In the functional medicine community, we’ve been taught that lowering homocysteine into the normal lab ranges by taking B-vitamins is one way to lower cardiovascular risk. But is it? Let’s take a look at what the research really shows.
In This Episode
Episode intro … 00:00:42
Overview of homocysteine … 00:03:32
Homocysteine and heart disease … 00:04:33
Using B-vitamins to lower homocysteine … 00:11:16
Does lowering homocysteine affect cardiovascular outcomes? … 00:12:34
MTHFR … 00:17:04
Diet for cardiovascular disease and overall health … 00:20:34
Homocysteine as a marker for a deeper, underlying health issue … 00:27:13
Episode wrap-up … 00:35:26
Subscribe for future episodes
Welcome to Dr. Ruscio Radio, discussing the cutting edge in health, nutrition, and functional medicine. To make sure you’re up to date on this and other important topics, visit DrRuscio.com and sign up to receive weekly updates. That’s D-R-R-U-S-C-I-O.com.
The following discussion is for educational purposes only and is not intended to diagnose or treat any disease. Please do not apply any of this information without first speaking with your doctor.
Now, let’s head to the show!
Dr. Michael Ruscio: Hey, everyone, this is Dr. Ruscio with your fast facts for today’s episode on homocysteine and heart disease.
There actually are not fast facts, and I think once you listen to the episode you’ll realize why. Apologies for not having that, but I think fast facts would be at the detriment to everyone’s learning on this one today, so enjoy, and if you have any comments or questions, please feel free to post them in the comments section with this post. OK, thanks. Bye.
DR: Hey, guys. Welcome to Dr. Ruscio Radio. This is Dr. Ruscio, and I am here with Susan McCauley of Evolve Nutrition. Hey, Susan, how’s it going?
Susan McCauley: It’s going good. It’s one of those balancing acts of making sure to get all your work done, but also taking care of yourself. I just got back from a one-hour walk, so I feel pretty energized right now.
DR: Nice. I am jealous.
SM: I had to set it in my schedule. That’s crazy, when you get so busy that you have to actually calendar in a walk.
DR: Yeah. Well, you have to take that time for you, so you’re there for today. You got your self-time checked off.
SM: Yeah, and I also put it on my to-do list because I love checking stuff off my to-do list. How about you?
SM: It makes me feel productive! Speaking of productive, we have a great topic. Why don’t you tell us all about it.
DR: Yeah. I thought we could talk today about homocysteine and heart disease. We don’t really talk a lot about heart disease on the podcast, and admittedly, it’s not one of the areas that I’m actively treating in the clinic and/or actively researching. However, I should say that the more I learn about the gut and the more we learn about the immune system’s impact on heart disease, I feel more and more comfortable about the positive impact that we can have on the cardiovascular system through the gut because of the huge gut-immune system tie-in. Even though I don’t have a primary focus on cardiovascular, it’s not unusual for us to see cardiovascular profiles improve, levels of inflammation go down, and I’ll see more and more being published in the literature that things like unfavorable particle size or particle counts may be an end byproduct of inflammation, and we know so much of inflammation is caused via the gut.
So even though it’s not something I am hyper-focused on, there was something I got pulled into as part of some of the research for the book, looking into betaine hydrochloride or just hydrochloric acid supplementation. I got pulled into some papers on betaine’s ability to lower homocysteine. There’s some interesting information on homocysteine I’d like to make people aware of, and so with that as our long intro, I thought we could jump into this topic.
Overview of Homocysteine
SM: Yeah, so can we start by just giving people an overview of what homocysteine is and maybe why we should or should not be concerned about it?
DR: Yes. Homocysteine is a protein molecule that, when elevated, has been correlated with cardiovascular disease. To put it simply, to give the very basic orientation, homocysteine is something that can be tested via a very simple blood test, and when elevated, it may put one at heightened risk for different types of cardiovascular disease.
SM: What is the mechanism that we think is in play? If your homocysteine is elevated, what is actually taking place in your body? Is your body not processing something somewhere else and you’re just ending up with too much?
DR: Well, that’s a good lead-in into a few of the studies I wanted to touch on.
DR: So I’ll use that as a jump-off point.
Homocysteine and Heart Disease
DR: One review paper looking at homocysteine in cardiovascular disease has reviewed a few mechanisms (1). The basic mechanism likely involves a couple of things. One is known as endothelial damage. The endothelium is just a lining on the inside of your blood vessels.
SM: And it’s only one-cell thick, correct?
DR: I’m not actually sure.
SM: Oh, OK.
DR: There’s the endothelium, and then there’s the media, the intima… There are a few layers, and be honest with you, off the top of my head, I don’t remember how thick every layer is. It may be, but I don’t want to say yes if I’m not sure on that.
SM: OK, fair enough.
DR: This is one of the innermost layers of your blood vessels, so it’s essentially the lining of your blood vessels. Anything that can cause damage there has the potential to initiate atherosclerosis, which can start the process of occlusion, which can then lead to heart attack or other cardiovascular episodes through the process of damaging your blood vessels, essentially. This is likely also through elevations of C-reactive protein, which is an inflammatory marker that has been shown to correlate with risk for cardiovascular disease.
So the really simple answer to that question is, homocysteine, you can almost picture it like this little—just to use a very loose analogy—a little piece of barbed wire that’s trickling through your blood vessels and kind of scraping the edges and causing inflammation and damage.
SM: OK, as opposed to what doctors tell people all the time, that the saturated fat that they’re eating is clogging the arteries.
SM: That’s a whole other thing, but the visual is all I’m saying. That visual of the little barbed wire guys kind of floating through is actually more accurate, the damage that’s being done to the vessels as opposed to the fat that you eat clogging your arteries.
DR: Sure. Ultimately the mechanism that we want to avoid is just something that may cause irritation to the blood vessels. Fat has been vilified in that regard. Of course, the answer to that question is not a simple one, but I think we all understand that it’s the trans fats, the synthetic processed fats, that tend to be harmful. Natural fats—even saturated fats, which were predominantly vilified—via further research, don’t seem to have that correlation. One of the newer kids on the block now is this molecule homocysteine.
Now, we’ve gone over the mechanism, so what do we see in terms of some of the studies? Well, we do have high-level scientific data, meta-analyses, that have looked at observational studies. As we’ve summarized what has been found from numerous observational studies, we have seen—and meta-analyses have concluded—that elevated levels of homocysteine are an independent predictor for later cardiovascular incidents or even cardiovascular death (2). When I say “independent predictor,” that means it doesn’t matter if you smoke or if you exercise or don’t exercise or if you eat well or poorly, irrespective of all those things, if the homocysteine is elevated, it is independently a predictor of subsequent cardiovascular events or death.
SM: So if you eat paleo and you walk every day but you have high homocysteine, there might be a problem in your future.
DR: Right. One of the things that’s important with observational studies is that we control for other variables.
DR: For example, if you have a sample of a hundred people and most of those people were eating a really, really poor diet, that poor diet may have caused high homocysteine, and the cause of cardiovascular disease may have ultimately been the poor diet, and the homocysteine was just kind of along for the ride. When we isolate for these things, we isolate for what effect homocysteine has. So when we say it’s an independent predictor, it means it’s not skewed or it’s not a false association that we’re seeing because someone has poor diet, poor lifestyle, or might smoke. All those things aside, when we isolate and control for all those different variables, this still seems to be a predictor of heart disease. That means it’s much more significant.
DR: And there have been other studies, and we’ll put the links in the transcript as usual, but other studies have also shown this association (3) (4). We have a fair amount of association data, and how this occurs may be through depletion of folate, vitamin B6, and vitamin B12. This ties in with some other interesting findings that it may be a vitamin deficiency that is driving this. Certainly the gene polymorphism MTHFR is something that factors into this. MTHFR is a gene polymorphism that can interfere with someone’s ability to absorb or utilize folic acid, which is what’s added to the food supply. There has been some speculation in some of the literature that that may factor in with this, so this high homocysteine may be caused by a deficiency of some common vitamins, and there may be a genetic component for people who can’t well absorb those vitamins, putting them at higher risk.
Are you with me on all of that, Susan?
SM: Yes. So if you have this gene polymorphism, you might process folic acid differently. It doesn’t guarantee that you will process it differently. Just because you have it doesn’t mean this is going to happen, correct?
DR: Right. There’s no guarantee, but it’s one of the things that has been proposed to increase one’s risk. Exactly.
Using B Vitamins to Lower Homocysteine
DR: Now, the next question would then be, if we see this high homocysteine associated with cardiovascular events like stroke and heart attack and/or cardiovascular death, like death from a stroke or a heart attack, and it may be associated with a vitamin deficiency, by giving certain vitamins like folate or B6 or B12, could we lower this homocysteine? This has been shown. There have been a few papers, even review papers, showing that administration or just supplementing with B vitamins, folate or even folic acid, B6, and B12, has been shown fairly consistently to lower homocysteine (5.1) (5.2) (5.3) (5.4) (5.5). Again, we even have meta-analyses of clinical trials showing that supplementation with folate, B12, and B6 can lower homocysteine. There’s definitely some favorable evidence that we see here for using vitamin therapy in this regard, in this realm.
SM: So should everybody run out and grab some B vitamins at their local health food store?
Does Lowering Homocysteine Affect Cardiovascular Outcomes?
DR: Well, I certainly think there is some evidence that supports this. It’s a very cheap and easy lab test to run, the treatment is straightforward and easy to track, and we have quite a bit of association data and we have some mechanism data, but I’m hoping that some of the people listening are asking themselves, through some of the concepts that we’ve been going over over the past several months, which is before we do anything based upon observation or based upon mechanism, we should look to clinical trials. Now, we’ve discussed that some of these clinical trials lower homocysteine, but as we’ve discussed in the past, we want to make sure that these clinical trials show a positive outcome. Moving a value up or down on a lab doesn’t mean that that value moving is going to have a positive impact in your health or in your life.
So when we transition into what the outcome studies show, we see a very different picture emerge, and I was actually a bit taken aback. We have quite a number of studies showing, yes, that using things like folic acid, B6, and B12—just vitamin supplementation—will lower homocysteine. That’s been very well documented. However, what has not been shown is that doing that has any positive impact on cardiovascular disease or cardiovascular death. The level of support here is incontrovertible. There are at least three—and I’ll put the links in here—meta-analyses of clinical trials. One meta-analysis looked at 12 clinical trials (6.1). Another meta-analysis looked at eight clinical trials (6.2). Another meta-analysis looked at 22 clinical trials. Most of these have shown that, yes, vitamin supplementation will lower homocysteine, but it has no impact on cardiovascular disease episodes or death. (6.3) (6.4) (6.7) (6.8) (6.9) (6.10) (6.11) (6.12)
There have even be two Cochrane Database systematic reviews (6.5) (6.6.1) (6.6.2), and the Cochrane reviews, they attempt to really isolate for bias to make sure that the results that we’re seeing are not biased. They’ve also concluded that there is no positive impact from the supplementation.
I’m hoping that people listening to or reading this will appreciate that it’s easy to get swept into this interesting mechanism of the homocysteine barbed wire causing inflammation in your arteries and the association with this marker and heart disease and the ability of a vitamin to even lower this marker. All this is very alluring. However, what people are ultimately after, I think, is, will taking said vitamin actually improve my health? And in this case, it will not. The evidence here is, again, incontrovertible.
With that, Susan, I guess I can pause for a second and ask, any questions on that?
SM: This is really interesting to me because in nutrition school we were taught a lot of about homocysteine and about MTHFR and that if somebody had high homocysteine and had the MTHFR SNP to give them methyl donors, so folate, B6, and B12. And my husband actually fits that scenario. He’s MTHFR 677 homozygous, he has high homocysteine, and he’s healthy in all other respects, so I have him on Methyl-Guard by Thorne right now. So now I’m like, wow, I think I could save some money!
SM: But what about food wise? Do you think that it’s different between maybe taking a supplement and getting all of these vitamins from leafy green vegetables? Do you think that there’s anything there, that that would be more beneficial? Are there any studies that look at that?
DR: Well, there are two excellent questions that you’re asking there.
DR: The first one, to MTHFR, I have to say that I really think much of the MTHFR concerns have been really taken out of context. MTHFR does not mean that you need to go on a bunch of supplements. It means that you don’t well utilize folic acid, but most of your food will be containing folate, so it’s not really a big deal. I think people forget that. If you eat a halfway decent diet with some vegetables in it, some leafy greens, you will be getting plenty of folate, and MTHFR has no impact on that at all. It only has an impact on your ability to utilize folic acid, so if you’re eating only processed foods and relying on the folic acid that’s fortified to those foods, this could become an issue.
SM: And taking cheap multivitamins, as well.
DR: Right. But what I see in the clinic is people thinking that when they come back heterozygous for homozygous for this SNP or that SNP of the MTHFR, thinking that this has a high clinical meaning, and it really doesn’t, in my opinion. And I say this after having used a MTHFR protocol for a year on all patients and tested this and monitored their response. There’s always a time and a place, but I have to say it’s my clinical observation that in most cases it really means little to nothing, because one of the best remedies for this is just eating a healthy diet, and then boom! Your MTHFR polymorphism has very little impact because now you’re just eating a bunch of folate and your body can absorb and process folate just fine if you have the MTHFR polymorphism. That’s the one part.
Then the second part, Susan, is regarding what you learned in nutrition school. I think that exemplifies a classic mistake, which is making a clinical recommendation based upon mechanism data. Like we discussed in one of our last podcasts, mechanism data is considered one of the lowest levels of clinical evidence. It’s pretty much at the bottom of the evidence pyramid for this very reason, because we cannot and should not make clinical recommendations based upon mechanism information. What you were taught and what this research is showing is a perfect illustration of that. This sounds very appealing and logical via a mechanism discussion, but when we look at the clinical trials, we find that the mechanism was a bunch of fanfare really that meant nothing.
SM: It’s so tempting because it seems so easy, such an easy fix. Just some B vitamins and you don’t have to worry about it, but what you’re saying makes so much sense. I’ve thought for a long time that the whole MTHFR thing that everybody needs to be taking methylfolate didn’t sit well with me as a blanket recommendation.
SM: And now all the pieces are kind of starting to fit into the puzzle for me.
Diet for Cardiovascular Disease and Overall Health
DR: Regarding food, it’s a harder question to answer because ultimately what we would be asking and answering there is, is there a diet that will give you the lowest incidence of cardiovascular disease? Not really so much is there a diet that’s going to be better or worse at lowering homocysteine, because we’ve already seen that lowering homocysteine doesn’t seem to have a huge effect on cardiovascular disease. I think, to the diet piece, that’s going to be very individual. Some people do better, for example, on more carbs, and other people more carbs cause high insulin, high cholesterol, and high inflammation. So when we look at some practical markers of overall health, which I think are always an excellent correlate to overall disease risk, when we look at things like body composition, blood sugar, cholesterol, inflammation, and just someone’s general well-being symptomatically, the diet there can be very different for different people. Kind of like Allison Siebecker and I discussed a couple of weeks ago, usually the best diet for someone is the diet that they feel best on. So to answer that question about what is the best diet in this regard, I think, is one that needs to be individualized.
SM: Right. More and more, I think, we’re starting to learn that with different research studies that come out, that different foods affect people differently. I can eat a higher carb diet than other people, but then I have to eat a lower carb diet than other people. I know when I’m in my sweet spot, and when I’m in that sweet spot, it’s easy because I feel good. Whenever I try to tweak it outside some, because I do a lot of n=1 and I’ll see something on the internet and try it, and whenever I get out of that comfort zone, it’s hard, it’s not fun, and I don’t get good results.
DR: You know, as you were making that point, I was reminded of a couple of things. Christopher Gardner, the PhD from Stanford who was on a while back (7), discussed that all healthy diets can work for some people, and the common trend that tends to provide most of the clinical benefit on any kind of diet, whether it’s paleo or Mediterranean or vegetarian or what have you, tends to be the removal of processed foods, the removal of sugar sweeteners and sugar-added drinks. That tends to get us the majority—60 or maybe 70 percent, I believe, was his estimate—in terms of the clinical benefit from diet.
Allison Siebecker made a remark that when you see different clinicians having very different opinions on a certain treatment, it probably means that that treatment doesn’t make a very large difference. If it made a really large difference, we would see people in agreement, right? Like I’ve said before, the closer we get to truth, the more commonalities we find. We see almost everyone and almost every study shows that things like reducing processed food, reducing sugar additives, and reducing soda drinks and things like that has a great impact. Then we get into high-carb/low-carb, high-protein/low-protein, and here the opinions and the studies vary wildly, and this is probably because they don’t make as much of a difference as the other factors that we discussed that everyone agrees upon. That remainder, that variability, is dependent upon personalization.
SM: That’s so funny. You just bring to mind that I think the second Ancestral Health Symposium in 2012 was the very first safe starch debate, and oh, my God, I think they were going to throw blows pretty soon because the people that believed that carbs were OK versus the people that thought you shouldn’t have any carbs ever, they were so staunch in their views that it got a little… I don’t know what the right word is, but it was a little uncomfortable!
SM: Everybody disagreed so much, so maybe it’s so individualized that what works for one person might not work for another person.
DR: Right. I have constantly been humbled over the past few years because early in my career, I used to be much more of one philosophy or school of thought, and as I have listened to my patients and learned from monitoring them and read the scientific literature with an unbiased eye, it’s very clear to see that people can get healthy on a higher-carb, low-fat diet, on a diet that’s higher in whole grains—this has been published. Now, there are some that that works terribly for, but there are also some that that works better for. The evidence is there. It’s just an issue of do you want to see it or not? Do you want to recognize it or not?
There’s an old quote. I remember it from Brian Tracy. I don’t know if he coined it or not, but a man convinced against his will is of the same opinion still. If you want to believe that all starches are bad, and I get into a debate with you and I out-debate you, you’re going to walk away from that debate still thinking the same thing as you did when you walked into the debate.
DR: Also it’s reminiscent of another quote. A mind is like a parachute; it only works if it’s open.
DR: When people have these very hard-driving views on things, this is why I just like to offer people that dogmatism can only exist in the presence of ignorance. I say that politely. I don’t mean ignorance as an insult. I mean ignorance as someone who truly hasn’t looked at all the information.
Homocysteine as a Marker for a Deeper, Underlying Health Issue
DR: But to kind of steer us back from this lovely philosophical tangent—
SM: Yes! Let’s go back to homocysteine!
DR: What is the deal, then, with homocysteine? There has been some discussion in the published literature. There’s one review (8) that has remarked on this and another paper (9) looking into this issue directly that also commented that the homocysteine levels may be a marker rather than a cause of cardiovascular disease, inflammation, or dysfunction, and that it also may be secondary to heightened inflammation and immune activation. Again, what we’re seeing is that homocysteine may be a marker of inflammation and immune activation, which is another reason why I feel so good about my somewhat gut-centered approach, because that’s a great way to help with the immune system and with inflammation. Now, I’m speculating there, but I certainly think that’s a reasonable point of supposition.
There has also been a paper (10) that has commented that it may be a marker of kidney dysfunction. Those with chronic kidney dysfunction may be more prone to having elevations of homocysteine. Now, whether that elevation is truly because of the kidneys or maybe because of some of the inflammation associated with the kidney dysfunction. I don’t know, and I don’t know if we know, but I think the picture that’s starting to emerge is that homocysteine may be a marker of a deeper, underlying inflammatory or immune issue rather than this marker that we just can just force down and expect things to be fixed.
SM: Kind of like when somebody takes a statin to lower their cholesterol and it doesn’t change overall outcome of mortality or morbidity. They’re just lowering a number. The high cholesterol is usually an indication that there’s some other problem going on.
DR: Mm-hmm. And I honestly don’t know what the data shows. I haven’t gone through a comprehensive review of statins’ impact on cardiovascular disease. I’ll be curious to do that at some point. I have heard that statins do have antiinflammatory properties, and that may be what yields their benefit, but what that benefit looks like I’m unclear on. Is that just a suppression of cholesterol levels? Or does it correlate with less cardiovascular disease or death? I don’t know. I’ve only heard what others have reported, but I have become much more skeptical about what others report because I know people are just looking to find information that reinforces their pre-existing paradigm. So unfortunately, I’m kind of at a place now where I don’t really trust what anyone else has to say until the research team and I dig into something and weigh the evidence. So to your statement, Susan, I don’t really know. I’m not really sure what I think on that because I can’t believe what I’ve heard anybody else say!
SM: Well, all of this stuff is just so interesting to me and just so eye opening, so this is the last question I’ll pose. Say you have somebody, let’s give my husband as an example, low CRP, cholesterol in the normal ranges, good blood sugar, no gut issues, and only has high homocysteine. Would that just maybe be his level? Like that’s just where he runs with homocysteine?
DR: I don’t think we really know.
DR: I could speculate, and what I would speculate is that if everything else looks favorable, then I am much less concerned about one marker, even though homocysteine has been shown to be an independent risk factor for heart disease. If you’ve done everything that you can do with diet and lifestyle, and you’ve screened for any kind of inflammatory issue in the gut and you’ve done some of this basic fact checking, and if he feels good and has good energy and has good body composition and everything else looks good, then I think you’ve really done all you can in that case. This is a position, and maybe this is me being a bit too simplistic, but maybe sometimes we’d be better off knowing a little bit less about what’s going on internally.
SM: I was just thinking that! I was just thinking that because he is the picture of health. If anybody saw him, he has a great body composition, he’s healthy, he has good energy, he sleeps eight hours a night, and he goes for a walk every day. There’s nothing that I would fix… well, I’m sure there are things I would fix. [laughter] Don’t let him listen to this one! But like I’m saying, one marker. And you know, B vitamins, there’s nothing wrong with taking them.
DR: No. And there’s something else that maybe I should say here, which is with heart disease especially, it can be the “silent killer,” where there are not many other frank symptoms and someone then just drops dead of a heart attack. I understand that people would like to have markers here, but I also think—again, this is not something I’ve done a very comprehensive review of the literature for—but I’d be inclined to think that when we examine all the literature, we see that there are some factors, some genetic factors and early life factors, that we can’t modify, and so you kind of have this hand that you’re dealt, but you can do your best with what you’ve been given. If you do your best with what you’ve been given, meaning that you exercise, you’re eating a healthy diet that feels good for you, your basic blood chemistries, like your cholesterol and your inflammatory markers and your blood sugar and your triglycerides, all look good and in the normal ranges, and you have good energy, and you sleep well and everything else, then you’ve really done everything you can to reduce your risk of cardiovascular disease, and these are probably the populations that have the lowest incidence. Might there be someone who is “healthy as a horse” that has a heart attack and passes away from that? Yes. But there are things that we can control, and there are things that we can’t control. I think in your husband’s case, Susan, it sounds like you’ve done the best that you can with all the controllable or modifiable factors. Then I just think it’s an issue of going out and living your life and not getting overly obsessive about a lab marker, especially if that takes you away from just enjoyment and fun and everything else.
SM: Which we’ve talked about so many time over all the podcasts, that stress can negate any changes you’ve made. The Dark Side of Being Healthy, the episode with you and Chris Kresser, all of those things, that sometimes we want to get out of the numbers and get into life.
DR: Certainly. On the other side of the coin, I geek out and get very deep into all this stuff, but it’s one thing to get really deep into a topic, and it’s another thing to maintain some responsibility and some practicality. That’s what I’m hoping I’m bringing to people, and from the feedback that we’ve gotten on the website with the comments, I think people really appreciate this. It’s good to be progressive, but we want to also be practical. I just want to reiterate that because I’m always looking for the next best thing, but I’m also not gullible.
SM: Right. We want to stay off the bandwagon. Let’s investigate, let’s do our own work, but let’s refrain from jumping on the latest whatever it is.
DR: Yeah. I think people get that, and so I’ll step away from beating this proverbial dead horse any longer!
SM: Any last words on homocysteine to wrap us up?
DR: Just a quick reiteration. I hope people are again reminded of the importance of just looking at clinical trial data and what kind of health impact the clinical trials have and not getting caught up into observation or mechanism. If you can adhere to that, I think you will be prevented from getting pulled down unnecessary and excessive rabbit holes. Hopefully this episode has articulated that, but you can rest assured, if we haven’t, we will keep at it until we’ve gotten that message very well articulated!
SM: Yeah, and if you have any comments or questions, head on over to the blog post where the episode is, and you can post them there. We’d love to hear what you have to say!
DR: Absolutely. Fire away!
SM: Fire away. OK, guys, that’s a wrap for this week. We’ll talk to you again next week.
DR: Thanks, guys.
Thank you for listening to Dr. Ruscio Radio today. Check us out on iTunes and leave a review. Visit DrRuscio.com to ask a question for an upcoming podcast, post comments for today’s show, and sign up to receive weekly updates. That’s D-R-R-U-S-C-I-O.com.