What is homocysteine?
Homocysteine is a sulfur-containing amino acid and a by-product of methionine. Homocysteine is toxic and is considered as a sign of many chronic diseases.
Why is high homocysteine level toxic and inflammatory?
Homocysteine (a combination of homocysteine and protein)
In people with high homocysteine, homocysteine can attach to protein and produce modified proteins called homocysteine thiolactone and N- homocysteine protein.
Homocysteine thiolactone can attack a variety of protein, including albumin, hemoglobin, immunoglobulin (antibody), low density lipoprotein, high density lipoprotein, transferrin, antitrypsin and fibrinogen in blood.
Homocysteine thiolactone can inhibit sodium/k+ATPase (an enzyme responsible for nerve signal transduction) in brain cells such as hippocampus and cortex of rats, which means that it can interfere with nerve function and health.
These modified protein can activate genes related to arteriosclerosis and cardiovascular diseases.
The immune system may also fail to recognize these modified protein and start attacking them, leading to autoimmune and inflammation. In addition, the adhesion of homocysteine to blood vessels will damage the blood vessel wall.
Increase oxidation pressure
The chemical groups in homocysteine will affect the overall potential of protein and cells, and increase the oxidative stress in cells. This may lead to increased cytotoxicity and misfolding of protein, which is related to neurodegenerative diseases.
Formation and decomposition of homocysteine
Methionine is a methyl donor and homocysteine is a methyl acceptor in vivo. When methionine provides methyl (demethylation), it becomes homocysteine. When homocysteine accepts methyl, it becomes methionine.
Foods with high methionine content include seafood, protein and muscle. Methionine is similar to cysteine.
Homocysteine can be made into cysteine, and then glutathione.
Homocysteine is converted into less toxic and more useful amino acids through two biochemical pathways (demethylation or sulfidation):
l？ Methylation-methionine is produced by adding methyl groups in 5- methyltetrahydrofolate (decomposition product of dietary folic acid or betaine) to homocysteine. Vitamin B 12 is an important factor in this process, and so is MTHFR enzyme.
l？ Transthio-homocysteine is converted into cystathionine by cystathionine β synthase, and then into cysteine. Vitamin B6 is an important cofactor in this transformation process.
Homocysteine blood test
80-90% of homocysteine in blood binds to protein. The deficiency 1% exists in the form of free reduction.
It is technically difficult to measure the total homocysteine in blood, because blood cells will release homocysteine even if they are taken out of the body. The homocysteine level in blood samples usually increases by 10% every hour.
Therefore, the laboratory must remove blood cells from the sample by centrifugation within 30 minutes after blood collection. After extraction and centrifugation, the sample was stable at room temperature for 4 days. Because of the variability of laboratory methods, it is important to use the same laboratory and test to ensure consistency when tracking homocysteine levels. High protein diet can significantly increase the level of homocysteine. So a person should be on an empty stomach before drawing blood.
reference range
Studies as early as 20 years ago showed that the homocysteine level should be lower than 9-10 μ mol/L. The increase of heart risk can be predicted when the homocysteine level exceeds 9μmol/l, and the risk is higher when the homocysteine level exceeds15 μ mol/L. ..
Hyperhomocysteine related diseases
Homocysteine is a neurotoxin with toxicity and inflammation. Homocysteine is associated with many diseases.
Homocysteine and cardiovascular health
1) may cause arteriosclerosis.
Since the early 1990s, hyperhomocysteinemia has been considered as a risk factor for diseases caused by vascular injury. For example, high levels of homocysteine are associated with an increased risk of atherosclerosis and coronary artery disease. Even moderately elevated homocysteine levels increase the risk of coronary artery, heart, cerebrovascular and peripheral artery diseases.
The level of homocysteine in patients with coronary heart disease is significantly higher than that in healthy people.
As we will discuss below, people with homozygous mutations in mthfr gene can produce very high homocysteine levels. People with these mutations were found to have early-onset cardiovascular disease.
Homocysteine can cause vasculitis injury and lead to plaque formation.
Technology: Homocysteine can cause inflammatory reaction of vascular smooth muscle cells by stimulating CRP production. The inflammatory cascade is mediated by NMDAR-ROS-ERK1/2/P38-NF-κ B signaling pathway.
A study found that compared with traditional risk indicators such as smoking, cholesterol or blood pressure, homocysteine levels can better predict heart disease.
2) Stroke
Once a stroke occurs, when excitatory amino acids such as glutamic acid and aspartic acid activate NMDA receptors, resulting in excessive stimulation of neurons, neuronal damage will occur. Therefore, high homocysteine level can increase neuronal damage during stroke.
3) Insulin resistance
Because of the influence of insulin on homocysteine metabolism and renal clearance, high homocysteine is a sign of insulin resistance.
4) Diabetic retinopathy is aggravated.
Diabetic patients with high homocysteine level have more severe retinal degeneration due to hyperglycemia.
5) increase free radical damage
High homocysteine level can lead to an increase in methionine synthesis rate, thus reducing cysteine level.
This may lead to a complete lack of cysteine, which is necessary for the production of glutathione, a maternal antioxidant. This may lead to the accumulation of free radical damage, which may be the main cause of atherosclerosis in hyperhomocysteinemia.
Homocysteine and brain health
Homocysteine is a neurotoxic substance, and neurons will die when they grow in homocysteine solution.
Homocysteine, as an agonist of glutamate receptors (including NMDA receptors), kills neurons by activating MAPK and p38 MAPK pathways.
Homocysteine can also kill other cells in the brain, such as glial cells (an immune cell in the brain).
In the brain, homocysteine induces mitochondrial damage and inhibits the production of energy (ATP), as well as the leakage of cytochrome C and reactive oxygen species.
Homocysteine can cause brain leakage (blood-brain barrier rupture) by increasing MMP-9; As an excitatory neurotransmitter of NMDA receptor, it can increase oxidative stress and make cerebral vessels more prone to leakage.
6) Depression
A study found that in 924 male studies, the people with the highest homocysteine level were more than twice as likely to suffer from depression as the people with the lowest homocysteine level.
The second study found that individuals with the highest homocysteine level (>: 12μmol/l) usually have low levels of adenosylmethionine, which is a vital nutrient to produce neurotransmitters related to emotional enhancement.
In fact, a recent study found that homocysteine levels are related to low serotonin levels.
Some researchers speculate that post-pregnancy depression is caused by temporary homocysteine levels.
Supplementation of vitamins B2, B6, B 12 and folic acid has been proved to be effective in reducing homocysteine level and relieving depressive symptoms.
7) Alzheimer's disease
High homocysteine levels are also associated with cognitive decline and Alzheimer's disease.
An Italian study found that elderly people with elevated homocysteine levels in their blood have a high risk of dementia. Their cognitive tests also performed poorly.
Another study found that elderly people with homocysteine levels higher than 1.4 μm ol/L were almost twice as likely to develop Alzheimer's disease as normal people.
Other studies have shown that homocysteine can cause neuronal damage through oxidative stress, DNA damage and activation of pro-apoptosis factors in cell and animal models.
For example, the researchers found that when neurons were cultured with homocysteine for 5 days, the production of reactive oxygen species increased by 4.4 times. The increase of reactive oxygen species leads to neuronal toxicity.
8) Parkinson's disease
Homocysteine can lead to Parkinson's disease, such as Parkinson's disease induced by injecting homocysteine into the brain of rats. At high doses, levodopa, which is mainly used to treat Parkinson's disease, will increase homocysteine.
Homocysteine and autoimmune diseases
9) autoimmune thyroiditis
In patients with autoimmune thyroiditis, serum homocysteine is increased. When levothyroxine (synthetic T4) is treated, the level of serum homocysteine decreases.
Malignant anemia is common in patients with autoimmune thyroiditis, suggesting that vitamin B 12 deficiency can lead to the increase of homocysteine, which is prone to thyroid diseases. Optimizing thyroid function may help to reduce homocysteine level, especially if folic acid level is sufficient.
10) rheumatoid arthritis
The level of homocysteine in patients with rheumatoid arthritis is increased. This increase is related to the low levels of folic acid, vitamin B 12, C3 and C4, and high inflammatory markers including CRP and cystatin C. ..
1 1) psoriasis
Psoriasis is a common skin disease, with high homocysteine content and low folic acid content in blood. In fact, a study concluded that "homocysteine level can be regarded as an independent risk factor for patients with psoriasis".
It may be that these high homocysteine levels increase the risk of heart attack in patients with psoriasis, although other factors may be involved.
12) Systemic lupus erythematosus
Compared with healthy people, the plasma homocysteine level in SLE patients is higher. Plasma homocysteine level is related to the severity of the disease.
13) 1 type diabetes mellitus
1 Homocysteine is elevated when diabetes has complications such as eye and kidney damage, but not when there are no complications.
14) multiple sclerosis
The level of homocysteine only increased in some cases of multiple sclerosis, but not in others. The level of homocysteine in male patients is more obvious.
Other diseases and homocysteine
15) cancer
Fast-growing cancer cells need a lot of methionine in protein production, because methionine is used as the first amino acid in every protein synthesis.
Normal cells can produce methionine by demethylating homocysteine, but cancer cells can't, so cancer patients usually have high homocysteine.
16) may lead to osteoporosis.
Hyperhomocysteine is a risk factor for osteoporosis.
Homocysteine groove: increase the activity of osteoclasts (cells that decompose bones); Reduce the activity of osteoblasts (cells that build new bone tissue); Increase MMP, an enzyme that degrades bone matrix; Damage hydroxyproline (an important amino acid in bones), mitochondria and collagen; Reduce blood flow to bones.
17) was associated with poor pregnancy outcome.
A study found that the level of homocysteine in women with a history of abortion in the second and third trimester of pregnancy increased in the first trimester.
Recurrent pregnancy abortion (or spontaneous abortion) in East Asian women is related to mthfr c677t mutation and homocysteine.
In addition, the level of homocysteine in women with pregnancy-induced hypertension increased significantly. Preeclampsia women have high serum homocysteine level and low serum folic acid and vitamin B 12 content.
18) dental health
Chronic periodontitis (inflammation of teeth and gums) is related to homocysteine levels. After treatment of periodontal disease, the level of homocysteine returned to normal.
19) migraine
Although we don't fully understand the cause of migraine, some clinicians speculate that homocysteine may cause migraine by igniting blood vessels and causing blood coagulation (thrombosis).
The concentration of homocysteine in cerebrospinal fluid (CSF) of migraine patients increases.
People whose gene mutation is related to homocysteine metabolism, such as mthfr mutation rs 180 1 133, are more likely to suffer from migraine.
Vitamin B supplementation can reduce the severity and frequency of migraine attacks.
Homocysteine is associated with migraine with aura in men, but not in other people.
The role of low homocysteine
May impair detoxification.
Although low homocysteine levels are rarer than high levels and usually cause fewer problems, low homocysteine levels may also cause problems.
For example, important factors (such as cysteine, taurine and sulfate) for detoxification (such as glutathione production) need adequate homocysteine levels. Therefore, low homocysteine level can limit the detoxification pathway of oxidative stress.
Factors of elevated homocysteine level
Besides the inflammatory diseases associated with hyperhomocysteinemia, there are other factors that may increase the homocysteine level. Generally speaking, factors that increase methylation demand will increase homocysteine levels.
1) high methionine diet
A diet rich in methionine, such as a diet rich in muscle, can increase the level of homocysteine in the blood.
2) Guanidinoacetate
Guanidine acetate is the precursor of creatine. Methylation of guanidine acetate produces creatine. Guanidine acetic acid can increase the homocysteine level in rats by 50%, and creatine can decrease the homocysteine level by 25%.
3) Kidney disease
The kidney is responsible for removing homocysteine from the blood. The kidney also helps to convert homocysteine into benign substances. So any decline in renal function will lead to the accumulation of homocysteine. This explains why people with severe kidney disease have very high homocysteine levels. Their incidence of cardiovascular diseases is also 30 times higher than that of healthy people.
.
In fact, even people with mild kidney problems have elevated homocysteine levels. Despite the intake of nutrients that reduce homocysteine (such as B6 and B 12, folic acid), high homocysteine levels still point to kidney problems. Therefore, improving renal function may be an important step to reduce homocysteine level.
4) drugs
Homocysteine levels were also observed in patients taking certain drugs, including methotrexate for rheumatoid arthritis, glucose phage (metformin) for diabetes, cholesterolamine with high blood triglycerides, nicotinic acid with high cholesterol and some antiepileptic drugs.
5) pressure
Inhibition of stress increased the level of homocysteine in rats. In women, psychological stress will temporarily increase the level of homocysteine, and return to normal level after the pressure is eliminated.
6) Genetic factors
Congenital hyperhomocysteinemia; In 1962, researchers found that individuals with a rare genetic disease called homocystinuria (in which a dysfunctional enzyme (CBS mutation) leads to the accumulation of homocysteine) are at risk of serious cardiovascular diseases in their teens and twenties.
Mthfr mutation
In this respect, lower mthfr activity leads to the accumulation of homocysteine. This is because the enzyme encoded by mthfr gene, methylenetetrahydrofolate reductase, helps to transform folic acid into its biologically active form.
Mthfr mutation is a common genetic risk factor for the increase of homocysteine level.
Each individual has two mthfr genes (each parent 1). Only one mthfr gene mutation is called "heterozygote"; Mutations in two genes are called "homozygotes". About 10% of Europeans have homozygous genes.
The genetic variation of mthfr gene leads to the decrease of enzyme activity, which is related to a series of diseases and disorders, including cardiovascular diseases, neurological defects, some forms of cancer, mental illness, diabetes and pregnancy complications.
The two most common mthfr mutations (polymorphisms) in humans are:
MTHFR C677T (RS1801KLOC-0/33). This mutation (allele A) is related to the decrease of enzyme activity, the increase of total homocysteine level and the change of folic acid distribution. The normal enzyme activity of people with this mutation "A" allele decreased by 35%, while the enzyme activity of "AA" individuals decreased by 70%.
MTHFR A1298c (RS1801131). This mutation can also affect mtfhr activity and homocysteine level, but the degree is lower than c677t.
The enzyme activity of mthfrc677t and a 1298c polymorphism with secondary allele is lower than that of single nucleotide polymorphism with secondary allele.
The decrease of mthfr enzyme activity leads to the decrease of the conversion of amino acid homocysteine to methionine, and homocysteine accumulates in the blood.
Bhmt mutation
Betaine homocysteine methyltransferase (bhmt) catalyzes the conversion of betaine and homocysteine into dimethylglycine and methionine.
CBS mutation
The cbs gene encodes an enzyme called cystathionine β synthase. It is responsible for converting homocysteine and serine into a molecule called cystathionine by vitamin B6. Another enzyme converts cystathionine into cysteine, which can be used to make protein or be decomposed and excreted in urine.
7) Quercetin
Quercetin significantly increased the concentration of homocysteine in human hepatocellular carcinoma cell culture. The increase of extracellular homocysteine (extracellular) may be related to the increase of methylation. Therefore, people should be more cautious when using quercetin supplements.
How to reduce homocysteine level
Homocysteine is usually considered as a modifiable risk factor, that is, proper diet, lifestyle and supplementation strategies can correct the level. The following are the key factors affecting homocysteine levels:
1) Vitamin B and folic acid
The best way to prevent homocysteine from rising is to ensure adequate intake of folic acid, vitamin B 12 and vitamin B6.
This can be achieved through food, because a nutrient-intensive diet containing fruits, vegetables, dark leafy vegetables, eggs and red meat should provide enough vitamin B to maintain the normal level of homocysteine. However, in patients with hyperhomocysteinemia, folic acid, B6 and B 12 supplementation can normalize homocysteine levels.
B 12 and B6 are necessary cofactors of homocysteine metabolism through demethylation or vulcanization, and the lack of any of these vitamins will lead to the increase of homocysteine level.
Folic acid is decomposed into 5- methyltetrahydrofolate by mtfhr enzyme, which provides the methyl group needed to metabolize homocysteine into methionine. 5- methyltetrahydrofolate (5-MTHF) is the active form of folic acid. Studies have shown that 5-MTHF supplementation can prevent the risk of high homocysteine levels.
For example, a study found that 5-mthf 1 13 mcg/ day reduced the homocysteine level of 14.6% on average within 24 weeks.
When trying to reduce homocysteine, it is important to take 5- methylfolic acid, which is the active form of methylfolic acid. 5- methyltetrahydrofolate is almost 7 times as high as common folic acid in improving blood folic acid level. In scientific research, the daily dose of 5-mthf at 1000-5000 mcg can reduce the plasma homocysteine concentration.
2) Methyl donor
The demand for methyl increases the level of homocysteine, so the level of homocysteine can be reduced by supplementing methyl donors such as choline and betaine. In rats, homocysteine can be inhibited by choline and betaine.
3) Estrogen
Higher estrogen levels are associated with lower average homocysteine levels. In fact, the level of homocysteine in pregnant women, premenopausal and postmenopausal women who receive estrogen replacement therapy is low.
The negative correlation between estrogen and homocysteine can explain why the level of homocysteine in men is higher than that in women. This also explains why estrogen therapy can reduce cardiovascular risk.
There is evidence that estrogen can reduce homocysteine by regulating the metabolism of sulfhydryl amino acids, especially methionine.
4) resistance movement
In rats with cancer, resistance exercise can prevent homocysteine metabolism from being damaged and help the liver to better cope with the increase of oxidative stress. Exercise can prevent the increase of homocysteine caused by tumor and increase glutathione.
Supplements to reduce the harmful effects of homocysteine: melatonin, vitamin E, α-fatty acids, astragalus, curcumin.
This article is translated from/blog/optimal-homocystine-levels-increase-decrease/
Current article label
# homocysteine