Methylation and sulfuration are complex processes and assessing them in clinical practice take skill, knowledge, and consideration of multiple genes and other factors. In this podcast, Dr. David Quig of Doctor’s Data Lab, talks with Dr. Fitzgerald about assessing methylation in clinical practice.
Dr. Quig received his BS and MS degrees in Human Nutrition from Virginia Tech and a Ph.D. in Nutritional Biochemistry from the University of Illinois. After a five-year stint as a research associate studying Lipid Biochemistry and Cardiovascular Disease at Cornell, he was a Senior Cardiovascular Pharmacologist for seven years. For the past 23 years, David’s been VP of Scientific Support for Doctor’s Data.
In this podcast, you’ll hear:
- The importance of considering multiple genes for a given metabolic process
- Understanding which patients are the best candidates for methylation investigation
- How to work with patients to explain that MTHFR status is just one data point in a much bigger, more complex picture
- The importance of looking at s-adenosylmethionine and s-adenosylhomocysteine
- The dangers of compromised collection at labs and draw centers
- The methylation profile available from Doctor’s Data, which includes methionine, cysteine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, and cystathionine.
- Why Dr. Quig doesn’t recommend supplementing with SAM
- The dangers of supplementing with SAM long-term
- How people tolerate 5-methyltetrahydrofolate differently
- The one benefit—and the many limits—of synthetic folic acid
- Understanding overmethylation / overmethylators
- Interventions for high homocysteine
David Quig, Ph.D. David received his BS and MS degrees in Human Nutrition from Virginia Tech and a Ph.D. in Nutritional Biochemistry from the University of Illinois.
After a five year stint as a Research Associate studying lipid biochemistry and cardiovascular disease at Cornell University, he was a Senior Cardiovascular Pharmacologist for seven years. For the past 23 years, David has been the Vice President of Scientific Support for Doctor’s Data, Inc.
He has focused on toxic elements, methylation and amino acid metabolism, the applied biochemistry of endogenous detoxification, and the influence of the gastrointestinal metabolome on overall health.
Dr. Kara Fitzgerald: Hi everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine and today is no exception. If you like what you hear from us, please circle over to iTunes and leave a review. I’m really excited to be talking to yet another brainiac but somebody who I’ve gotten to know over the years and I appreciate his intelligence, Dr. David Quig with Doctor’s Data Lab. Let me give you a little bit of his background and I’ll talk to you about the topic we’re going to be diving into today.
David received his BS and MS degrees in Human Nutrition from Virginia Tech and a PhD in Nutritional Biochemistry from the University of Illinois. After a five-year stint as a research associate studying Lipid Biochemistry and Cardiovascular Disease at Cornell, he was a Senior Cardiovascular Pharmacologist for seven years. For the past 23 years David’s been VP of Scientific Support for Doctor’s Data. He’s focused on toxic elements, methylation, and amino acid metabolism, the applied biochemistry of endogenous detoxification, and the influence of the gastrointestinal metabolome on overall health. David, welcome to New Frontiers.
Dr. David Quig: Thank you, Kara. It’s a pleasure to be here.
Dr. Kara Fitzgerald: It’s always great to be able to pick your brain. Today we’re going to be talking about kind of methylation. Maybe we’ll dabble a little bit with sulfuration because you really can’t talk about one without the other, and then the folate vitamer cycle, and some of the ways that we can use it in clinical practice. It’s incredibly useful and important in perhaps some of the things that we’ve misstated in the functional medicine or integrative medicine community. Just what’s your overall view of the clinical importance on assessing methylation?
Dr. David Quig: Thank you for that lead in because you dropped the word transsulfuration. But I want to take it back, preface this whole discussion with starting with methionine. If it were up to me, I would call this type of testing methionine metabolism, which is very boring and nerdy. But the fact of the matter is, you can’t synthesize a single protein in the body without methionine. That’s because the start codons of messenger RNA transcripts for every protein in the body starts with the code for methionine. Even if ultimately that methionine is cleaved post-translation, you can’t even start protein synthesis without that methionine…
Dr. Kara Fitzgerald: Without a smidge of methionine around.
Dr. David Quig: That’s right. And so…
Dr. David Quig: That’s the very first thing we look at when we look at methylation, transsulfuration. That’s the very first step. There’s people that try to evaluate methylation by looking at SNPs. But as you know, even a homozygous SNP with sufficient documentation of potential for impact may be physiologically insignificant. MTHFR is a classic example. For a given individual we have to consider multiple genes for a given metabolic process. For this process of methylation you really can’t look at MTHFR without looking at MTR and MTRR or even CBS. You’ve got to look at the whole picture.
But most importantly, in order to truly know what’s going you have to consider also substrate levels and very, very important, epigenetic factors including nutritional deficiencies, the co-factors, environmental toxicants, oxidative stress, and even drugs that the patients might be taking. We really need to look at the whole metabolic process as it’s actually playing out in the body. We can do that by looking at a blood sample. It’s sort of like hyper focused mini metabolomics really, pulling it all together, what’s really happening genetically and epigenetically.
Dr. Kara Fitzgerald: So all right. Let me just unpack a little bit of what you just said. Oh my goodness. Thank you. A lot of people listening to this are obviously going to be versed in methylation and transsulfuration, but for those of you whose jaw you’re actually right now scraping up off the ground, I just want to assure you that we’ll put a pathway chart up. In fact, we will also put sample reports of Doctor’s Data’s methylation panel. In fact, we could put the DNA panel up there too since we’re talking about some of the SNPs. We’ll just put the glutathione test and then the folate test. We’ll just put a bunch of sample reports up there of things that we’re going to be talking about today. Then we’ll put a pathway chart up there so what David has just mentioned you can kind of go back and look at, or start this over and have that open in front of you.
So you said that you can’t look at this in a vacuum. A lot of folks are just beginning and ending with their looking at single-nucleotide polymorphisms within the enzymes of the methylation and transsulfuration cycle. You’re saying you can’t do that. You’re saying that we need to look at substrates. We need to look at the activity happening in methylation and sulfuration.
Dr. David Quig: Absolutely.
Dr. Kara Fitzgerald: And then you also said, let me just say this and then I’m going to turn it back over to you. Then you also said, which I mean I’m so in agreement with you here, David, but you also said something that’s really near and dear to my heart, and that is the epigenetic influence. When we back up and think about that, you need to think about whole person and being in environment, so their nutritional status and their toxin exposures and the medications they’ve been on and their mental emotional sort of stress response. The whole kit and caboodle can have an influence on this pathway. Would you agree with that summary?
Dr. David Quig: Oh, absolutely. Especially with people that are new to this type of testing. When they call for a consult they’ll tell me the lab number, I’ll look up the report, and they’ll say, “What’s going on with this patient?” I say, “Well.” Then I have to start asking all these questions. “Tell me about their stress level. Tell me about their exposures.” All these different things. Then probably the last thing I ask is, “Do you have any genetic data for this individual?” So, so many more things other than just the genes.
Dr. Kara Fitzgerald: Yes. All right. Listen. Just so I don’t forget, are you available for consults?
Dr. David Quig: Absolutely.
Dr. Kara Fitzgerald: Are you still? You are? Okay. So clinicians, when you’ve got a head scratcher panel. Actually, I do this to you all the time, Dr. Quig.
Dr. David Quig: Yes, you do.
Dr. Kara Fitzgerald: You can consult with him. As you’ll hear from our conversation it’s just, he’s a goldmine of information. So who’s the best candidate for the investigation or methylation status?
Dr. David Quig: The classic would be just your simple LabCorp elevated homocysteine. That’s the branch point where you’re going all the way back up to methionine or irreversibly removing the homocysteine. Also, difficult hormone cases. We’ve got issues with COMT and estrogen metabolism. For that matter, people with, what do you call them? Psychiatric or psychological kinds of issues where you’ve got methylation involved in the metabolism of the catecholamines and serotonin. Then you’ve just got people with really bad or very limited diets, people with unexplained cognitive dysfunction, which as you know can be associated with so many different things. Especially…
Dr. Kara Fitzgerald: Even…
Dr. David Quig: Mm-hmm (affirmative)?
Dr. Kara Fitzgerald: I mean, wouldn’t you say even known, even if you’ve diagnosed the cognitive decline or I mean, wouldn’t they be appropriate to investigate?
Dr. David Quig: Absolutely.
Dr. Kara Fitzgerald: And any neuro, I would say neurological. Anyway. You go ahead. I’m going to hush.
Dr. David Quig: Absolutely. Then at the other side of that, the extreme cases like people on the spectrum, people with ADHD, and one of my favorites is just patients that are paranoid about their MTHFR analysis.
Dr. Kara Fitzgerald: Right. That’s great.
Dr. David Quig: If it’s something else you want to. I mean that single SNP causes more anxiety psychologically and may not really be affecting their metabolism at all. So simply to rid their anxiety before they self-medicate according to some blogger and make things even worse and really get anxiety.
Dr. Kara Fitzgerald: Yes. Amen, Dr. Quig. Jeez, Louise. That’s right.
Dr. David Quig: There was a doc at a conference one time that came up to me with her iPad. She said, “Oh.” She was just so depressed looking. She said, “Here’s my MTHFR results.” I just couldn’t believe it. She was just totally anxious and depressed because of this single little SNP. That led to a long discussion.
Dr. Kara Fitzgerald: Yes. Well, I’ll tell you what. I see it in clinical practice all the time, now that people can grab their genome or at least chunks of their genome, they can look at single-nucleotide polymorphisms very readily, there’s a lot of anxiety. I don’t think that it’s really been languaged well. It’s been overstated and you’re right. People show up at my office just really kind of desperate and scared. There’s a lot of reeducation involved in our work. I appreciate that you’re doing it.
That said though, that said, I just want to juxtapose with this statement, so we don’t want to overstate and get really anxious. We’ve got, what, like four million single nucleotide polymorphisms? I mean if we’re going to be getting anxious about our SNPs we’re all in deep trouble. So on one hand we need to nuance how we look at it but on the other hand, you just gave an extremely comprehensive list of folks who might want to consider investigating methylation. There’s utility in looking at methylation fitness, would you say in most individuals?
Dr. David Quig: I don’t know about most but certainly a high percentage of people, particularly people that are coming in with mood disorders. It’s very common. There’s more and more psychiatrists now that are getting so much more involved with nutrition and they actually deal with methylation and methionine metabolism and get people off their psychoactive drugs. They go to the source of the problem instead of covering up the symptoms and they fix it. It’s really fun.
Dr. Kara Fitzgerald: It really is. In fact, if you want to hear a pretty cool podcast folks, I talked to Dr. Bob Hedaya, who’s just a functional medicine luminary. He’s a psychiatrist. To listen to him talk about methylation and using it in his practice is quite inspiring. Then you also talked about estrogen detox. He gives an interesting case where correcting a woman’s methylation imbalance using folate also turned around her estrogen detox and resolved her endometriosis. He didn’t go in planning to treat endometriosis; he’s a psychiatrist. She’s like, “Hey, by the way, my endometriosis is gone.” It was pretty mind blowing.
Dr. David Quig: Wow.
Dr. Kara Fitzgerald: All right. You guys are looking at s-adenosylmethionine, like just a fundamental player in the methylation cycle. You’re also looking at s-adenosylhomocysteine. Some labs are only looking at s-adenosylhomocysteine and not s-adenosylmethionine. Talk about limitations with that, why they might be. Let’s just, yeah, go into it.
Dr. David Quig: Yeah. Absolutely. Well SAM, s-adenosylmethionine, the methyl donor, the first step down from methionine, is very, very labile or fragile. When you do a blood draw, you spin it down to get the plasma, you have to immediately pipette off that plasma and acidify it. If you don’t acidify it, that SAM will actually just disappear very rapidly over time, making null and void the results for that particular analyte. But it’s such an important analyte. The instructions for how to do this are so straightforward. I do understand in busy clinics people put stuff in a centrifuge and they get busy and they forget and, “Oh my, it’s too late. It didn’t get acidified.” But it’s so critical because that is the very first step.
If all you’re reporting is SAH without knowing the balance between SAM and SAH it’s really hard to try to judge in conjunction with the presentation of the patient whether there’s truly inhibition, whether there’s possibly over-methylation. True SAH is in fact an extremely potent inhibitor, but that’s exacerbated when you have very low levels of SAM. We continue to look at SAM. In some cases I look at reports and say, “Yes, that was mishandled but there’s still a lot of useful information in that report.”
Dr. Kara Fitzgerald: All right. So handle the specimen, pay attention, follow the collection instructions. If you’re sending somebody to a phlebotomist, have them pay attention.
Dr. David Quig: Yeah. Those are the worst. I’m not real fond of draw centers. They tend to not take you seriously, the instructions, and do things as they get around to it.
Dr. Kara Fitzgerald: But what’s going to be the tip off for compromised collection?
Dr. David Quig: Let’s say, this is a classic reaction of a precursor in a product. If there’s a problem in that first step, let’s say it’s just simple magnesium deficiency so that methionine isn’t being converted to SAM. Well if that was truly happening, the level of methionine would be high because there’s a block there. The product, SAM, would be low. So if you see a very low SAM and it’s been done at a draw center or, you know, and the methionine is not elevated, that’s a real clue that it’s not an issue of a step down but rather sample mishandling.
Dr. Kara Fitzgerald: Okay. Okay. So basically, if SAM disappears and you don’t see a really high methionine.
Dr. David Quig: Right.
Dr. Kara Fitzgerald: Okay. Okay. I think the other piece, you know a lot of the good science looking at methylation uses the SAM:SAH ratio, the methylation index which you have on the panel. I just can’t imagine not having that piece of information.
Dr. David Quig: Well, and the other thing is that SAM itself, the actual level of S-adenosylmethionine in the cell as indicated in the plasma, is in fact a metabolic switch. When SAM goes high, it shifts the metabolism around and says, “Okay, we don’t want to put as much back up through methionine synthesis. We don’t want to take homocysteine back to methionine because that’ll just make more SAM.” So it inhibits at MTHFR and turns on, throws the switch like on a railroad track, to increase the flux down through transsulfuration so homocysteine will now be removed from that whole pathway so that you’re not continuing to generate excess SAM. So, SAM is a really important metabolic switch, if you will, to direct the metabolism.
Dr. Kara Fitzgerald: That’s really fascinating. And also, under conditions of oxidative stress those enzymes are going to kind of grind to a halt so homocysteine can be shunted down into glutathione synthesis.
Dr. David Quig: Yes.
Dr. Kara Fitzgerald: All right. So, I just want to let folks know. You probably know this but in case you don’t, the methylation profile from Doctor’s Data is, as David said, done in plasma. Methionine is on it, cysteine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, and cystathionine. So you get a snapshot of methylation as well as sulfuration and then the SAM:SAH ratio is there. Now you just kind of led us into my next question to you. That is, you don’t recommend supplementing with SAM. Why is that?
Dr. David Quig: Well certainly not long-term. Short-term, I would say, again I’m not a clinician but I’ve known people that use it for diagnostic approaches. If they truly believe that a shortage of SAM is the issue you can try throwing in some SAM and see what happens. But it’s not a pharmacological fix by any stretch of the imagination. Again, you have to figure out why SAM was low, why that person needed more SAM. Did they have a greater demand for methylation? If so, let’s increase their methionine or their choline, eat some eggs.
Dr. Kara Fitzgerald: Right.
Dr. David Quig: But the other really important thing is that if people just go to the corner drugstore and buy a bottle of SAM, it’s probably useless. Because again, SAM is very, very unstable. Unless it comes in blister packs, individually wrapped tablets or capsules of SAM, it’s likely to be a brick and probably not do a whole lot. The compounding pharmacies I know definitely sell SAM in individual blister packs. Again, the other thing, why not to use it long-term? It actually inhibits MTHFR and the conversion to tetrahydrofolate, which is an essential component of the folate cycle.
When we talk about going through MTHFR, yes of course it’s to make 5-methyltetrahydrofolate, the most bioactive form of folate, but you also kick tetrahydrofolate back into the folate cycle to keep that going. That’s critical because the folates have a critical role in DNA and RNA synthesis and the recycling of BH4. Again, you got BH4 involved with neurotransmitter metabolism, catecholamines, serotonin. Also, if you get SAM too high it not only inhibits MTHFR, which you’re trying to normalize the product from that, it also inhibits MTR, the next enzyme up, and critically, BHMT the route where you don’t have to go through MTHFR. So you’re really potentially totally disrupting the entirety of methylation by throwing in pharmacological dosing with SAM.
Dr. Kara Fitzgerald: Right. For long-term. So, a quick…
Dr. David Quig: Yes, long-term.
Dr. Kara Fitzgerald: Okay. Because it can be actually quite helpful in certain patients. But without question in my practice I’ve seen folks come to me taking it and have some unusual looking methylation panels as a result, some imbalances requiring correcting, so yeah.
Dr. David Quig: You have to remember that all SAM in the body will ultimately become SAH. If a person starts feeling better taking X grams of SAM, the classic North American approach is, “Oh, that was good so more is better.” So they take a lot more and next thing you know they’ve created so much SAH that they’re, again, impeding or inhibiting the process that they’re trying to facilitate.
Dr. Kara Fitzgerald: Yeah, that’s right. And as you point out, there’s all sorts of feedback inhibition and you just end up imbalancing this delicate and rather involved folate cycle. Okay. The Doctor’s Data folate metabolism panel, you’re looking at, and I’m going to ping you on some questions, but you’re looking at folinic. You measure folic acid or synthetic folate. You’re looking at tetrahydrofolate. And then, of course, 5-methyltetrahydrofolate. That’s the panel available in plasma.
Let’s just talk about, you talk about SAMe actually being able to throw off a folate-vitamin cycle. You’re talking now too about using high doses of MTHF with patients. But just talk to me about what you’ve seen in labs and from talking to other clinicians and your thoughts around how you dose different folates, when to use what, and what kind of problems we might encounter.
Dr. David Quig: The interesting thing about 5-methyl is there’s pretty much three different types of people. Some tolerate it just fine. Others crash immediately, anxiety, insomnia, anger to rage, just totally brain fog. Others will do okay for a little while and then crash. It’s really difficult and why I don’t want to get into specific dosing, again, because I’m not a clinician. But I just think with all my background in pharmacology it always makes sense to start out low and even pulse. Maybe even not even every day. Start out low and slowly build up. You don’t want to throw a big dose at people and then have them come back or call you and say, “Oh my God. I’m going crazy.”
Dr. Kara Fitzgerald: What do you think is prompting that reaction with methylfolate in particular? What’s happening biochemically do you suspect?
Dr. David Quig: Well, you’re creating an excessive amount of SAM. High levels of SAM also inhibit a super enzyme called GNMT, glycine N-methyltransferase. Glycine N-methyltransferase is the way for the body to handle an overflow of SAM. It’s unlike other methyltransferase, GNMT is not down-regulated or inhibited by SAH. When you have an excess amount of SAM the body comes to the rescue with this very robust enzyme that takes that SAM and converts it, methylates glycine and converts it into sarcosine, which is very safe and actually beneficial for the liver.
You just don’t want to knock out that enzyme because that is the enzyme that will naturally keep, under normal conditions, normal genetic and epigenetic conditions, the level of SAM at a level that will provide adequate methyl donation and not overdo it.
Dr. Kara Fitzgerald: Huh, that’s pretty interesting.
Dr. David Quig: And to follow on that, that’s with 5-methyl. I think that underappreciated is folinic acid. Let’s take a step back and talk about uncooked green leafy vegetables. We got to start there.
Dr. Kara Fitzgerald: Yeah, that’s right.
Dr. David Quig: But folinic acid is an awesome form of folate vitamers. It can go as the body needs in through MTHFR, it has its own path going in through and being involved in DNA synthesis, and even over to recycling BHT. Folinic acid is also, as you well know, the rescue drug for methotrexate, which trashes folate metabolism, period. Also, in many autistic children that have auto-antibodies to the folate receptor and they basically get cerebral folate deficiency. Folinic acid is awesome because it can cross the blood-brain barrier without that receptor and it normalizes everything that goes on methylation related in the brain. Whereas 5-MTHF wouldn’t do that. Certainly synthetic folic acid wouldn’t do that.
Folinic acid I don’t think is as well appreciated as it should be. It’s just not as trendy to recommend folinic acid right now. But there’s many good reasons to do that.
Dr. Kara Fitzgerald: Yeah, I agree with you. I like folinic acid. I think after just this whole cerebral folate story hit the benefit of folinic home to me. Likewise, in folks who don’t tolerate methylfolate folinic acid is great. Even when, you and I were just talking offline, even in folks with significant polymorphisms in MTHFR and elsewhere, the folate cycle wears on and wears on probably fine in many of us. Again, I think looking at the folate vitamers that you’re offering on your panel and looking at that in the context with methylation information and glutathione, you have red blood cell glutathione as well, you can really get a good snapshot of what’s going on actively in the body versus just stopping at SNPs. What about synthetic folic acid? That’s certainly been vilified in the biggest way. Where’s your position on that?
Dr. David Quig: Yeah. Well I think it’s great for preventing neural tube defects. Period. End of story. The research clearly shows that this synthetic folic acid, it can be useful up to it looks like about 400 micrograms a day. But here’s the problem. With mandatory food fortification with folic acid, people eating their processed foods are just getting so much folic acid. Even giving them 400 micrograms which, when in controlled feeding studies where that’s all the folic acid they were getting, they were fine.
You put somebody who’s eating Twinkies and Cheerios and everything else fortified, all of a sudden now in it’s actually a serum folate panel, what you’ll see is this nasty and really fun to say is UMFA, U-M-F-A, unmetabolized folic acid. Now that unmetabolized folic acid, it blocks the whole metabolic process from natural folates on down. It binds to folate receptors and transporters and just gunks up the works. It’s even been associated with certain types of cancer. A pretty scary study out of Canada recently showed that they found significant levels of unmetabolized folic acid in the blood of all of the mothers and their newborn infants. It’s this UMFA, it’s not good.
Dr. Kara Fitzgerald: Yeah. Okay. So unmetabolized folic acid folks, aka folic acid, aka synthetic folic acid. You can hear it listed, you’ll see it written as a handful of different names. We’re talking about the same thing. It is, as David points out, pretty hard to activate in the body. It actually, it has to cycle through DFR, dihydrofolate reductase twice before it’s activated. Yeah, it can gunk up the works, I concur. Because we’re eating massive amounts and there’s this mandatory folic acid fortification program, there are really high blood levels that you’ve pointed out, and some of the fallout like the increased risk in cancer.
Yet the flip side of that is that they started this public health initiative with good intentions and actually did reduce birth defects. It really had an amazing, almost miraculous beneficial effect. But now over years we’re seeing that there’s some negative fallout. Certainly we’re advising our patients not to eat fortified grains anymore.
Dr. David Quig: Yeah. The reason that that particular form, that synthetic folate is used is because it’s…
Dr. Kara Fitzgerald: It’s stable.
Dr. David Quig: Very, very stable and it’s dirt cheap, the two primary reasons. I get why they use that but when it’s in so many different things and now with this craze of people taking folates indiscriminately then it becomes a problem.
Dr. Kara Fitzgerald: Right. Yep. That’s right. So on that note, talk to me about this whole idea of overmethylation. What are your thoughts around that? There’s a lot of questions. There’s just a lot floating around on overmethylation. I have patients call me all the time, “I think I’m an overmethylator.” What do you think?
Dr. David Quig: I think it’s a great question. I do think that it’s very much overemphasized because there are some very smart people that are doing some great things working with schizophrenia, where it’s estimated to be about 35% or so of schizophrenic patients do appear to be over-methylating. But that generalization has been applied to the whole population. There’s really no research out there about the general population, about why is this potential over-methylation even happening.
Traditional concern about over-methylation relates to the percentage of DNA in a very standardized test in say lymphocytes where there’s a pretty set normal percentage of DNA that’s methylated because methylation turns genes primarily off or on. It’s an important way to regulate gene expression, looking at the DNA and lymphocytes. But there’s just so little published in the literature about overmethylation outside of the whole DNA phenomenon.
The really interesting thing is, I was rereading on this the other day, MAT, the conversion of methionine to S-adenosylmethionine is under expressed when there is hyper methylation. So the gene that’s responsible for the synthesis of the first step in methionine metabolism to make SAM is turned off when there’s too much methylation. I’m not shy to say that I don’t really know what’s going on here. I know a lot of people talk about overmethylation, and I’ve certainly read the literature on schizophrenia. I just don’t know how much it’s really happening in the general population.
Dr. Kara Fitzgerald: Yes. That’s right. At least at this biochemical level if you could just sort of artificially distinguish epigenetic methylation or DNA methylation as you mentioned and biochemical methylation that is just what overmethylation, the production of too much SAM initiating too many biochemical activities? Is that…
Dr. David Quig: Right. I think some of it might come from people having read little snippets here and there. I shouldn’t say snippets. Little pieces here and there about, “Oh, they have a low histamine level.” Well histamine gets methylated and so one reason that histamine could be low, it would be if you’re methylating it and forming N-methylhistamine. However, there’s also another enzyme that can cause lower histamine, not to mention low histadine in the diet. I think it’s maybe part of the reason why people, they’ve come to say, “Oh, a simple way without looking at all this plasma methylation stuff, just look at histamine. If it’s low, oh, you’re overmethylating.” There’s more to it on the front end and the back end. While that might be a good place to start and say, “Oh, now let’s look at plasma methylation,” I don’t think you can just stop there.
Dr. Kara Fitzgerald: Yeah. That’s right. And certainly you’re not going to be dumping out a heck of a lot of histamine unless there’s an assault on mast cells an up regulation, some exogenous, well I supposed endogenous stimuli to enact.
Dr. David Quig: Oh yeah. Blastocystis would be a classic example.
Dr. Kara Fitzgerald: Right. Yeah, that’s right. That’s a good point. Right, parasites or an allergic reaction.
Dr. David Quig: Right.
Dr. Kara Fitzgerald: All right. So, yeah, I do think, in fact just as you were talking David, I wanted to pull up a histamine reference range. I was curious, like how would one actually determine that their homocystine is low? I just grabbed ARUP. It just popped up quick. Their reference limit is zero to eight, so I don’t know how you would necessarily infer low unless you were negative.
Dr. David Quig: Yeah. Zero’s normal so how’s…
Dr. Kara Fitzgerald: Yes. Yeah.
Dr. David Quig: Negative, negative.
Dr. Kara Fitzgerald: Right. Right, right. Undetected. Well, undetected is normal for them so.
Dr. David Quig: Right.
Dr. Kara Fitzgerald: Yeah. I think we need to be careful about this idea of over-methylation and definitely, as you say, it is a phenomenon, epigenetics. We turn genes off by methylating them but we don’t have access yet to those kinds of epigenetic panels, at least not super routinely. You’ve made a couple of allusions to single-nucleotide polymorphism and their utility. What about CBS? So, talking about methylation and transsulfuration, CBS mutation either up or down regulating activity has a lot of press in our world.
Dr. David Quig: It does. Just so everybody’s on the same page, what we’re talking about here is at that branch point of homocysteine, leaving the whole methionine cycle, if you will, and irreversibly pulling homocysteine out down through transsulfuration, sulfuration to produce cysteine, essential sulfates, ultimately glutathione. CBS is the enzyme I referred to that’s actually upregulated, it’s actually stabilized by high levels of SAM. Again, the body’s saying, “I got too much SAM. Let’s get rid of this stuff. We’ll send it down through transsulfuration. Oh, by the way, nice byproduct. We’ll get some cysteine and glutathione.”
There are SNPs for every enzyme in the body. There are numerous CBS SNPs out there that have been documented and, yes, this is for real. But interestingly about CBS, the only one of clinical relevance that I’ve seen to date, it actually up regulates the activity which is going to result in pulling homocysteine down, pulling basically out of the loop to get back to methionine. But the beneficial effect would be going on down to make cysteine, taurine, and glutathione. So right now I haven’t seen any SNPs that cause for sluggish transsulfuration.
More important there would be the next step, which is cystathionine gamma-lyase or CTH. Now there where you have a significant disruption, there you’re going to bottleneck the whole sulfuration process and ultimate worst scenario would be low cysteine sulfate, not sulfite but sulfate, and low glutathione. So that next step, both of which are B6-dependent, is apparently much more important than the CBS SNP itself.
Dr. Kara Fitzgerald: Well, and is that something that we’re seeing relatively common?
Dr. David Quig: No.
Dr. Kara Fitzgerald: Okay. I know you’re looking at, you’ve looked at thousands of these reports. Do you see evidence of that on the panels?
Dr. David Quig: Occasionally, yes, but not very often. When I see it I get very excited because it’s pretty clear what’s going on there.
Dr. Kara Fitzgerald: What are you advising for intervention? Are you saying B6?
Dr. David Quig: That would be your first shot, B6. Then also because it may be that if it’s too sluggish for that individual’s environmental exposures and their needs for cysteine and glutathione, you might have to just bypass it and give some N-acetylcysteine and/or liposomal glutathione or S-Acetyl Glutathione, worst case scenario. That’s pretty benign to bypass that one.
Dr. Kara Fitzgerald: Right, right. You might see evidence of, you might see low glutathione on a red blood cell glutathione and higher oxidative stress?
Dr. David Quig: Yes.
Dr. Kara Fitzgerald: Yeah. Okay. Okay, so if you see that panel, if you see that pattern, if you’re concerned about cystathionine, is it cystathionine gamma-lyase?
Dr. David Quig: Yes. CTH.
Dr. Kara Fitzgerald: Okay, so if you see what you suspect is a CTH mutation or if you’re aware of that in your patient, you can actually talk to David about it at Doctor’s Data but you can also look at some of the downstream products to make sure they’re sufficient and if not, we have access to those. We can treat them. There’s lots of good oxidative stress markers that we can use to see whether or not there’s a significant fallout with a CTH mutation.
All right. Well, we’ve covered a lot. I think we’re … I think we’ve gotten really some of the important high points here. Let me just ask you, we started this conversation and I think the whole interest in methylation was really kind of born out of more routine measurement of homocysteine. Generally speaking, we see an elevated homocysteine we know it’s associated with cardiovascular disease risk but it’s also, obviously as we’ve talked about today, related to a whole lot more. Most of us go to address a homocysteine, successfully actually, using a natural folate and B12 but what else? What else do you think about with a higher homocysteine?
Dr. David Quig: Yeah. The old school, I mean you go back and look at the literature in the late 80s and 90s when homocysteine was really come of day for being a significant risk factor for cardiovascular disease and the way they approached it then was with betaine.
Dr. Kara Fitzgerald: Oh, was it? That’s pretty cool.
Dr. David Quig: And B6 because 85% of methylation reactions take place in the liver and that’s also the greatest source, tissue for the BHMT. So without having to go through MTHFR you can take a shortcut at the liver and turn that homocysteine back into methionine. It’s just a nice easy single-step process where the donor is the trimethylglycine or betaine and that’s great. It’s just a very simple way and you don’t have to worry about hyper methylation or anything like that.
The only thing to keep in mind, and there’s always a caveat, and that is that the central nervous system has minimal if any BHMT activity. So in terms of trying to lower homocysteine, betaine, B6, B12 are great. But if you have reason to need to deal with methylation on the north side of the blood-brain barrier then you really have to go, you can’t rely on the betaine to do that. You have to go through the 5-methyltetrahydrofolate step. Yeah.
Dr. Kara Fitzgerald: Okay. Okay.
Dr. David Quig: It’s very tissue-specific. We always have to keep that in mind. So many times people, they look at a pathway and they say, “Mm-hmm (affirmative), yep, there’s the product” and, “Oh, uh-oh, if there’s too much of that it’ll inhibit it.” But not only do you have to think about the kinetics, the enzyme kinetics. What is too high? Just because there’s a little bit high? No. What are the real kinetics? Then most importantly, and back to my point is, tissue-specificity.
Dr. Kara Fitzgerald: Right. Right. If you’re going to actually be preserving, if you use betaine and work specifically in the liver you’re going to be preserving B12 and folate for the central nervous system so you might actually get away with that. But would you argue when you’re dealing with some sort of a neurodevelopmental or neurodegenerative condition or psychiatric condition you might want to address both pathways?
Dr. David Quig: Absolutely.
Dr. Kara Fitzgerald: Would you…
Dr. David Quig: Absolutely. Again, that’s where our friend folinic acid comes in.
Dr. Kara Fitzgerald: And as you said earlier, start really low dose.
Dr. David Quig: Yes.
Dr. Kara Fitzgerald: Have patients kind of slowly titrate up. All right. As usual, David, it’s always just a pleasure to get to talk to you. You did a teach-in for us not too long ago in our clinic immersion program and it was quite popular. Actually, we were talking about heavy metals and you just offered some great background on considerations for detoxing and we went to your lab. It was fabulous to have you there and I’m sure you’re going to be back either on a teach-in or another podcast with us in the not-so-distant future. Keep up the great work and thanks for coming on.
Dr. David Quig: Oh, thank you, Kara. You’re very welcome. Thank you.