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.

Peter


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.