Homocysteine: Why Do We Care?

Can't say that I learned a great deal about testing homocysteine in my clinical education, but it certainly has been a mainstay of practice as a functional medicine practitioner. If you have heard of MTHFR or even methylation, then homocysteine is in that camp. However, the more gene polymorphisms you have, the more susceptible you will be to methylation issues. Homocysteine is the laboratory marker that we use to evaluate whether we are effectively methylating, or detoxifying our bodies, and whether our bodies are properly utilizing our B vitamins - in the most simplest of terms.

When we have this understanding, we can better support our health by correcting any nutrient deficiencies, supporting the health of the immune system by eating an anti-inflammatory diet, getting plenty of sleep, moving the body regularly, and repairing gut health. Visiting with a functional medicine doctor can help you better understand your epigenetics and if you are properly methylating, or at least optimally. Testing is an important and objective way to make this assessment, but you can also support your methylation pathways by assuring you are getting enough B vitamins in your diet. These are our green leafy vegetables and sulfur-rich foods like cabbage, and broccoli sprouts, wild-caught fish, grass-fed beef, and organ meats like grass-fed liver. The healthier your diet and lifestyle, the lower your homocysteine, and the better your methylation process will work for you.

We use this test as an inflammatory marker, but conventional medicine is entirely structured around diagnosing overt disease rather than recognizing early indicators of inflammation in effort to minimize consequence. One has abnormal blood sugars for years before they are diagnosed with diabetes, but in conventional medicine, identifying that is not covered by insurance providers so this testing is not done. Unless there is a true indication, meaning pathology, conventional medicine practitioners aren't likely to evaluate homocysteine, ever, but as a functional medicine clinician, we often include this laboratory test in our wellness panel. When levels are high we recognize this may reflect poorly on methylation and ultimately detoxification, so we ensure the client is supplementing with a methylated B complex. This can prevent the accumulation of toxins in the body and ultimately, minimize inflammation. The fix isn't just supplementing though, because as Goldilocks taught us, the porridge can be too hot, but it can also be too cold.

More recently, in my own practice, I've noticed lower homocysteine levels in a few of my clients. This is typically related to over supplementation, but I've had several lately who hadn't been supplementing at all. This got me a little more curious. What do we know about lower homocysteine levels, particularly when organically discovered? My thoughts are that they are over methylating for whatever reason, likely related to epigenetics. If elevated homocysteine is pathologic, toxic even, then is it best to just aim for a lower level or is there a too low level in which we see increased risk again, and if so, what does that look like? Let's dive in.

Elevated homocysteine is associated with a wide range of diseases such as Alzheimers disease, various birth defects, blood clots, cancer, coronary artery disease, dementia, endothelial damage, miscarriage, myocardial infarction, Parkinson's disease, pre-eclampsia, and stroke. Certain medications, a poor diet, toxin exposures, hormonal imbalances, and stress can all influence homocysteine, and of course B vitamins. It would seem that in itself, homocysteine is toxic and the less the better. Over the years, decades in fact, the range of normal has dropped and some experts lecture that levels less than 6 are optimal.

B vitamins from food and supplements act as methyl donors that help keep your body's homocysteine at a healthy level and methylation working optimally.

Homocysteine will use these methyl donors to produce the super-beneficial compounds SAMe and glutathione, which are extremely important for your health. Your body requires these to put autoimmune symptoms into remission. Glutathione is the grandmother of all antioxidants, the most powerful. SAMe's ability to protect our nervous system and support our neurotransmitters like serotonin and dopamine is vital, so when methyl donors are inadequate, homocysteine can build up and progressively increase.

If you're familiar with the biochemistry of glutathione, as all nerdy functional medicine clinicians are, then you'll recognize that the homocysteine and methylation cycle is right in the middle of a lot of metabolism. Like cholesterol has long been vilified, and assumed to be normal at any point below 200 because it is clearly a concern at higher levels, we now know that our brains and all aspects of our physical body depend upon a healthy level of cholesterol. Lower than 160 and suicide rates increase. There is a minimum criterial for optimal health and I am highly suspicious this is true for homocysteine as well.

Homocysteine 101

Again, not one of your more commonly discussed laboratory evaluations, so homocysteine is not one most are super familiar. Vitamin B12, vitamin B6 and folic acid break down homocysteine and change it into other substances your body needs. After this, there should be very little homocysteine left in the bloodstream. It's regulated through methylation, a biochemical superhighway, which regulates your immune system, brain, hormones, and gut. The entire methylation process occurs about a billion times every second in your body, and if it isn't working as well as it should, chances are you're going to notice it one way or another. We often see autoimmune-inflammation spectrum issues.

One of the most important things methylation does is keep the good genes turned on, and keeping the bad genes turned off. When this is ineffective, genes can trigger autoimmune issues leading to significant health issues.

Among those who are familiar with homocysteine, within conventional medicine, relate it to its notorious connection to increasing risk for cerebrovascular, heart, coronary, and peripheral artery disease. We know that when levels are especially high, coronary artery disease is significant along with hardening of the arteries. Even moderate levels can increase risk.

Heart attacks and strokes can also be triggered by autoimmune conditions, such as Lupus and autoimmune thyroid disease, in particular - which we have seen are also affected by homocysteine levels, creating a double whammy of dysfunction. Homocysteine is really a better indicator of heart disease than other well-known risks like smoking and high blood pressure (de Ruijter et al., 2009).

There is also the homocysteine connection with cognitive decline and we know that homocysteine is toxic to the brain neurons. Bad cells are typically pruned from the body, but many of our neurological diseases are actually autoimmune. Parkinson's disease, Alzheimer's, and multiple sclerosis are all neurological autoimmune spectrum diseases and can be linked to high homocysteine levels. As homocysteine rises, it can destroy the blood-brain barrier and create a "leaky brain syndrome," similar to leaky gut. We know that when homocysteine levels rise to 14 or higher, the risk of Alzheimer's doubles (Seshadri et al., 2002). Lowering your levels is important for protecting brain health.

Depression is also related to homocysteine. Various studies have connected depressive thoughts to higher homocysteine levels, even low serotonin levels (Aishwarya et al., 2013). High homocysteine levels have been linked to postpartum depression, and even a study on men have found the highest levels doubled their risk of depression.

The first clue that homocysteine plays an important role in the body is that this synthesis requires energy. Homocysteine is a nonprotein, a product of cysteine and biosynthesized from methionine by the removal of a terminal methyl group (Pizzorno, 2014).

Interestingly, contrary to the understanding of most clinicians, low homocysteine levels do indeed have disease correlations. When low, homocysteine is associated with peripheral neuropathy. A surprising 41% who have lower levels also have idiopathic peripheral neuropathy. Think of homocysteine as a storage molecule for cysteine, utilized for glutathione production. Homocysteine enables single carbon units to be shuttled from the reduced folate pool to the principle methyl donor in each cell, and low levels, less than 6 are rare, found only in about 0.5 to 1% of the population (Pizzorno, 2014). I have had three in the last two weeks and these were not in more healthy clients.

Low homocysteine may also be indicative of excess conversion to cystathione for use in the transsulfuration pathways for production of glutathione, taurine, and sulfate. Sound like Greek to you? Yeah, it is to most clinicians, but again, functional medicine clinicians have spent quite a bit of time studying the kreb cycle which is important for methylation and detoxifying the body, which relates to inflammation and chronic disease. Low homocysteine would suggest impaired ability for de novo production of glutathione and thus increased susceptibility to oxidative stress (Pizzorno, 2014).

The question remains then, is homocysteine itself toxic? We do know that elevated levels are associated with cardiovascular disease, and since this first discovery, many more disease entities have been associated. Is it the homocysteine itself though, or is this a causative factor? Maybe both?

Homocysteine can induce cell death in human vascular endothelial cells by interfering with protein syntheses, and it can initiate an immune response as they are foreign to normal body tissues. In addition to impairing protein synthesis, homocysteine is also directly toxic to endoplasmic reticulum, activates glutamate receptors, and damages DNA (Pizzorno, 2014). It certainly isn't benign. Equally important, homocysteine elevation is clearly a marker of dysfunctional metabolism. The many nutritional, hormonal, and genetic factors that raise homocysteine are also associated with common pathologic conditions, such as cancer, autoimmune disease, endothelial dysfunction, and neurodegenerative disease.

Reducing Homocysteine

Functional medicine practitioners do seem to more routinely evaluate homocysteine in effort to evaluate the methylation cycle, but also to assure that we aren't over supplementing those who struggle to assimilate B vitamins. In my experience, this optimal levels seems to be at about 7-8 for homocysteine, but there are clinicians that argue 5-7 and others in functional medicine who argue less than 7. I am still digging in to assure my rationale is sound, but if less than 1% have levels as low as 5, then it doesn't seem within an optimal range in my mind.

When levels are higher than optimal, I have three options or pathways for reducing that level. Two of these pathways are for homocysteine remethylation to methionine and the third is through conversion into cystathione for transulfuration (Pizzorno, 2014). The first is dependent on folate coenzyme 5-methyltetrahydrofolate which can donate a methyl group to homocysteine in a reaction catalyzed by the vitamin B12-dependent enzyme methionine synthase - or in layman's terms, we supplement with a methylated B complex supplement. Folic acid should specifically be avoided. We want this methylated because the supply of 5-methyltetrahydrofolate depends on vitamin B6 and the catalytic activity of MTHFR where single nucleotide polymorphisms, also called SNPs or historically - mutations - of MTHFR (C677T) are common which impairs folate-dependent remethylation of homocysteine.

If one has a MTHFR variant then they may not offer the necessary folate to methylate homocysteine and we will find elevated levels which is associated with disease pathology. Supplementing a methylated B complex is often encouraged, not folic acid.

The second pathway for homocysteine remethylation is independent of the 1-carbon pool, using betaine, derived from diet or the oxidation of choline, as a methyl group source in a reaction catalyzed by betaine-homocysteine methyltransferase (BHMT). The folate-dependent remethylation is found in all tissues, but the betaine pathway is found only in the liver and kidneys. Most of the research available finds the folate-pathway most associated with disease pathology, which substantiates the argument that although homocysteine is directly toxic, more importantly, hyperhomocysteinemia is a marker of metabolic dysfunction, primarily methylation disruption (Pizzorono, 2014). If the B complex is not effectively lowering homocysteine, then the betaine may prove helpful.

Bumping Up Homocysteine

We've established there is a narrow window of optimal homocysteine in the body and some is important to identify, so it isn't entirely toxic in itself. When levels are low, supplementation with methionine, N-acetylcysteine, and taurine is indicated (Pizzorono, 2014). Methioinine is an amino acid that the body needs to build chemicals; its active form is calls S-Adenosyl-L-Methionine (SAMe). This supplement is often encouraged for those with ADHD and to treat depression. It can improve hepatic steatosis, insulin resistance, inflammation, fibrosis, and bone health. Methionine supplementation can also be a double-edged sword, as high levels can increase homocysteine too significantly, cause weight loss, and increase cholesterol levels so monitoring is important.

N-acetylcysteine is a compound derived from the amino acid L-cysteine. It is widely used as a medication and dietary supplement for its antioxidant and anti-inflammatory properties. It is approved by the FDA as a prescription drug and recognized by the WHO as an essential drug. Interestingly, it is used to treat Tylenol poisoning, but more often in my practice, I use it to help break down thick mucus in the lungs and airways, making it easier for individuals with chronic respiratory conditions, to breathe. It was utilized often during the COVID pandemic. It's primary role is in its antioxidant and anti-inflammatory activities. It helps maintain a balance in cellular redox processes so improving scenarios in which oxidative stress and inflammation are playing a role. This translates to improving mental health disorders and addiction behaviors by regulating glutamate levels, a key neurotransmitter in the brain. Studies suggest it may help with bipolar disorder, schizophrenia, OCD, and withdrawal symptoms in individuals addicted to substances like cocaine. When I have a client with NASH, I offer them NAC to improve liver health, but it can also be important for those with asthma, even improving insulin sensitivity in those with PCOS, improving fertility, and lowering cardiac health risk. Common doses are 600 - 1,200mg daily. It may cause dry mouth, nausea, vomiting, and diarrhea. Inhaled NAC, which is what I recommended during COVID, may cause runny nose and drowsiness, rarely allergic reactions. There are some blood pressure medications and blood thinners that are contraindicated with NAC.

Taurine plays a significant role in cardiovascular health, including helping with blood pressure regulation, improving cardiac fitness, and enhancing vascular health. It is naturally found in meats and fish. The body uses taurine for energy production, and to create bile acid and balance our fluids, salts and minerals.

Genes Directly and Indirectly Involved in Homocysteine Metabolism

We typically think of MTHFR or methylenetetrahydrofolate reductase when we think of homocysteine, as this gene plays an important role in methylation and this is why I am lead to evaluate homocysteine in my wellness panel. CBS or cystathionine-B-synthase is yet another gene involved in homocysteine metabolism, as are MTR, MTRR, and RFC1 and GCP2, ENOS, TC2, SHMT1, TYMS, CTH, MTHFD, MTHFS, APOE, VEGF, PON1, BHMT, MAT1A, AHCY, CBL, F5, and PAI1. Many of my clients have their epigentic profiles reviewed and join our Nature verses Nuture program to understand how they might optimize their health based on their genetics.

Enzyme deficiencies such as cystathione-B-synthase, methionine synthase, and 5-methyltetrahydrofolate reductase are causes of elevated homocysteine, and vitamin deficiencies including folate, vitamin B6 and vitamin B12 can also play a role. Renal dysfunction, systemic lupus erythematosus, malignant neoplasm, psoriasis, and osteoporosis are also related so these would want to be considered when homocysteine remains outside the optimal range.

Although supplementation with folate, B6 and B12 does normalize homocysteine levels, the clinical outcomes have been quite mixed. This seems to further support the idea of elevated homocysteine as an indirect measure of disturbed metabolism. Interestingly, the Mediterranean diet is associated with a lower homocysteine level, which correlates to it being associated with reducing essentially every chronic disease (Mietus-Snyder et al., 2012).

Homocysteine is not an expensive test to run, although our practice does offer cash prices very inexpensively but it can offer a great deal of information with a huge impact on optimizing health.

References

Aishwarya, S., Rajendiren, S., Kattimani, S., Dhiman, P., Haritha, S., & Ananthanarayanan, P. H. (2013). Homocysteine and serotonin: association with postpartum depression. Asian J Psychiatric, 6(6), 473-477.

de Ruijter, W., Westendorp, R. G., & Assendelft, W. J. (2009). Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study. BMJ, 338.

Mietus-Synder, M. L., Shigenaga, M. K., & Suh, J. H. (2012). A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial. FASEB J, 26(8), 3515-3527.

Pizzorno, J. (2014). Homocysteine: friend or foe? Integr Med, 13(4), 8-14.

Seshadri, S., Beiser, A., & Selhub, J. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med, 346(7), 476-483.