High homocysteine is linked to many health problems including heart disease, stroke, autoimmune disease, cancer, and neurodegenerative disease.

This post describes:

  • How homocysteine levels can affect your health
  • How homocysteine can be toxic and inflammatory
  • Lab tests for homocysteine levels, with optimal ranges
  • Factors that influence homocysteine levels, including diet, lifestyle, and ways to support the methylation pathways given the relevant genetic information (i.e. MTHFR mutation)
  • How you can optimize your homocysteine levels to improve your performance and wellbeing.

Contents

What is Homocysteine?

Homocysteine is a sulfur-containing amino acid that is a byproduct of methionine (R).

Homocysteine is toxic and has been implicated as a marker for many chronic diseases.

Why High Homocysteine is Toxic and Inflammatory

Homocysteinylation (Attachment of Homocysteine to Proteins)

In people with high homocysteine, homocysteine can attach to proteins, resulting in modified proteins called homocysteine-thiolactone and N-homocysteinylated protein.

Homocysteine-thiolactone can attack many types of proteins including albumin in the blood, hemoglobin, immunoglobulins (antibodies), LDL, HDL, transferrin, antitrypsin, and fibrinogen (R).

Homocysteine-thiolactone can inhibit Na+/K+ ATPase (an enzyme responsible for conduction of nerve signals) in the hippocampus, cortex, and other brain cells of rats, which means it can interfere with neuronal function and health (R).

These modified proteins can activate genes that are involved in hardening of the arteries and cardiovascular diseases (R).

The immune system may also not recognized these modified proteins and start attacking them, resulting in autoimmunity and inflammation (R).

In addition, attachment of homocysteine to blood vessels can damage the blood vessel walls (R).

Homocysteine Increases Oxidative Stress

Chemical groups in homocysteine can affect the overall electrical potential of proteins and cells, and increase oxidative stress in the cells.

This can lead to increase cellular toxicity and protein misfolding, which is linked to neurodegenerative diseases (R).

The Production and Breakdown of Homocysteine

Homocysteine Metabolism https://www.ncbi.nlm.nih.gov/pubmed/27775595

Homocysteine Metabolism https://www.ncbi.nlm.nih.gov/pubmed/27775595

Methionine is a methyl donor in the body, whereas homocysteine is a methyl acceptor. When methionine donates the methyl group (is demethylated), it becomes homocysteine (R). When homocysteine accepts a methyl group, it becomes methionine.

Foods that are high in methionine include seafood, egg whites, and muscle meats (R).

Methionine is similar to cysteine.

Homocysteine can be made into cysteine and subsequently glutathione (R).

Homocysteine is converted into less toxic and more useful amino acids via two biochemical pathways, i.e. remethylation or transsulfuration:

  • Remethylation – A methyl group from 5-methyltetrahydrofolate, a breakdown product of dietary folic acid, or betaine is added to homocysteine to create methionine. Vitamin B12 is an important co-factor in this process, as is the enzyme MTHFR (RR2).
  • Transsulfuration – Homocysteine is converted to cystathionine by cystathionine β-synthase, before conversion to cysteine. Vitamin B6 is an important cofactor in this conversion (R, R2).

Homocysteine Blood Test

80-90% of homocysteine in the blood is bound to protein. Less than 1% is present in the free reduced form (R).

Measuring total homocysteine in the blood is technologically difficult because blood cells release homocysteine even after being taken from the body. Homocysteine levels in blood samples typically increase by 10% per hour (R, R2).

For this reason, it is vital for the lab to remove blood cells from the sample by centrifugation within 30 mins of the blood draw.

After being drawn and centrifuged, the sample is stable for 4 days at room temperature.

Because of the variability in lab methods, it is important that, when tracking homocysteine levels over time, you use the same lab and test to ensure consistency.

A high protein meal can significantly increase homocysteine levels. Thus, an individual should be in an overnight-fasted state before the blood draw (R).

Reference Ranges and Optimum Ranges

Research dating back two decades suggests that homocysteine levels should be under 9-10 micromoles per liter (µmol/L) (R).

Homocysteine levels over 9 µmol/L predict increased cardiac risk, with even higher risks when homocysteine levels go over 15 µmol/L (R, R2).

Optimal homocysteine levels should be under 7 µmol/L (R).

Japanese researchers found that individuals with homocysteine levels below 7 µmol/L were much less likely to suffer a stroke than patients with homocysteine levels higher than 11 µmol/L (R).

screen-shot-2016-12-22-at-15-38-27                                                                      (R)

Diseases Associated with High Homocysteine

Homocysteine is toxic, pro-inflammatory, and is a neurotoxin. Elevated homocysteine is linked to many diseases.

Homocysteine and Cardiovascular Health

1) Homocysteine Can Cause Hardening of the Arteries

heart exercise

High homocysteine (hyperhomocysteinemia) has been recognized as a risk factor for diseases caused by damaged blood vessels since the early 90s (R).

For example, high levels of homocysteine have been associated with increased risks of hardening of the arteries and coronary artery diseases (RR2)

Even moderately elevated homocysteine levels increase the risk of coronary, heart, cerebrovascular and peripheral artery diseases (R).

Fasting blood homocysteine levels in those with coronary artery disease were significantly higher than levels in healthy patients (R).

As we will discuss below, people with homozygous mutations of MTHFR gene can develop very high homocysteine levels. People with these mutations have been noted to have premature cardiovascular diseases (R).

Homocysteine can cause inflammatory damage to blood vessels, leading to plaque formation (R, R).

Technical: Homocysteine can cause an inflammatory response in vascular smooth muscle cells by stimulating CRP production. This inflammatory cascade is mediated through the NMDAR-ROS-ERK1/2/p38-NF-κB signal pathway (R).

One study found that homocysteine levels are a better predictor of heart disease than conventional measurements of risk, such as smoking, cholesterol or blood pressure (R).

2) Elevated Homocysteine and Stroke

During a stroke event, neuronal damage can occur when excitatory amino acids like glutamate and aspartate activate NMDA receptors, causing overstimulation of the neurons (R). Therefore, high homocysteine levels can increase neuronal damage during a stroke (R).

3) Elevated Homocysteine and Insulin Resistance

Elevated homocysteine is a marker for insulin resistance due to the effects insulin exerts on homocysteine metabolism and kidney clearance (R).

4) Elevated Homocysteine Worsens Diabetic Retinopathy

Diabetic patients with higher homocysteine levels have worse degeneration of the retina due to high blood sugar (R).

5) Elevated Homocysteine Increases Free Radical Damage

High homocysteine levels can cause increased rates of methionine synthesis and, thus, diminished levels of cysteine (R).

This can cause an overall lack of cysteine, which is necessary for the production of glutathione (the mother antioxidant) (R). This can lead to a build-up of free radical damage – possibly the main cause of atherosclerosis seen in hyperhomocysteinemia.

Homocysteine and Brain Health

Homocysteine is neurotoxic, as neurons grown in a solution with homocysteine die (R).

Homocysteine acts as an agonist for glutamate receptors, including NMDA receptors (R), so it can kill neuronal cells by activating MAPK and p38 MAPK pathways.

Homocysteine also kills other cells in the brain, such as the glial cells (a type of immune cells in the brain) (R).

In the brain, homocysteine induces mitochondrial damage and suppress energy (ATP) production, and leaking cytochrome C and reactive oxygen species (R).

Homocysteine can cause leaky brain (disruption of the blood brain barrier) by:

  • increasing MMP-9 (R)
  • Acting as excitatory neurotransmitter for NMDA receptors, which can increase oxidative stress and make the blood vessels in the brain more leaky (R, R2)

6) Elevated Homocysteine and Depression

One study found that, of the 924 men studies in men, those in the upper third of homocysteine levels were more than twice as likely to be depressed than those in the lowest third (R).

A second study found that individuals with the highest homocysteine levels (>12 µmol/L) tend to have lower levels of SAMe, a nutrient that is vital for the production of neurotransmitters associated with mood-enhancement (R).

Indeed, a recent study found that high homocysteine levels are correlated with low levels of serotonin (R).

Some researchers have speculated that post-pregnancy depression is caused by temporarily high homocysteine levels (R).

Supplementation with vitamins B2, B6, B12, and folic acid has been shown to effectively decrease homocysteine levels and reduce depressive symptoms (R).

7) Elevated Homocysteine and Alzheimer’s Disease

brain_133874900

High homocysteine levels are also associated with cognitive decline and Alzheimer’s disease (RR2).

An Italian study found that elderly individuals with elevated blood levels of homocysteine had a high risk of developing dementia. They also performed poorly on cognitive tests (R).

Another piece of research found that elderly individuals with homocysteine levels greater than 14 µmol/L were nearly twice as likely to develop Alzheimer’s disease (R).

Other studies have shown that homocysteine is able to trigger neuronal damage through oxidative stress, DNA damage and activation of pro-apoptotic (pro-cell death) factors in cell and animal models (R).

For example, researchers found that incubating neuronal cells with homocysteine for 5 days increased reactive oxygen species production by 4.4 times. This elevation in ROS caused neuronal toxicity (R).

8) Elevated Homocysteine and Parkinson’s Disease

Elevated homocysteine can cause Parkinson’s disease, as injecting homocysteine into rat brains induced Parkinson’s disease (R).

At high doses, L-Dopa, the main treatment for Parkinson’s disease, increases homocysteine  (R).

Homocysteine and Autoimmune Diseases

9) Homocysteine is Elevated in Hashimoto’s and Autoimmune Thyroiditis

In patients with autoimmune thyroiditis, serum homocysteine is elevated (R). When treated with levothyroxine (synthetic T4), serum homocysteine levels decrease (R).

Pernicious anemia commonly occurs in patients with autoimmune thyroiditis, suggesting that vitamin B12 deficiency could lead to elevated homocysteine and susceptibility to thyroid disease (R).

Optimizing thyroid function may help lower homocysteine levels, especially in the presence of adequate folate levels (R).

10) Elevated Homocysteine and Rheumatoid Arthritis

Homocysteine levels are elevated in rheumatoid arthritis patients. This elevation is associated with low levels of folate, vitamin B12, C3 and C4, and high inflammation markers including CRP, cystatin C (R).

11) Elevated Homocysteine and Psoriasis

Individuals with psoriasis, a common skin disorder, tend to have high blood levels of homocysteine and low levels of folic acid (R).

Indeed, one study concluded that “homocysteine levels can be considered an independent risk factor in psoriatic patients” (R).

It might be these elevated homocysteine levels that increase the risk of heart attack in psoriatic patients, although other factors may be involved (R).

12) Elevated Homocysteine and Systemic Lupus Erythematosus (SLE)

SLE patients have elevated plasma homocysteine levels comparing to healthy people (R).

Plasma homocysteine levels correlate with disease severity (R).

13) Elevated Homocysteine and Type 1 Diabetes

Homocysteine is elevated in type 1 diabetics with complications such as eye and kidney damage, but not in cases without complications (R).

14) Homocysteine and Multiple Sclerosis

Homocysteine levels are only elevated in some cases of multiple sclerosis, but not others (R). Elevated homocysteine levels are observed more in male patients (R).

Other Diseases and Elevated Homocysteine

15) Homocysteine and Cancer

Rapidly growing cancer cells need a lot of methionine in cellular protein production, because methionine is used as the first amino acid in every protein synthesis.

Normal cells can make methionine by remethylating homocysteine but cancer cells cannot, so cancer patients usually have high homocysteine (R, R2).

16) Elevated Homocysteine May Cause Osteoporosis

High homocysteine is a risk factor for osteoporosis (R).

Homocysteine can (R):

  • increase the activity of osteoclasts (cells that break down bones)
  • decrease the activity of osteoblast (cells that build new bone tissues)
  • increase MMP, an enzyme that degrades the bone matrix
  • damage hydroxyproline (an important amino acid for the bone), mitochondria and collagen
  • decrease blood flow to the bone

17) Elevated Homocysteine is Associated with Worse Pregnancy Outcome

pregnancy-week-13-fingerprints_4x3

One study found that women with prior history of second or third-trimester pregnancy losses had elevated homocysteine levels during their first trimester of pregnancy (R).

Recurrent pregnancy losses (or spontaneous abortion) are associated with MTHFR C677T mutation and high homocysteine among East Asian women (R, R2).

Also, homocysteine levels were significantly elevated in women who had experienced a hypertensive disorder during their pregnancy (R).

Women with pre-eclampsia have high levels of homocysteine, and low levels of serum folate and vitamin B12 (R).

18) Elevated Homocysteine and Dental Health

Chronic periodontitis (inflammation in the teeth and gum) is linked to elevated homocysteine levels. This elevated homocysteine level returns to normal after the periodontal diseases are treated (R, R2).

19) Elevated Homocysteine and Migraine

While we still don’t completely understand the causes of migraine, some clinicians speculate that homocysteine may cause migraine by inflamming the blood vessels and causing blood clotting (thrombotic) (R).

The concentration of homocysteine in the brain fluid (cerebrospinal fluid) is increased in migraine patients (R).

People who have mutations in genes that are involved in homocysteine metabolism, such as MTHFR mutation rs1801133, are more likely to get migraine (R).

B vitamin supplementation decreases severity and frequency of migraine attacks (R).

Higher homocysteine is associated with migraine headache with aura among men, but not among other groups (R).

Effects of Low Homocysteine

Low Homocysteine May Impair Detoxification

Although much rarer, and generally less of an issue than high levels, low homocysteine levels can also cause problems.

For example, adequate homocysteine levels are necessary for the production of factors important for detoxification (e.g. glutathione production), such as cysteine, taurine, and sulfate. Thus, low homocysteine levels can restrict detoxification pathways that respond to oxidative stress (R).

Factors That Increase Homocysteine Levels

Aside from inflammatory diseases that are linked to high homocysteine, there are other factors that may increase homocysteine levels. Generally, factors that increase the need for methylation will increase homocysteine levels.

1) High Methionine Diet Increases Homocysteine Levels

A diet high in methionine, such as a diet rich in muscle meats, can increase blood homocysteine levels (R).

2) Guanidinoacetate Increases Homocysteine Levels

Guanidinoacetate is a precursor of creatine. Methylation of guanidinoacetate results in creatine. Guanidinoacetate administration in rats increases homocysteine levels by 50%, whereas, administration of creatine can reduce homocysteine by 25% (R).

3) Kidney Disease

Kidneys are responsible for removing homocysteine from the blood (R, R2).

The kidneys also help transform homocysteine into benign substances (R).

Therefore, any decrease in kidney function causes an accumulation of homocysteine.

This explains why individuals with severe kidney disease have very high homocysteine levels. They also have rates of cardiovascular disease up to 30 times higher than healthy individuals (R, R2)

In fact, even people with mild kidney problems have elevated homocysteine levels (R, R2, R3).

High homocysteine levels despite consumption of homocysteine-lowering nutrients (e.g. B6 and B12, folic acid) points towards kidney issues (R, R2, R3).

Thus, improving kidney function might be an important step to lowering your homocysteine levels.

4) Medication

High homocysteine levels are also observed in those taking specific medications, including methotrexate for rheumatoid arthritis, Glucophage (metformin) for diabetes, cholestyramine for high blood triglycerides, niacin for high cholesterol, and a number of antiepileptic drugs (R).

5) Stress

Restrain stress increases homocysteine levels in rats (R).

In women, psychological stress temporarily increases homocysteine levels, which return to normal levels after the stress resolves (R).

6) Genetic Factors and Homocysteine Levels

For a full list of genes that affect homocysteine levels, click here view on SelfDecode.

SelfDecode is the best genetic analysis tool, which will help you understand your 23andme results.

Congenital Homocystinuria

In 1962, researchers found that individuals with a rare genetic condition named homocystinuria, in which a dysfunctional enzyme (CBS Mutations) leads to an accumulation of homocysteine, were at risk of severe cardiovascular disease in their teens and 20s (R).

MTHFR Mutations

Case in point, less MTHFR activity causes a build up of homocysteine. This is because the MTHFR gene codes for the enzyme, methylenetetrahydrofolate reductase, that helps to convert folic acid into its bioactive form (R).

Mutations in MTHFR are a common inherited risk factor for elevated homocysteine levels.

Every individual has 2 MTHFR genes (1 from each parent). Mutations in just one MTHFR gene is referred to as “heterozygous”; mutations of both genes is called “homozygous”.

Approximately 10% of Europeans have this gene in its homozygous form.

Genetic variations in the MTHFR gene results in reduced activity of the enzyme produced and have been associated with a series of diseases and conditions, including cardiovascular disorders, neurological defects, some forms of cancer, psychiatric disorders, diabetes, and pregnancy complications (R, R2).

The two most common MTHFR mutations (polymorphisms) found in humans are:

  • MTHFR C677T (Rs1801133). This mutation (the A allele) is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate (R). People with an “A” allele for this mutation present a 35% decrease in the normal enzyme activity and “AA” individuals a 70% decrease (R)
  • MTHFR A1298C (rs1801131).  This mutation also impacts the MTFHR activity and the homocysteine levels but to a lesser extent than C677T (R).

The enzymatic activity of MTHFR in people with one minor allele in each MTHFRC677T and A1298C polymorphisms is lower than the activity present if each SNP separately had a minor allele (R).

Reduced MTHFR enzyme activity results in a decreased conversion of the amino acid homocysteine to methionine and accumulation of homocysteine in the blood (R).

BHMT Mutations

Betaine-homocysteine methyltransferase (BHMT) catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine (R).

CBS Mutations

The CBS gene encodes an enzyme called cystathionine beta-synthase. It is responsible for using vitamin B6 to convert homocysteine and serine to a molecule called cytathionine. Another enzyme converts cystathionine to cysteine, which is used to build proteins or is broken down and excreted in urine (R).

7) Quercetin 

In human liver cancer cell culture, quercetin significantly increased homocysteine concentration [R].

This increase in homocysteine outside of the cells (extracellular) may be related to increased methylation. Thus, people should be more cautious when using quercetin supplements [R].

How to Decrease Homocysteine Levels

Elevated homocysteine is generally known to be a modifiable risk factor i.e. appropriate dietary, lifestyle and supplementation strategies can correct levels (R). Here are the key factors that affect homocysteine levels:

1) B-vitamins & Folate

The best way to prevent elevation of homocysteine is by ensuring adequate intake of folic acid, vitamin B12 and vitamin B6.

This can be done through foods, as a nutrient-dense diet containing fruits, vegetables, dark leafy greens, eggs, and red meats should provide sufficient B vitamins needed to maintain homocysteine at normal levels. However, in those with elevated homocysteine, supplementation with folate, B6, and B12 can normalize homocysteine levels (R).

B12 and B6 are necessary cofactors in the metabolism of homocysteine via remethylation or transsulfuration (R).

Studies show that a deficiency in either of these vitamins causes homocysteine levels to increase (R).

For B12 I like the Pure Encapsulations Methylcobalamin drops. Thorne Research make a great B6 supplement that I often recommend.

Folic acid is broken down by the MTFHR enzyme to 5-methyltetrahydrofolate, which supplies the methyl group needed to metabolize homocysteine into methionine (R).

5-methyltetrahydrofolate (5-MTHF) is the active form of folic acid. Studies have shown that supplementation with 5-MTHF provides protection against the dangers of high homocysteine levels.

For example, one study found that 113mcg/day of 5-MTHF lowered homocysteine levels by an average of 14.6% over a 6- period (R).

When trying to lower homocysteine, it is important to take 5-MTHF, the active form of methyl folate. 5-MTHF is nearly 7 times more powerful than ordinary folic acid at raising blood folate levels (R).

In scientific research, doses of 1,000 mcg – 5,000 mcg per day of 5-MTHF achieve desirable reductions in plasma homocysteine concentrations.

I recommend L 5-MTHF by Seeking Health

2) Methyl Donors Can Decrease Homocysteine Levels

Increased need for methyl group increase homocysteine levels, so supplementation with methyl donors, such as choline and betaine, can decrease homocysteine levels.

In rats, high homocysteine can be suppressed with choline and betaine (R, R2).

3) Estrogen May Reduce Homocysteine Levels

Higher estrogen status is linked with lower average homocysteine levels (R).

Indeed, pregnant, premenopausal and postmenopausal women who are on estrogen replacement therapy have lower levels of homocysteine (R).

This negative relationship between estrogen and homocysteine might explain why, on average, men have higher homocysteine levels than women (R).

It also explains why estrogen therapy lowers cardiovascular risk (R).

Evidence suggests that estrogen lowers homocysteine by modulating thiol amino acid metabolism, especially methionine metabolism (R).

4) Resistance Exercise May Decrease Homocysteine Levels

In rats with cancer, resistance exercise prevents impaired homocysteine metabolism and helps the liver better handle increased oxidative stress. The exercise prevented the increase in homocysteine that would have been caused by the tumors and also increase glutathione (R).

Supplements that Mitigate Harmful Effects of High Homocysteine

  • Melatonin (R)
  • Vitamin E (R)
  • Alpha-lipoic acid (R)
  • Astragalus (R)
  • Curcumin (R)

Further Reading

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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12 COMMENTS

  • Tam

    Have tried EVERY supplement/diet change recommended in this article and Yasko and RichVanK’s MTHFR/CBS Protocol and EVERY one of them makes me profoundly sick (I can tolerate very small doses for a few days then BAM…flattened bad sick). I get it, what I need to take. What happens with those of us who CANNOT start “slowly enough” due to enzyme deficiencies or genetic dysfunction? If we can’t tolerate choline, methyls, etc.etc. Is there no hope? As an intelligent person who has researched 6 archives boxes’ worth of info in order to heal, what if my body will not allow it due to deficiencies I cannot overcome? Seriously…I have tried EVERYTHING. And today I just found out my Homocystein level has doubled…am I destined to simply deteriorate and waste away because my body cannot tolerate the very things it desperately needs?

    1. Nattha Wannissorn, PhD

      Sorry to hear. I’ve seen many clients tell the exact same story on my genetic consults. I’d say do the other things first to address the problem. If you need more help, you can book a consult with Joe at selfhacked.com/contact, or me or other specialists at selfhacked.com/consult-specialists/. We just recorded a podcast episode about this which will help you a lot. It will be released around end of this month.

  • KD

    What’s an alternative to 5-MTHF. I can’t handle taking any methyl supplements but need to lower my homocysteine.

    1. Nattha Wannissorn

      You should book an appointment with Joe at selfhacked.com/contact.

    2. Sean

      Can’t handle Trimethylglycine? (TMG, referred to as betain in the article) have you tried methyl-b12 instead of the normal otc b12(cyano-b12)? Some people have trouble trouble converting the cyano to the methyl form

    3. Sean

      Choline / lecithin is a methyl donor as well.

  • Bernadette Pascua Andrada

    How about if your homocysteine is very low 2.3 ?? What is causing this?

  • Lonalee

    Do you have any information regarding migraines. If I eat a good I am sensitive to I get a migraine about 20minutes later. Migraine can last 12 hours. Only relief and sometimes that doesn’t work ….is the migraine medicine. Narcotics and pain relievers do nothing. Have taken liquid benedryl to calm my stomach when I am nauseated.

    1. Nattha Wannissorn

      updated – see #19 ~Nattha @ Team SelfHacked

  • Paul

    My doctor used to test for homocysteine on my annual exams, but for some reason he stopped doing so. Does anyone know a lab or home test I can use? Also, I read that glycine can lower homocysteine. Do you have any information on this?

    1. Nattha Wannissorn

      Here:
      Homocysteine lab test

      Yes, it makes sense that glycine can lower homocysteine since it’s kind of the opposite of the amino acid to methionine in the pathway. Let me know if you find a source so I’ll add it to the post. ~Nattha @ Team SelfHacked

    2. Sean

      Trimethylglycine (TMG), not just glycine. The article mentions betain, wich is referring to TMG. TMG is a betain, and is usually synonymous, but it’s not the only betain. TMG is how is a methyl group storage and donor. Google methylation protocol for lots more info.

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