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
- 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 well-being.
What is Homocysteine?
Homocysteine is a sulfur-containing amino acid that is a byproduct of methionine .
Homocysteine is toxic and has been implicated as a marker for many chronic diseases. High levels may be caused by an abnormality in the methylation pathway in the body, which is essential for immune and inflammatory regulation.
Why High Homocysteine Levels are 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 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 .
These modified proteins can activate genes that are involved in hardening of the arteries and cardiovascular diseases .
The immune system may also not recognized these modified proteins and start attacking them, resulting in autoimmunity and inflammation. In addition, attachment of homocysteine to blood vessels can damage the blood vessel walls .
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 increased cellular toxicity and protein misfolding, which is linked to neurodegenerative diseases likely because of protein modification and amyloid or other aggregate formation .
The Production and Breakdown of Homocysteine
The methylation pathway is complex; some key players are methionine, homocysteine, and glutathione (a very powerful antioxidant).
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 . When homocysteine accepts a methyl group, it becomes methionine.
Foods that are high in methionine include seafood, egg whites, and muscle meats . Methionine is similar to cysteine.
Homocysteine can be made into cysteine and subsequently glutathione .
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 [1, 9].
- Transsulfuration – Homocysteine is converted to cystathionine by cystathionine β-synthase, before conversion to cysteine. Vitamin B6 is an important cofactor in this conversion [1, 9].
As you can see, many enzymatic pathways are needed in the methylation pathway to accommodate the body’s demands at the same time. When homocysteine can not be converted to other compounds, it builds up in the body and causes damage. B vitamins play a very important role in this balance.
Homocysteine Blood Test
80 – 90% of homocysteine in the blood is bound to protein. Less than 1% is present in the free reduced form .
It is important to know the method of lab collection when obtaining your homocysteine level because there can be a false elevation depending on method of collection.
Measuring total homocysteine in the whole blood is technologically difficult because blood cells release homocysteine even after blood collection. Homocysteine levels in blood samples typically increase by 10% per hour after patient collection [11, 12].
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 or high protein diet may increase homocysteine levels, but not if an individual is fasting Overnight fasting before a blood draw is suggested for accuracy and consistency .
Research dating back two decades suggests that homocysteine levels should be under 9 – 10 micromoles per liter (µmol/L) .
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) Can Cause Hardening of the Arteries
High homocysteine (hyperhomocysteinemia) has been recognized as a risk factor for diseases caused by damaged blood vessels since the early 90s .
Even moderately elevated homocysteine levels increase the risk of coronary, heart, cerebrovascular and peripheral artery diseases .
Studies show fasting blood homocysteine levels in those with coronary artery disease were significantly higher than levels in healthy patients and increased with severity of disease .
As we will discuss below, people with homozygous mutations of the MTHFR gene can develop very high homocysteine levels. People with these mutations have been noted to have premature cardiovascular diseases .
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 . CRP or C-reactive protein is a well known and commonly ordered marker to assess acute inflammation in someone presenting with cardiac or autoimmune disease symptoms.
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 .
During a stroke event, neuronal damage can occur when excitatory amino acids like glutamate and aspartate activate NMDA receptors, causing overstimulation of the neurons. High homocysteine can also increase the activation of these receptors, and is, therefore, implicated as having a role in neuronal damage during a stroke .
3) Insulin Resistance
Elevated homocysteine is a marker of insulin resistance due to the effects of insulin exerts on homocysteine metabolism and kidney clearance .
4) Worsens Diabetic Retinopathy
Diabetic patients with higher homocysteine levels have worse degeneration of the retina due to high blood sugar .
5) Increases Free Radical Damage
High homocysteine levels can cause increased rates of methionine synthesis and, thus, diminished levels of cysteine.
This can cause an overall lack of cysteine, which is necessary for the production of glutathione (the mother antioxidant) . 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 was neurotoxic in a cellular analysis when neurons grown in a solution with homocysteine produced free radical species that are known to lead to cell death .
Homocysteine acts as an agonist for glutamate receptors, including NMDA receptors, 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) .
In the brain, homocysteine induces mitochondrial damage and suppress energy (ATP) production, and leaking cytochrome C and reactive oxygen species .
Homocysteine can cause leaky brain (disruption of the blood-brain barrier) by:
- increasing MMP-9 
- Acting as an excitatory neurotransmitter for NMDA receptors, which can increase oxidative stress and make the blood vessels in the brain leakier [33, 34].
One study found that, of the 924 men, those in the upper third of homocysteine levels were more than twice as likely to be depressed than those in the lowest third .
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 .
Some researchers have speculated that postpartum depression (PPD) involves temporarily high homocysteine levels as seen by a statistically significant study showing a positive association between homocysteine levels and PPD .
Supplementation with vitamins B2, B6, B12, and folic acid has been shown to effectively decrease homocysteine levels and reduce depressive symptoms .
7) Alzheimer’s Disease
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 .
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 .
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 .
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 .
8) Parkinson’s Disease
Elevated homocysteine can induce Parkinson’s disease in rat brains injected with homocysteine.
At high doses, L-Dopa, the main treatment for Parkinson’s disease, increases homocysteine .
Homocysteine and Autoimmune Diseases
9) Autoimmune Thyroiditis
A few noteworthy studies with autoimmune thyroiditis patients showed serum homocysteine may be not only elevated, but when treated with levothyroxine (synthetic T4), serum homocysteine levels decrease [45,46].
10) Rheumatoid Arthritis
Homocysteine levels are commonly high 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 .
Individuals with psoriasis, a common skin disorder, tend to have high blood levels of homocysteine and low levels of folic acid .
Indeed, one study concluded that “homocysteine levels can be considered an independent risk factor for psoriatic patients” .
It might be these elevated homocysteine levels that increase the risk of a heart attack in psoriatic patients, although other factors may be involved .
12) Systemic Lupus Erythematosus (SLE)
SLE patients have elevated plasma homocysteine levels comparing to healthy people .
Plasma homocysteine levels correlate with disease severity .
13) Type 1 Diabetes
Homocysteine is elevated in type 1 diabetics with complications such as eye and kidney damage, but not in cases without complications .
14) Multiple Sclerosis
Other Diseases and Elevated Homocysteine
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.
16) May Cause Osteoporosis
High homocysteine is a risk factor for osteoporosis .
Homocysteine can :
- 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) Associated with Worse Pregnancy Outcome
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 .
Also, homocysteine levels were significantly elevated in women who had experienced a hypertensive disorder during their pregnancy .
Women with pre-eclampsia have high levels of homocysteine, and low levels of serum folate and vitamin B12 .
18) Dental Health
Chronic periodontitis (inflammation of the teeth and gum) has been linked to elevated homocysteine levels in studies. This elevated homocysteine level returns to normal after the periodontal diseases are treated [65, 66].
While we still don’t completely understand the causes of migraines, some clinicians speculate that homocysteine may cause migraine by inflaming the blood vessels and contributing to the blood clotting cascade (thrombosis).
The concentration of homocysteine in cerebrospinal fluid that bathes the brain is increased in migraine patients .
People who have mutations in genes that are involved in homocysteine metabolism, such as MTHFR mutation rs1801133, are more likely to get a migraine .
A narrative review showed B vitamin supplementation decreases the severity and frequency of migraine attacks . The association between migraine and Homocysteine levels is speculative and increases the need for further research.
Higher homocysteine is associated with a migraine headache with aura among men, but not among other groups .
Effects of 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 .
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
A diet high in methionine, such as a diet rich in muscle meats, can increase blood homocysteine levels .
However, it is important to note that methionine consumption through diet is a small influencing factor in pathology in comparison to genetic variations that play a much bigger role. A low methionine diet may play a role in those with known elevated homocysteine.
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% .
3) Kidney Disease
The kidneys also help transform homocysteine into benign substances .
Therefore, any decrease in kidney function causes an accumulation of homocysteine.
Thus, improving kidney function might be an important step in lowering your homocysteine levels.
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 .
Restraint stress increases homocysteine levels in rats .
In women, psychological stress temporarily increases homocysteine levels, which return to normal levels after the stress resolves .
6) Genetic Factors
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 .
Now, with our growing research and knowledge in the field of genomics, we are uncovering the genetic mutations that lead to high levels of homocysteine in the blood and in severe cases in the urine. We know that the methylation process involving homocysteine is commonly disrupted through the MTHFR gene mutation. Homocysteinemia is not considered rare.
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 .
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 [89, 90].
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 . People with an “A” allele for this mutation present a 35% decrease in the normal enzyme activity and “AA” individuals a 70% decrease .
- MTHFR A1298C (rs1801131). This mutation also impacts the MTFHR activity and the homocysteine levels but to a lesser extent than C677T .
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 cystathionine. Another enzyme converts cystathionine to cysteine, which is used to build proteins or is broken down and excreted in urine .
Quercetin is a supplement commonly used for its anti-histamine properties. In human liver cancer cell culture, quercetin supplementation significantly increased homocysteine concentration .
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 .
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 . 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 .
B12 and B6 are necessary cofactors in the metabolism of homocysteine via remethylation or transsulfuration .
Studies show that a deficiency in either of these vitamins causes homocysteine levels to increase .
For B12 I like the Pure Encapsulations Methylcobalamin drops. Thorne Research makes 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 .
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 24–week period .
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 .
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
Increased need for methyl group increase homocysteine levels, so supplementation with methyl donors, such as choline and betaine, can decrease homocysteine levels.
It is important to note that there may be side effects to supplementation and should be done only after a full genomics analysis and review from your provider.
Higher estrogen status is linked with lower average homocysteine levels .
Indeed, pregnant, premenopausal and postmenopausal women who are on estrogen replacement therapy have lower levels of homocysteine .
This negative relationship between estrogen and homocysteine might explain why, on average, men have higher homocysteine levels than women .
It also may explain why estrogen therapy lowers cardiovascular risk .
Evidence suggests that estrogen lowers homocysteine by modulating thiol amino acid metabolism, especially methionine metabolism .
4) Resistance Exercise
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 .
Supplements that May Mitigate the Harmful Effects of High Homocysteine
Irregular Homocysteine Levels?
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