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Wow, this morning I got this blast from the past: my colleague surfaced and sent me a 2006 paper I had co-authored with the esteemed Dr. Richard Lord, who was my post-grad supervisor at the time and is my mentor still, on the risks of having your homocysteine run too low.
The issue of having too little homocysteine is still as relevant now, as it was then. In the excitement over reducing a high homocysteine, and overcoming methylation deficits, it’s easy to forget that homocysteine still has a positive role to play.
I wanted to share with you some excerpts from this paper, which you can also find in full here.
In opposition to transmethylation, homocysteine undergoes transsulfuration forming cystathionine (Figure 1). Through this pathway, homocysteine is an intermediate in the conversion of methionine to cysteine. A sensitive enzyme regulation mechanism controls whether homocysteine is predominantly transmethylated or transsulfurated. The function of this regulation is to allow rapid response to oxidative challenge by increasing the formation of glutathione, a process dependent on cysteine availability (Figure 2). Restriction of the substrate (homocysteine) can limit the formation of the product (glutathione). This means that a low homocysteine can restrict the amount of glutathione that can be produced in response to oxidative stress. Two additional detoxification factors, taurine and sulfate, are produced from cysteine (and therefore, also influenced by low homocysteine) .
While high plasma homocysteine is widely recognized as a cardiovascular disease risk factor, individuals with low homocysteine may also be at risk. The risk of hypohomocysteinemia derives from the fact that homocysteine is the normal intermediate for conversion of methionine into cysteine, and thus for production of glutathione, taurine and sulfate. Individuals with low homocysteine have limited capacity for response to oxidative stress and certain kinds of toxin exposure. The most common treatment for low homocysteine is administration of sulfur-containing amino acids such as methionine, N-acetylcysteine and taurine. Preformed glutathione and inorganic sulfate salts (potassium sulfate) may also be employed. Plasma methionine and urinary sulfate, pyroglutamate or alpha-hydroxybutyrate are related tests that may be performed for confirmation of significant cysteine deficit.
How low is too low? Data suggests that a low limit of 4.0 nmol/mL should be what flags you to a homocysteine level that indicates a potential need for support, either supplemental and/or diet/lifestyle.
And if you’re wondering what my upper range for homocysteine is, I like to see it below 7.0 nmol/mL.
Find out more about advanced metabolic and epigenetic methylation support here.
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Dr. Fitzgerald, thank you SO much for commenting on low homocysteine and how it connects with the OATS testing. So helpful to have this explained as this is the first place I have found this mentioned. Most of the discussion is around elevated homocysteine 🙂 I really enjoy reading your information.
Dr. Julie A Martin
Chiropractor
Thank you, Dr. Martin! So glad you like our content.
Thank you for this.
A very similar situation can be found with LDL. After an education that is intensely focused on strategies to combat heart disease it is easy for clinicians to forget that this molecule is the raw material for myriad steroid hormones. It is common to find fatigue in individuals with ultra-low LDL/HDL ratios (i.e. <0.75-0.5) either natural or iatrogenic, due to aggressive diet restriction and statins. Verdure and Goldberg found "a tenfold increase in relative risk was associated with cholesterol less than 3.4 mmol/l, and the least risk was associated with the middle tertile of cholesterol levels (4.0-5.0 mmol/l)." 3.4 mmol/l equals 131.3 ml/dl which is not really extreme. Guy et al. (1996) found that "both hyper- and hypocholesterolemia have a highly significant relationship to mortality."
Gui, D., Spada, P.L., De Gaetano, A., and Pacelli, F. (1996). Hypocholesterolemia and risk of death in the critically ill surgical patient. Intensive Care Med. 22, 790–794.
Verdery, R.B., and Goldberg, A.P. (1991). Hypocholesterolemia as a predictor of death: a prospective study of 224 nursing home residents. J. Gerontol. 46, M84-90.
Great, thank you for the comments and references. DrKF
I wonder if a patient also has a CBS issue that they wouldn’t want to increase sulfuric compounds. I wonder if low homocysteine could be caused if one has a BCHE mutation like rs1799807 which can cause a shortage of Butyrylcholinesterace which causes the person to not breakdown choline therefore the body has high choline due to the BCHE and high choline leads to low homocysteine
I’d say for sure that the best way to answer those questions would be to look at the associated biomarkers-as many as possible- to see whether there is any corroborating pattern. We also can trial a “therapeutic probe” where time limited intervention(s) are initiated and observed for clinical outcome. Thank you for your comments and interest! DrKF
I am not familiar with the biochemistry you are discussing, but an interesting takeaway I am getting is that it is possible that telling a vegan “You are not getting enough meat protein” based on low homocysteine levels might be misguided in some cases. Am I drawing the right conclusion?
When homocysteine is low, we do want to address protein sources (especially amino acid sources) as well as other relevant cofactor nutrients that may be deficient in the diet. That may include upping meat intake (for protein and other significant factors), or may require supplementation or inclusion of other food sources. It’s also very important to note, that consumption is only part of the picture. We want to ensure proper absorption and utilization of nutrients is happening, so we usually will lean on some advanced testing to asses digestive function and nutrient status.
That’s interesting. I remember hearing that tribes in Africa tested over a hundred years ago that lived a low-meat hunter-gatherer lifestyle had an almost non-existent heart attack rate and LDL levels that hovered near 70. I don’t think that HDL/LDL ratio was mentioned, though, and I am having trouble putting this new stat into context. Any thoughts?
I’ve seen these studies in traditional populations following indigenous diets, and they’re absolutely fascinating. I think in light of what we know from longevity studies, we have to consider factors like lifestyle, family/social connections, stress and sleep, as well as environmental pollutants and food nutrient density.
Thanks for the article. My Neuro recently found lower than 4.0 on my homocysteine. She didn’t mention it but I saw it on my bloodwork. I also have zinc deficiency since March and even with an additional 10mg zinc per day I am deficeint. I also suffer from neuropathy, anemia that won’t get better even with 2 scripts of iron a day. I have suffered 2 rounds of Mycoplasma pneumonia, EBV and am 21 weeks pregnant with 5th child. My adrenal levels are low, gut dysbiosis, Candida , and have fought off parasites external and internal. My hair has thinned, I have had lots of itchy crawly skin issues and I generally and very fatigued irritable and do not feel well. I have bouts of harder breathing, muscle eeakness, numbness. I have seen many docs both natural and western. I can’t find anyone to tie it all together and feel rotten as a 36 year old mom. Please help.
I’m sorry to hear about your health issues. I’d recommend an appointment with my colleague Dr. Ken Litwin. He can work via remote educational consults if you’re not in our local area. If you’d like to schedule, please contact frontdesk@drkarafitzgerald.com.
Neuropathy and anemia that won’t get better with iron is caused by a copper deficiency, you’ve likely caused it by taking zinc
Dr. Fitzgerald,
I was diagnosed years ago 2006 with compound Hetero MTHFR C677T / A1298C. My Homocysteine was very low <0.3. I have advanced C.A.D. None of my doctors EVER took any precautions after this diagnosis. I was never told to take any supplements or to follow any diet. I have other health related issues that both of these positive results have caused. Can you PLEASE tell me if a vascular Dr. Is whom I should seek. With my advanced heart disease, my high cholesterol has now caused atherosclerosis in my legs and feet. I barely leave my home I'm in so much pain. I'm in SE Michigan about 30 north of Detroit. Please send me the name of a specialist who is familiar with cytsyteine and MTHFR Disorder. Thank you.
Thanks so much for reaching out, and so sorry to hear you’ve been having a hard time. I would suggest working with a Functional Medicine practitioner – begin with the Institute for Functional Medicine’s (IFM) website under the “find a practitioner” tab. I popped in Detroit and was able to find a list of Functionally trained practitioners: https://www.ifm.org/find-a-practitioner/?location=detroit%2C+mi&country=US&rad=150&pos=
We also offer remote nutrition consultations if you’d like to work with a nutritionist familiar with MTHFR/methylation disorders. She would be able to work with you on a comprehensive plan and potentially collaborate with a physician locally to help co-manage your care. Please Email FrontDesk@drKaraFitzgerald.com if you would like to learn more. ~Lara Zakaria RPh MS CNS CN CDN
Hi Dr Fitzgerald,
Thank you for this great article! I have experienced a homocysteine plummet in the last 6 months, and I’m hoping your insight can help me get to the bottom of what is going on. In August my homocysteine levels were at a normal range of 7.8. I began working with a functional health doctor for a parasite detox, so I changed my diet around significantly, and also added on a few good detox supplements. (Side note, I have the double A, MTHFR defect, as well as autoimmune progesterone dermatitis, as well as possible elhor’s danos syndrome, awaiting genetic confirmation.) In the period from August until now, I went from a normal grain-free diet, to a grain-free diet that was also high in arugula/spinach/kale, cruciferous vegetables, root tubers, etc… on a daily basis. I switched my prenatal to a non-folic acid version, as well as added on an adaptogen supplement. My levels in mid-February showed a homocysteine measure of 3.0. I have not drastically decreased my protein intake or made other major changes that I feel would decrease my levels so significantly, and in fact, I had added on liposomal glutathione and NAC supplements daily. However, I just noticed some overlap in 3 of the supplements I am taking, that gets me to a daily intake of B12 at a VERY significant level of 900mcg / day (methylcobalamin + cyanocobalamin). Is it possible that I am OVER supporting my methylation with this significant B12 intake due to my supplemental overlap, and that could be the cause of the homocysteine plummet? We have been trying for a third child over this time period, and I want to be sure that I am in a healthy range before proceeding. Any tips, would be greatly appreciated! (apologies for any medical errors in crafting this message… just a layperson trying to get to the bottom of this issue 😉
Thanks-
Mary
Thanks Mary for reaching out. It’s great to see that you’ve been working with FxMed practitioner in addressing the detox and GI components. It’s possible that the reduction in homocysteine might be due to the supplementation and extra focus on methylation. It’s also possible that nutritional imbalances or extra emphasis on detoxification might be eating up the homocysteine as well. Some advanced lab testing and nutrition intake analysis can help determine if adjustments in dosing of your supplements or a shift in your diet is indicated. If you’re not currently working with a Functionally trained nutritionist, maybe your FxMed physician can refer you he/she works with. Alternatively, the Institute for Functional Medicine’s website has a “find a practitioner” button at http://IFM.org. I’ll also mention that our staff nutritionists provide remote support in implementing the Methylation Diet and Lifestyle approach. If you’re interested in learning more, I’ll provide the link to available services: https://www.drkarafitzgerald.com/our-clinic/nutrition-services/
– Lara Zakaria RPh MSc CNS CN CDN
Does low folate and B12 also cause low homocysteine? mthfrsupport says so. I thought folate and B12 will lower homocysteine. Can you help?
Generally speaking – supplementation with B12 and folate can lower elevated homocysteine. Over supplementation is one factor contributing to low homocysteine and one of the reasons we try to rely on supporting patients through food and lifestyle factors. We talk about our epigenetic approach here: https://www.drkarafitzgerald.com/professionals/methylation-diet-lifestyle/
Sorry can you clarify this – Can having a B12 and/or Folate deficiency cause homocysteine levels to be too low?
Thanks
That’s a tricky question – we often associate homocysteine balance with B12, folate, and B6 needs. However, stress on detoxification pathways might also show up as low homocysteine. I would say it’s not a specific reflection on B12 or folate deficiency.
There doesn’t seem to be a consensus on the normal range for homocysteine…..Some places say 4-15 is normal, https://www.emedicinehealth.com/homocysteine/article_em.htm#what_are_normal_and_elevated_homocysteine_levels whereas others think it should be < 9, http://drbenkim.com/articles-homocysteine.html
Would homocysteine or cardio-CRP be a better marker of inflammation w/regards to heart disease?….Thanks
There’s a distinction between the “normal” reference range and the optimized function. In our clinic, we like to see homocysteine optimized between 4-7. However, that doesn’t mean that a homocysteine of 9 or 10 is out of range, but it’s “functionally high” and indicative of inadequate methylation. When combined with other markers, including hsCRP and lipid particle size, we can get a much better predictor of cardiovascular health. We often lean on comprehensive cardiovascular tests like the Boston Heart profile to get the full picture.
Thank you Dr Kara! I have low SAM/SAH ratio of 3.3, (90/27.2) due to high SAH. Lowish Methionine 1.9 and lowish Homocysteine 6.0. I am also low zinc 11.2umol/L and low vit D. All indicating hypomethylation. My main symptom is chronic urticaria and think there is a link to my ability to support metabolism of histamine. I tried supporting with Meth B’s, active B6, Mg, vit D, reduced glutathione and with quercetin and liposomal vit C. It has reduced the symptoms considerably, but I still get symptoms twice a week usually in the evenings. Should I a) stop my methylated B’s and maintain active B6; b)support my liver function with milk thistle and NAC c) should I stop reduced glutathione, start taking zinc (alone, or as a zinc and copper combined). These functional test results were done in Feb this year, I have not done any genetic testing, should I do that as well? Or what other test should I do to find out which system (or gene) is needing support? Many thanks in advance,
Stephanie- Thank you for the careful synopsis of your case. Honestly, I don’t think the chronic urticaria is sourced to solely to methylation cycle issues, but I do think the methylation issues likely impact the urticaria. My recommendation is that you cast a wide net- with a provider you trust- and capture your full history with pertinent labs, exam, etc. Your treatment plan should reflect this systems-approach. My concern is that if you limit your focus you won’t completely resolve the urticaria. Make sense? DrKF
Thanks for writing this. I am encouraged to see this. Other sources on the web seem to be confused. For example, I have from one (more trusted) source that B12, B6, and follate can be used to treat high homocysteine levels and vegans without B12 come in at 16 compared with SAD eaters at 11 and greens-eating vegans with B12 between 4 and 5. I saw a less trusted source that used a lot of scientific names 🙂 saying pretty much the opposite – normal ranges are 10-12 and B12 and follate deficiencies can cause *hypohomocysteinemia*? (huh?)
I hope you are right about a proper range of 4-7 because I am hopeful that we can eat a diet where you avoid both the “normal” range of 10-12 and the “normal” heart disease that has become the leading cause of death in the US.
So my question would be, what is the confidence that a diet producing 4-6 range across a group of people is strictly healthier than a diet producing a 10-12 range? 70%? 90%? 99%? Thanks!
Thanks for the very thoughtful question. I think we need more large-scale data analysis to quantify the benefit of this tighter goal for homocysteine. What we can take away from the emerging research at this point is that there’s likely an ideal range of 4-7 mmol/L (which cannot be considered in isolation of other contributing factors) and hypo-homocysteine value is possibly as significant as an elevated value. Conventionally, the literature has focus on relative risk associated with elevation >10 mmol/L (though I’ve seen occasional mention of lower upper limit). I look forward for population studies with a more nuanced range in the near future to give us a benefit/risk analysis to predict outcome.
Dr Fitzgerald, my homocysteine levels are 4.0 and I am on Metabolics HydroxoB12 – 3 drops under my tongue daily. I am concerned that this will decrease my levels further? I also had a high sulpher reading on a OATS test but on a hair analysis test it stated I was low on sulfer, very confusing! I have mostly constant bloating and strange smelling stools. I have introduced high sulfer veg gradually in the hope that this will help and have started a plant based diet.
June, Consider jumping on a consult with one of our physicians or nutritionists- your questions are good and important, and deserve careful attention (beyond email medicine ;)!) DrKF
Great article! Question- I keep finding articles showing that NAC lowers homocysteine levels. Why then do you recommend NAC for low homocysteine levels? Is it to be used in conjunction with other supplements to ensure homocysteine levels don’t drop further?
Thank you!
Homocysteine levels are impacted by various biochemical pathways and cofactors, NAC is one of them. Typically if supplementing using one of those cofactors, we will regularly monitor metabolic markers (including homocysteine). However, we also like to lean more heavily on modifiable lifestyle factors like diet, exercise, and stress management. You can learn more about this approach here: https://www.drkarafitzgerald.com/2016/06/28/methylation-diet-lifestyle-introduction/
My teenage daughter is currently being treated for lyme disease. She had some labs done and we found that her homocysteine level was not even showing at all. The Dr was concerned with very low level. As I’ve been researching this I came upon your article and this comment specifically stood out to me because she has been taking NAC for the past few months as part of the treatment. Could NAC be aiding in lowering her homocysteine levels?
I don’t think so, Amber. I would suggest that your doctor run a methylation panel – Doctor’s Data has a great one, and broad nutrient test like Genova’s ION or NutraEval to see what else is going on. I suspect your doctor is already thinking in this direction. Please keep me posted on what you find. An undetectable homocysteine could be an important piece of her clinical puzzle. DrKF
Dr. Fitzgerald,
Thank you for this information! I’ve been reading that NAC lowers homocysteine. You recommend for hypo homocysteine levels to supplement with NAC. Is there concern that NAC will lower it even more, or do you supplement with others to ensure that even lower levels won’t be obtained?
Thank you!
I’m so happy that I found your page. My homocysteine levels were low and my doctor, who I was dating at the time, put me on 3,000 mcg Optimized Folate (L-Methylfolate). I always thought that was for high levels. ???
Thank you for following us! In the case of low homocysteine, we still want to support glutathione production (as mentioned above), but using L-methylfolate might be part of a more comprehensive approach along with some additional key nutrients like B12. There may have been another reason your doctor thought to dose you with 3,000 mcg L-methylfolate, but that is what I would consider more aggressive dosing and not something I would continue long-term with monitoring very closely.
Dr Fitzgerald. thanks for your article. There are few about low Homocysteine. I have a low level of 3.9 and Polycithemia Vera and the associated low iron, but I can not take iron. Even my health is good, my doctor told me to take folic acid. I don`t want to take it because of several studies aout cancer increase risk due to folic acid. I would appreciate if you have any suggestion about that or if I should ask a different type of doctor. Thanks a lot.
Thanks so much for your question. Without knowing your full history, I can’t make any specific recommendations. Folate (the natural form of folic acid) might be a safe option. We want to also make sure we’re looking at the complete picture, including broad nutrient need and lifestyle factors. If you can, work with a physician trained in Functional Medicine and who can help you address the root of this imbalance. You can find one in your area at http://IFM.org. You’re also welcome to contact our office to inquire about working with our team.
I was wondering if you could comment on why could one see or what would cause low cysteine levels in a child ?
Low cysteine or homocysteine? There are multiple reasons and I would need more context/background on the case to comment. It could be inadequate intake or absorption of amino acids (protein), increased need, enviromental factors, or potentially genetic variation.
Thank you for such a great article! So little info on this subject online, so really appreciate you taking the time to put this one together.
One question – you mention the most common treatment for low homocysteine includes administration of NAC and taurine. But I was under the impression that NAC and taurine can both lower homocysteine levels further*, by up to 45% (via NAC) – Am I missing something? Would you mind explaining why you’d give NAC and taurine, for low homocysteine levels, if they tend to lower them further?
Again, really appreciate this article, and genuinely curious about the point above. Thank you!
*Sources:
https://www.ncbi.nlm.nih.gov/pubmed/8929261
https://www.ncbi.nlm.nih.gov/pubmed/25731901
https://academic.oup.com/ajcn/article/102/5/1014/4564368)
https://www.lifeextension.com/protocols/heart-circulatory/homocysteine-reduction
Thank you for reading and for your thoughtful question.
The mechanism suggested here for low homocysteine is that due to increased demand, it’s being drained as it’s converted into cysteine for production of glutathione. As it’s being pulled down that pathway, it means there’s more demand for glutathione and it’s sign of low cysteine (which can be confirmed through testing).
Providing NAC and taurine (detoxification factors produced from cysteine and needed for the production of glutathione) helps to support detoxification pathway downstream, providing the needed intermediate so that it doesn’t continue to drain homocysteine.
Can you tell me what would cause low homosysteine levels and low iron in a child? Also has pyrrole disorder with only symptoms being anxiety? Thanks
Sarah, kids normally have lower homocysteine. You’ll have to give me a number (and a reference range, since depending on the lab, there can be some variation). Low iron: I would first think about dietary intake, next think about absorption, or iron loss. I am not an expert in pyroluria, so you’ll have to check in with whomever made that dx. Anxiety can have a lot of underlying causes, using a full functional approach should help- you tease out any and all causes. My best, DrKF
Hi Kara: can you please send over the source for the low homocysteine data? Also any potential etiologies for low homocysteine?
thanks,
Danielle
Hello – are you looking for the original publication I co-authored with Dr Lord? You can find the full article https://www.drkarafitzgerald.com/2017/04/04/low-homocysteine-concern/
My 4 year old son has high plasma b12, elevated MCV (95), low homocysteine (<3.0), and high urine methionine. I can find no one able to help me figure this out, but I know it’s all related. Any insight?
Tonya,
yes- possibly all are related. I would work with a doc who will take a good history and run the Doctors Data or Genova methylation panel for a little more insight (plus any other labs that are pertinent when history is taken). Who can you work with? We have a great pediatrician on staff now- Dr. Lizzie Bird (and she’ll present his case to me and the rest of the team during our Rounds meeting so you’ll really be getting insights from all of us). You can also look at providers at the Institute of Functional Medicine’s website. There are definitely clinicians who can tease out the metabolic details you’re looking for- don’t lose hope. DrKF
Thank you for responding!!!! How can I work with Dr. Bird?
just reach out to us directly at frontdesk@drkarafitzgerald.com DrKF
Did you ever figure this out? I have the same thing. Thanks!
My five year old son has been having tremors in his hands for over a year ( otherwise healthy/active) The Children’s Hospital in Randwick ran some bloods which just came back with low homocysteine levels, high b12 levels and low iron levels. Could this be correlated as I read low homocysteine levels are related to your nerves. Is there any questions or further tests you recommend I ask for?
Amber, if possible- consult with someone versed in Functional Medicine in your area for further testing and treatment ideas. IFM.org has a listing of trained clinicians all around the globe! That said, judging from what’s been ordered by the Children’s Hospital- they are ordering tests that we would be looking at, also. DrKF
Hi, I’m so worried obout my children and gradchildren because many of them have so low homocysteine levels (under five). Many of them have also mtrr 66 as homotsygous and mthfr 677 as heterotsygous which normally could mean tendency to high homocysteine. Two of them have also GSTT1 deletion (others were not tested). So much information is available for high homocysteine but not for low one. Here in Finland is not so easy to find a doctor knowing enough about these problems, especially here in northern Finland.
I’m so thankfull for Your papers.
Birgitta Nyman-Järvinen
Oh man, I was overjoyed that my homocysteine has come down from 8 to 3.6 after starting methylation support nutrients a few months ago (B2, choline & bethaine, creatine, folinic acid), as I am homozygous for the MTHFR 677 variant — and now I read that I have to worry about it being “too low” *sigh*. I have been taking NAC for several months as well, which would suggest my current homocysteine level is what my body prefers when getting all needed methylation nutrients, but I guess I will add some SAMe (S-adenosyl-L-methionine) to my regimen just in case.
My 2 year old daughter’s homocysteine is 3.5 and her B12 is 750. The doctors have no idea what to do, is it ok to leave those things alone?
Drew, that’s on the low side, but kid’s homocysteine naturally runs lower than adults. You want to see whether its significant in the context of how she’s doing overall. Is she happy, healthy and well? If yes, its probably NOT a big deal. If she’s got any neurodevelopmental imbalances, the homocysteine might need a closer look, along with other labs. I suggest you connect with a clinician versed in the methylation cycle. We have a great pediatrician here, Dr. Lzzie Bird, who could certainly do this analysis for you. My best, DrKF
Thank you, I just got my results and Homocysteine is 6.08 , I need to support my Glutathione levels.
Hi
I have low homocystein. Bloodsample shows 2,8
What can I do to get the level up?
My doctor knows nothing about this, and did not comment the low levels.
I have high levels on the liver to.
I have ME/CFS (so I struggle cognitive, and have a hard time to read much in english)
and I use NAC and glutatione and use a high thiamin protocol.
Any advise?
Regards Randi from Norway
Hi Dr. Fitzgerald,
I am reaching out in hopes that I can get guidance for dosing my 15 year old with these supplements as her dr said a level of 3.7 Umol/L for Homocysteine wasn’t of concern; only if it is is high. However, these low levels seem to be what is causing her shakiness, chronic fatigue, and frequent headaches and dizziness. She has seen specialists and there are no concerns there, so I am trying to take an integrative route to medicine here.