding... What's the cost of artificially lowering HCy? We pay significantly for taking warfarin and aspirin.

Stan, that's how I see the world. The OD and homocysteine is interesting, two posts time I think. Though I don't know when that might happen!


Stephen Boulet said...

I have to wonder if unmetabolized folic acid doesn't cause a lot of problems:

"Is unmetabolized folic acid the culprit? ... would it be safer to use methylfolate instead of folic acid as a supplement?":

"Unmetabolized FA was detected in the plasma of 78% of the women in this study.":

Peter said...

I certainly agree that taking a folic acid pill is not in any way comparable to eating a few leaves. Mono-"therapy" at mega dose rates with a substance found in small amounts in leaves has you so wide open to the law of Unintended Consequences that putting it in a nation's food supply is like putting fluoride in the drinking water. Or a statin in the drinking water for that matter.

It's interesting to consider folate toxiciy vs homocysteine reduction on CVD. I was wondering about a mechanism for folic acid toxicty?


Unknown said...

I will be eagerly awaiting more posts from you on this. I am heterozygous for MTHFR and FVL (Factor V Leiden) My homocysteine level was 2.1 3 weeks ago not taking any medication. I'm wondering how I will know if it's too low? Should I lay off the B vitamins for a bit even though I have 2 genetic thrombophilias?

Keep up the great work, I love reading.

Peter said...

Hi Holly,

That's an interesting position to be in. I don't doubt that homocysteine of 10mg/dl (100mg/l or 740micrograms/l) is bad news dierctly from the homocysteine. But in people with normal genetics homocysteine correlates extremely well with metabolic syndrome. So when we are looking at homocysteine levels of 13micromol/l (just under 2mg/l, your ball park) being reduced to 9micromol/l (25% reduction) in Norway using B vits we see no CVD benefit and increased all cause mortality. Now the problem here is that these people have metabolic syndrome and are treating a number without treating the metabolic syndrome.... They are doing it with excess folic acid, a very minor component of plant and liver mixed folates, which may or may not be responsible for the increased all cause mortality. On this we just don't know.

So that leaves the gaping hole in our knowledge about whether the reduction in HCy might be good and folate bad per se or the reduced HCy might be bad in the context of metabolic syndrome. Obviously a genetic problem which elevates HCy is a total unknown and may not be extrapolate-able from metabolic syndrome... Genetically elevated HCy is not up for a potentially beneficial reason. So dropping it ought to be fine IF the folic acid is non toxic. Which we don't know! We also don't know if geneticaly elevated HCy circa 2micromol/l is a problem without metabolic syndrome. I would suggest that anyone with any thrombotic disorder is not in a position to have metabolic syndrome under any circumstances!

If you are going to treat I feel you might be tempted to use mixed folates from liver topped up with (retch and gag in the corner) juiced leaves, if needed, on a LC background. Please bear in mind that these are logic and CVD-study driven thoughts. I've no experience with the rare combination of double gene dose you carry! Probably very few people do, yourself excepted.

Anyway that's how logic makes it look to me. You have to decide..... Stay well,


David said...

Regarding your comment on Ornish, I realize it's a sample of one, but Ornish claims to have been eating the Ornish diet since age 18 and he also claims to have a heart scan score of zero.

Peter said...

Hi David,

Ornish has a number of facets to his program which have nothing to do with diet, plus a diet which is low in sucrose and omega 6 PUFA. His having a heart score of zero is of no consolation to those of us being flatulated to Mediterranean temperatures in Glasgow...


Chris Kresser said...

I can't help wondering if the results would have been different had the researchers used methyl folate (5-methyltetrahydrofolic acid) instead of folic acid. They don't affect the body in the same way, and several studies suggest that folic acid (but not methyl folate) may be carcinogenic.

Toxic said...

All so relevant to me, suddenly. What a pity I am not up to speed. Just been diagnosed with pernicious anaemia, everyother daily injections of B12, and 5mg folate supplement. Wondering whether that will be too high.

Answers on a postcard please to. Anyone here have PA? Tx

Toxic said...

Suddenly so relevant. Just wish I was up to speed. Just been diagnosed with pernicious anaemia and folate deficiency.

Anyone have it? Know about it? Ideas about supplementation with folate when you know you are deficient?

Toxic said...

Sorry guys, thought it had eaten one of those posts.

Docww said...

When it comes to brain health lowing homocysteine does seem like a good idea. You want to do it L-methyfolate, not folic acid. L-methylfolate is the only form of folic acid to cross the blood brain barrier. It has been approved as a medical food to treat depression under the name of Deplin.