About homocysteine

Homocysteine is an organic compound (amino acid) that is essential for life and essential for maintaining normal cell function. However, high homocysteine levels have undesirable effects, so there are two ways to get rid of excess homocysteine:

1. In most tissues, two enzymes (MS and MTHFR) - In the presence of vitamin B12 and vitamin B9 (folate) - into another amino acid (methionine). Consequently, if blood levels of vitamin B9 (folate) and/or vitamin B12 are low, homocysteine levels will be high.
2. It is converted by an enzyme in the liver (BHMT), in which betaine is involved - with the help of vitamin B6 - which can then be excreted in the urine.¹

It should be noted that many products containing vitamin B9 contain folic acid, while folic acid utilisation is not equivalent to that of natural folate (vitamin B9) in patients with related gene defects (MTHFR 1298C and MTHFR C677T); folic acid does not reduce homocysteine levels, but may cause kidney damage!²

Where both parents have inherited the MFHFR gene defect (homozygous T/T), the function of the homocysteine-lowering enzyme is impaired by 50-60%. In the case of a gene defect inherited from only one parent (heterozygous C/T), there is a 25-30% decrease in homocysteine-lowering enzyme function.³

The clinical significance of homocysteine became apparent in 1962, when it was first discovered that patients with high homocysteine levels are at particularly high risk of vascular occlusion was. In healthy humans, the optimal blood homocysteine level is between 5.0 and 15.0 μmol/l (measured by high-performance liquid chromatography - HPLC) or 5.0-12.0 μmol/l (determined by immunoassay). More recently, even lower levels (10 μmol/l) set the level at which above the homocysteine level is already a risk factor.⁴

In a comprehensive analysis more than 100 diseases or conditions have been identified that are associated with elevated plasma total homocysteine levels. The most common associations are with cardiovascular disease and central nervous system disorders, but they are also associated with a number of developmental and age-related conditions.⁵ High levels of homocysteine are associated with inherited genetic disorders, dietary habits and medication, among other things. Homocysteine levels are increased by higher intakes of animal protein, fat and sugar. The folate intake of the EU population is very low, only about a third of the level recommended by international and EU dietary recommendations. In terms of the medications taken, those who are receiving any of the following active substances are particularly affected: cholestyramine, insulin, metformin, oestrogen, tamoxifen, carbamazepine, phenytoin, phenobarbital, methotrexate, thiazide diuretics, sulphasalazine.^6,7

Harmful effects of high homocysteine levels⁸

1. Damages the inner surface of blood vessels (endothelial function) by harmful substances (superoxide and peroxide).
2. It increases the adhesion of platelets to each other and thus the risk of blood vessel blockage.
3. Increases blood clotting: increases the activity of factors XI and V and decreases the activation of protein C and increases the function of several tissue factors.
4. Damages the ability of blood vessels to dilate (insufficient nitric oxide is produced).
5. Inhibits the activity of glutathione peroxidase (an enzyme that plays a crucial role in neutralising harmful oxygen radicals).

Several risk factors such as ageing, smoking and oxidative stress contribute to the severity of high homocysteine levels, which risk factors for other diseases: Alzheimer's and Parkinson's disease, dementia, neuropsychiatric diseases, thrombosis, cerebrovascular diseases, osteoporosis, cardiovascular diseases, cancer and SARS-Cov-2 - consequently, high homocysteine levels are associated with an increased risk of death.^9,10

1. Betaine, vitamin B9 (folate), vitamins B6 and B12 reduce elevated levels of homocysteine in the blood, contributing to normal heart and vascular function, which can maintain heart and circulatory health. A HARITAKI (Terminalia chebula = Indian tansy, Black balsam nut) fruit peel extract is involved in cardiovascular health, contributes to normal cholesterol levels. Chromium is part of the enzymes required for carbohydrate and fat metabolism, important for normal carbohydrate, fat and protein metabolism.

• Atherosclerosis (atherosclerosis, arteriosclerosis), heart disease (angina pectoris, myocardial infarction), stroke, vascular occlusion (thrombosis, embolism), abnormal blood lipids (dyslipidemia, high LDL cholesterol, high triglycerides), hypertension (hypertension), SARS-Cov-2 infection (COVID).

Abnormal increase in blood homocysteine levels increases the risk of atherosclerosis in the arteries of the limbs, the coronary arteries of the heart and the brain and increases the risk of serious complications such as coronary syndrome (coronary artery spasm and myocardial infarction due to myocardial blood flow disturbance), stroke (stroke) and thrombosis (blockage of blood vessels in the limbs). According to the studies the damaging effects of abnormal blood lipids, high blood pressure, smoking and type 2 diabetes are significantly enhanced by homocysteine. The rise in blood homocysteine levels is equivalent to the importance of cholesterol in terms of vascular damage.^11,12

The cardiovascular diseases are among the leading causes of death worldwide.¹³ In EU, the cause the 49%-percentage of deaths. More than 80% of deaths of cardiovascular origin heart attack and stroke-and of these deaths, approximately one third for people under 70 will occur.¹⁴ Traditional risk factors, such as elevated LDL cholesterol and/or triglycerides, reduced HDL cholesterol, high blood pressure, smoking or diabetes do not fully explain the incidence of disease and death. Several studies have shown that elevated blood homocysteine levels are a risk factor for cardiovascular disease independent of traditional risk factors. The measurement of homocysteine levels in blood tests can be used to predict the development of disease.^15,16,17,18

The elevated blood homocysteine level is the result of a deficiency in the enzymes responsible for processing homocysteine, which may be caused by a gene mutation (MTHFR 1298C and C677T) or by a deficiency in vitamins B9 (folate), B12 and B6. The homocysteine oxidation leads to the formation of hydrogen peroxide, which damages the inner surface of blood vessels - the endothelium - through oxidative stress and contributes to the ageing of blood vessels.^19,20 One of the functions of the endothelium is to produces vasodilators, which regulate blood circulation and thus the blood supply to tissues.²¹ In patients with high homocysteine levels, the endothelial dysfunction is also associated with an increased susceptibility to thrombosis (vessel occlusion), which may be due to inhibition of several systems that regulate blood clotting. Due to homocysteine in endothelial cells reduced levels of nitric oxide, which causes vasoconstriction of small blood vessels in the central nervous system and is a risk factor for high blood pressure.^22,23

In counteracting the adverse effects of homocysteine and improving endothelial function vitamin B9 (folate) is of particular importance, but also vitamins B12 and B6 plays a role in maintaining normal homocysteine levels. With vitamins B9 (folate), B12 and B6 avoid the development of vascular diseases associated with high homocysteine levels: 20% in coronary artery disease, 40% in cerebrovascular disease, 60% in limb vascular disease. By using these three vitamins, the risk of vascular disease can be reduced by 62% and the number of cases by 66%.²⁴

A clinical study of 100 patients investigated changes in the amount of plaque in the main carotid artery After daily administration of vitamins B9 (folate), B6 and B12. Effects of the treatment the increase in plaque area over 1 year has slowed down significantly. They argue that treatment is needed at homocysteine levels >9 μmol/l. In another clinical trial, 158 healthy and 167 a person with early atherosclerosis treated with vitamin B9 (folate) and vitamin B6 for 2 years. At the end of treatment, homocysteine concentrations decreased by 50% and also improved abnormal heart function detected by exercise ECG.²⁵

The above shows how gene mutations and inadequate vitamin utilization lead to vitamin B9 (l-methylfolate) depletion, elevated homocysteine levels and hypertension, and vitamin B9 and B6 supplementation offers a safe option to combat therapy-resistant hypertension, which ultimately improves neurological and cardiovascular outcomes. Betaine, vitamin B9 (folate), vitamin B12 and B6 is a safe therapy to treat high blood pressure and reduce the risk of stroke, up to 6-13 mm Hg blood pressure lowering effect. Successfully reducing treatment-resistant hypertension is essential to reduce damage to the heart, brain and vision.²⁶ The a 5 ~mol/l reduction in blood homocysteine levels is estimated to reduce the risk of cardiovascular disease by 20-30%. A betaine-rich diet may be effective in reducing the risk of cardiovascular disease.²⁷ Betaine supplementation is most important when used in patients who do not respond to vitamin B6 supplementation and those who do not follow a low protein diet.²⁸

Emerging evidence suggests that the COVID-19 patients are at high risk of developing thrombosis and haemophilia. Thromboembolism is an important part of the disease development and progression process caused by SARS-CoV-2 infection, as it elevated blood homocysteine is a predictor of increased blood clotting and increased susceptibility to thromboembolism. In COVID-19 patients with stroke, homocysteine levels are associated with the course of the disease, as homocysteine plays a crucial role in blood clotting.^29,30 The homocysteine levels can predict the severity of COVID-19 disease, and high homocysteine levels are considered a risk factor in COVID-19 patients.³¹ In one study, researchers found that measurement of blood plasma homocysteine levels - inflammatory disease of the blood vessel walls (vasculitis) - important in the context of severe COVID-19 complications, both in terms of predicting disease outcome and targeted prevention.³² Genetic predisposition to altered homocysteine metabolism may play a role, as a clear association between MTHFR C677T gene defect and COVID-19 incidence and mortality at a worldwide frequency.³³

The effects of homocysteine include processes that may exacerbate COVID-19 disease and prevent more successful treatment of the disease. SARS-CoV-2 enters cells through its spike proteins, which bind to cellular receptors for the enzyme ACE2 to form a tunnel through which the virus enters the cell. The homocysteine to the enzyme (ACE2) can inhibit its binding to receptors, and can allow more viruses to enter cells. The high levels of homocysteine increases the overproduction of inflammatory substances (cytokines), the in a "cytokine storm" impairs endothelial function and leads to vascular occlusion. In patients with respiratory failure with COVID for a few days Treatment with vitamins B12 and D3 and magnesium reduced the need for oxygen therapy from 62% to 18%.³⁴

The long COVID syndrome (post COVID), which is emerging in patients who have recovered from COVID 19 infection, is now increasingly common worldwide, with an increasing number of patients who do not return to their original state of health after recovery from COVID 19. A SARS-CoV-2 in the stage of viraemia (appearance in the blood), methyl groups (folate and betaine, as a methyl donor) for the host cell is impaired high levels of homocysteine. Long-COVID has many overlapping symptoms with severe anaemia and chronic fatigue syndrome, which respond well to vitamin B12. From oxidative stress increases the risk of damage to vitamin B12 in the body, from this the conversion of homocysteine to methionine is impaired.³⁵ Thromboembolism is an important part of the disease development and progression process caused by SARS-CoV-2 infection, as it elevated blood homocysteine is a predictor of increased blood clotting and increased susceptibility to thromboembolism.³⁶

The HARITAKI (Terminalia chebula) - traditional ayurvedic herbs - a clinical trial significantly improved 2-endothelial functions in type 2 diabetics (improves nitric oxide production, reduces oxidative stress), increased HDL cholesterol levels in the blood (good cholesterol), lowered LDL cholesterol levels (bad cholesterol) meanwhile other cardiovascular risk indicators also improved significantly.^37,38

The chrome a trace element that helps lower total cholesterol contributes to the achievement of adequate levels of blood lipids, thus indirectly reducing the risk of atherosclerosis and supporting the prevention of cardiovascular disease.^39,40 Research shows that total cholesterol by 7%, LDL cholesterol by 10% and chromium picolinate by 7% and the apolipoprotein B levels decreased by 16%⁴¹, blood fat (triglyceride) levels decreased by 17.4%.⁴²

• Neurodegenerative and neuropsychiatric diseases: Alzheimer's disease, Parkinson's disease, mental decline (dementia) and depression

In the late 1990s, two studies found that the elevated blood homocysteine is associated with Alzheimer's disease. The histological study also found that vascular dementia was associated with elevated levels of homocysteine and pro-inflammatory cytokines.⁴³ B vitamins are the main determinants of homocysteine levels and folate concentrations in red blood cells, blood serum low levels of vitamin B9 (folate) and B12 are also associated with a diagnosis of Alzheimer's disease. Since elevated homocysteine levels can be reduced with B vitamins and betaine, it is may be key to preventing dementia and Alzheimer's disease for older people.⁴⁴

Several studies have shown a link between vitamin B6 and brain function in older age. Analysis of data from one study in 70 men (age 54-81 years) found an association between higher vitamin B6 concentrations and better memory test scores.⁴⁵

In one study of 168 participants who underwent MRI scans, the Vitamin B treatment reduced homocysteine levels by 30.2% and slowed the rate of brain atrophy by 29.6%, while participants with homocysteine levels >13 μmol/l slowed the rate of brain atrophy by 53%. In these individuals, vitamin B treatment slowed or prevented mental decline in episodic memory (the ability to acquire new knowledge), semantic memory (remembering basic concepts) and overall mental ability. Studies in older people with intellectual impairment show that homocysteine-lowering vitamin B treatment significantly slows the rate of total and regional brain atrophy and slows mental decline.⁴⁶

In a study in Tianjin, China, patients with mild cerebral palsy (MCI) showed significant improvement after 400 μg of folate (vitamin B9). A folate supplementation improved intelligence quotient scores over 12 months, can significantly improve mental performance.⁴⁷

An elderly patients with mental impairment (597 women and 264 men) examined the association between blood uric acid and homocysteine levels and cerebrovascular disease. A people with high homocysteine levels had lower blood folate and vitamin B12 levels and higher uric acid levels, than those with normal homocysteine levels. The authors of the study recommend that supplementary vitamin B9 (folate) and vitamin B12 would be useful for high uric acid and homocysteine levels in cases of mental decline with vascular lesions.⁴⁸

Depressive symptoms are found in a quarter of the population worldwide, with an even higher prevalence among people aged 60 and over.

In a study 52% of depressed patients had elevated blood homocysteine levels. Previous studies have shown that the up to a third of patients with major depression may be folate (vitamin B9) deficient and vitamin treatment can help restore a healthy mental state. Other studies suggest a link between folate deficiency and impaired metabolism of brain neurotransmitters - serotonin, dopamine and noradrenaline - which play a role in mood disorders.⁴⁹

In a study on odds of depression increased by 4% with each unit (μmol/l) increase in homocysteine. The analysis showed that older people with high homocysteine levels are at increased risk of depression. Those with the MTHFR C677 TT gene defect (see middle of page 1) are 22% more likely to be currently depressed - or to have been depressed in the past - than those without the gene defect.⁵⁰

Low folate levels are not only associated with the development of depression, but can also cause antidepressant treatment to fail. Increased homocysteine levels are observed in depression-prone individuals.⁵¹

A recent study has shown that Homocysteine levels higher than 20 μmol/l were associated with 8.64 times more Parkinson's disease involvement.⁵² A 2019 study showed that elevated homocysteine levels are associated with greater motor impairment in men with Parkinson's disease and poorer mental performance in women.⁵³

The anti-inflammatory properties of the herb TERMINALIA CHEBULA have been well documented in various experiments. Terminalia chebula has strong antioxidant and neuroprotective properties for the treatment of Alzheimer's disease, dementia.⁵⁴

• Tumours and cancer

Results from animal studies show that the Diets low in vitamin B9 (folate) and betaine increase the likelihood of certain cancers. The but folate supplementation can be an effective way to prevent cancer. This is evidenced by the research that reports a 20-40% reduction in the risk of developing colorectal cancer in people who consume adequate amounts of folate or have high blood plasma folate levels. Even within the normal range, different blood serum folate levels affect the incidence of tumours. In individuals with folate levels at the upper end of the healthy range (≥31.04 nmol/l), the the risk of developing colorectal cancer is about half as high, than those with lower values (≤12.23 nmol/l).⁵⁵

The timing of the replacement is extremely important, because while it is beneficial in healthy tissues before cancerous transformation, it worsens the pre-cancerous state!

It has been shown that the MTHFR C677T gene mutation is associated with cancer of the uterus, cervix with abnormal cells growing on its surface (Cervical Intraepithelial Neoplasia), increased risk of breast cancer, stomach cancer, bladder cancer, etc. A total of 29 studies were included in a comprehensive analysis, the results of which showed a significant association between the MTHFR C677T gene mutation and esophageal cancer Between.⁵⁶

One study aimed to show the link between MTHFR (methylenetetrahydrofolate reductase) gene defects and cervical cancer. Blood serum folate levels gradually decreased with the development of cervical lesions. Low folate levels were significantly associated with cervical cancer risk. In contrast to the MTHFR A1298C gene defect may increase both cervical cancer and abnormal cells growing on the surface of the cervix (cervical intraepithelial neoplasia) risk.⁵⁷

A comprehensive analysis included 50 studies with 19 260 cases and 26 364 controls, including 39 studies on breast cancer and 8 studies on ovarian cancer. A significant association with risk of breast cancer and/or ovarian cancer was observed in Asian women the MTHFR C677T gene defect. In contrast, there was no strong association between ovarian cancer risk for people of European origin, but found to have a significantly increased risk of breast cancer.⁵⁸

2. Chromium is important for blood sugar levels, blood sugar tolerance, insulin function, normal carbohydrate, fat and protein metabolism. Chromium promotes carbohydrate and fat metabolism - as it is a component of the enzymes required for this - and helps maintain body weight. A HARITAKI (Terminalia chebula) fruit peel extract has a role in maintaining normal blood sugar levels. Helps maintain normal blood sugar levels. Betaine, vitamin B9 (folate), vitamins B6 and B12 reduce elevated blood levels of homocysteine, contributing to normal heart and vascular function, which can maintain heart and circulatory health.

• Diabetes mellitus (diabetes mellitus, diabetes, type 2 diabetes, gestational diabetes), insulin resistance, diabetes-induced nerve damage (diabetic neuropathy), metabolic syndrome (metabolic syndrome), diabetic neuropathy (diabetic retinopathy), macular degeneration (yellow eye disease), diabetic kidney disease (diabetic nephropathy)

During insulin resistance, the organs involved in carbohydrate metabolism (skeletal muscle, liver, adipose tissue) become insensitive to insulin, which is mainly manifested by reduced sugar uptake by their cells and the inability of the pancreas to maintain blood glucose levels in the ideal range, meaning that the 120-minute glucose value rises above 7.8.

Symptoms of metabolic syndrome include glucose intolerance (a tendency to increase blood sugar levels), high blood pressure, abdominal obesity, high blood fat and cholesterol levels, which together increase the likelihood of developing cardiovascular disease and type 2 diabetes. Patients with metabolic syndrome have significantly higher blood homocysteine levels, which is associated with an increased incidence of coronary and cerebrovascular disease. Homocysteine levels are directly related to age, waist circumference, fasting blood glucose, blood fat and uric acid levels.^59,60

The prevalence of type 2 diabetes is on the rise worldwide, with an estimated 8.8% of the adult population and around 500 million people affected in 2018. Near-normal blood glucose levels can prevent or delay the development of diabetes complications and slow their worsening. The distribution of possible complications of diabetes among patients: optic disc disease 12%, limb nerve damage 18-35%, persistently high urine protein levels 16% (a sign of kidney damage).⁶¹
Diabetes is also the leading cause of blindness in the working-age population in EU, with 4.5% of people with diabetes being blind. Long-term elevated or fluctuating blood sugar levels in the wrong setting damage the walls of small blood vessels (capillaries).

If the wall of the macula begins to leak, it causes a deterioration of vision and, in the long term, a permanent loss of vision. Blockage of the peripheral retinal blood vessels leads to oxygen starvation. The best and most effective way to prevent and treat the ophthalmic complications of diabetes is to maintain proper control of blood glucose levels, blood pressure and blood lipids.⁶² In a study on vitamin B9 (folate), vitamin B12 and B6 supplementation reduced the risk of macular degeneration by 34% and 41% for macular degeneration that significantly affects vision. Elevated homocysteine is associated with the development of diabetic neurodegenerative retinopathy and macular degeneration, and therefore reducing high homocysteine is a promising intervention in ageing diseases such as diabetic retinopathy and macular degeneration.^63,64

A study involving 208 patients and 49 controls showed that baseline homocysteine levels are significantly elevated in patients with diabetic kidney disease and are associated with disease severity. The results confirm that the high blood plasma homocysteine an independent risk factor, and early predictor of the development of diabetic kidney damage in type 2 diabetic patients.⁶⁵

The chrome trace element supports the proper functioning of many life processes. It increases insulin sensitivity and sugar uptake into cells, thereby helps to control blood sugar levels in the long term. The chromium plays a role in glucose intolerance, type 2 diabetes and gestational diabetes. A case study of the sick diabetes and nerve damage (neuropathy) have been alleviated, when supplemental chromium was added to artificial feeding solutions. The chromium requirement depends on the severity of insulin resistance and type 2 diabetes: 200 µg/day of supplemental chromium is sufficient for people with mild glucose intolerance. However, people with more severe cases of glucose intolerance and diabetes usually need more than 200 µg/day, as do women with gestational diabetes. In a clinical trial, 180 people with type 2 diabetes were studied. Those who received 200 µg chromium picolinate twice daily had significantly improved HbA1c levels after 4 months (8.5 +/- 0.2% -> 7.5 +/- 0.2%). These data show that chromium had a significant beneficial effect on HbA1c, glucose, insulin and cholesterol levels in people with varying degrees of glucose intolerance and type 2 diabetes.^66,67

The Compounds in Terminalia chebula fruit peel extract all have a significant beneficial effect on blood sugar levels.⁶⁸ The loss of function of the squamous epithelium lining the inner surface of blood vessels (endothelial dysfunction) a major complication of type 2 diabetes, which is associated with the risk of cardiovascular disease. A clinical trial has shown that HARITAKI (Terminalia chebula) 12-week dosing of its extract can significantly improve endothelial dysfunction among people with type 2 diabetes. Terminalia chebula is the minimised the risk of cardiovascular disease and high blood glucose levels by adjusting blood lipid and HbA1c levels is. These data suggest that Terminalia chebula extract may be used as a primary ingredient in therapeutic preparations acting on the cardiovascular system.⁶⁹

• Gout (arthritis uricat), kidney damage (nephropathy)

Gout can be hereditary, but it can also develop due to lifestyle factors such as diet, alcohol consumption habits, etc., and it can also be caused by improper kidney function, enzyme deficiencies, enzyme dysfunction. High blood levels of uric acid (hyperuricemia) do not in themselves indicate gout, but increase the susceptibility.

A study provides evidence that supports the the causal role of high homocysteine in the development of chronic renal failure, and describes a number of processes by which the homocysteine causes kidney damage.⁷⁰ Another study found an inverse correlation between homocysteine levels and estimated glomerular filtration rate (eGFR - a laboratory measure of impaired kidney function), i.e. higher homocysteine levels are associated with lower kidney function. This study included 91 male patients with gout and 97 age-matched healthy men. Serum uric acid levels did not differ significantly between the gouty and healthy controls, but blood serum homocysteine levels were significantly higher in patients with gout. This shows that the uric acid levels alone are not related to gout, but impaired kidney function is associated with blood plasma homocysteine levels and the likelihood and worsening of gout.⁷¹ A study in the USA concluded that the homocysteine 8.80-fold increased risk of elevated blood serum uric acid levels after 1 increment. This effect was more pronounced among boys aged ≥17 years and those with low eGFR.⁷²

Blood serum uric acid concentrations rise steadily with age. One study shows that compared to people taking only antihypertensives antihypertensive drugs and folate together were better at reducing the rise in uric acid concentrations and reduced the incidence of new-onset high uric acid levels. Folate had a greater uric acid lowering effect in participants with higher baseline homocysteine levels.⁷³