Homocysteine

 

Homocysteine

•        Homocystein is a homologue of the naturally-occurring amino acid cysteine

•        differing in that its side-chain contains an additional methylene (-CH2-) group before the thiol (-SH) group. 

•        Alternatively, homocysteine can be derived from methionine by removing the latter's terminal Cε methyl group.

•        Homocysteine is not obtained from the diet; it is a normal temporary and chemically reactive reaction product that can be measured in blood!!

•        In blood, it is found bound to albumin and to hemoglobin.

 

•        It affects enzymes with cysteine-containing active sites, for example, it inhibits lysyl oxidase a key enzyme in the production of collagen and elastin, two main structural proteins in artery, bone and skin

•       Elevated homocysteine

•        Deficiencies of the vitamins folic acid (B9), pyridoxine (B6), or B12 (cyanocobalamin) can lead to high homocysteine levels.

•        Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream.

•        Increased levels of homocysteine are linked to high concentrations of endothelial asymmetric dimethylarginine.

•         Elevations of homocysteine also occur in the rare hereditary disease homocystinuria and in the methylene-tetrahydrofolate-reductase polymorphism genetic traits.

•         Common levels in Western populations are 10 to 12 and levels of 20 μmol/L are found in populations with low B-vitamin intakes (New Delhi) or in the older elderly (Rotterdam, Framingham).

•         Women have 10-15% less homocysteine during their reproductive decades than men which may help explain the fact they suffer myocardial infarction (heart attacks) on average 10 to 15 years later than men.

•          homocysteine concentration in the blood is associated with an increased risk of cardiovascular disease (CVD). Therefore, homocysteine-lowering strategies are being investigated for their ability to reduce the risk of CVD. Nutrients involved in the metabolism of homocysteine include folate, vitamin B12, vitamin B6, riboflavin, and choline. Although supplementation with folate, vitamin B6, and vitamin B12 successfully lowers homocysteine concentration in the blood, no significant effect on CVD risk has been demonstrated. There is some evidence that riboflavin supplementation may lower homocysteine and blood pressure in individuals with a certain genetic predisposition. 

•       How Much Is Safe?

•        Children with genetically elevated homocysteine levels experienced heart disease similar to the heart disease found in middle-aged patients.

•        People with elevated homocysteine levels are more likely to have strokes, Alzheimer's disease and dementia, kidney disease, diseases of the eye, erectile dysfunction, and, especially, heart disease.

•      Homocysteine and Heart Disease

•        Having an elevated homocysteine level is an independent risk factor for heart disease.

•        A highly elevated homocysteine level was associated with a more than 3-fold increase in the risk of heart attack over a 5-year period.

•        It causes thickening of the intima, or inner wall of the arteries.

•        homocysteine has been shown to affect the production of nitric oxide, a substance that causes arteries to relax and blood flow to increase.

 

•        Having an elevated homocysteine level has been associated with:

•        First and second heart attacks .

•        Coronary artery disease.

•        Total cardiovascular mortality.

•        Adverse outcomes after coronary balloon angioplasty.

•        Heart failure.

•        Homocysteine Levels

•        Normal—5 to 15 µmol/L

•        Moderate—16 to 30 µmol/L

•        Intermediate—31 to 100 µmol/L

•        Severe—Above 100 µmol/L

•        People try to keep their homocysteine level between 7 µmol/L and 8 µmol/L.

•        A homocysteine level over 12 µmol/L should be treated aggressively.

•        One study found that each 3-µmol/L increase in homocysteine caused a significant increase in the risk of having a heart attack.

•      Homocysteine: Linked to Diseases of Aging

•        elevated homocysteine levels have been linked to the following disorders or diseases:

•        Stroke—Homocysteine's effect on the arteries that supply the brain with blood (carotid arteries) is similar to its effect on the arteries in the heart.

•        Vascular disease—There is evidence that homocysteine combines with low-density lipoprotein (LDL) cholesterol and contributes to the creation of plaque inside artery walls.

•        Homocysteine has also been implicated in the formation of blood clots, which can cause a heart attack, stroke, or peripheral vascular disease.

•        Liver disease—Elevated homocysteine and low levels of SAMe are linked to liver toxicity and cirrhosis. Homocysteine likely contributes to liver damage, leading to the formation of fibrin, clots, and vascular complications.

•        Kidney disease—The kidneys filter, reabsorb, and metabolize amino acids, including homocysteine. In kidney failure, homocysteine levels rise due to improper kidney filtration.

•        Folic acid, trimethylglycine, and vitamins B6 and B12 reduce homocysteine in people with kidney failure.

•        High doses of folic acid can normalize homocysteine levels. Once kidney failure occurs, folic acid is much less effective, and high doses of vitamin B12 are required to help normalize homocysteine levels

•        Thyroid conditions—Elevated homocysteine levels may contribute to accelerated heart disease among people who have hypothyroidism.

•        Alzheimer’s disease and dementia—High levels of homocysteine indicate impaired methylation in the brain. Individuals with Alzheimer's disease have been shown to have elevated homocysteine levels.

•        Depression—Depression has been linked to low levels of folic acid in women. Low folic acid levels have been shown to decrease the effectiveness of the antidepressant fluoxetine (Prozac®), and vitamin B6 may alleviate depression.

•       Erectile dysfunction—Homocysteine has been shown to reduce the production of nitric oxide. Nitric oxide causes blood vessels to relax, increasing blood flow to organs and tissues. In one case study, a man with erectile dysfunction, who also had a genetic defect that causes elevated homocysteine levels, did not initially respond to treatment with sildenafil (Viagra®). However, after treatment with 5000 micrograms (mcg) of folic acid and 1000 mcg of vitamin B12, his erectile dysfunction was successfully treated with sildenafil.

•       Diseases of the eye

     Homocysteine's ability to damage blood vessels also has implications for the tiny blood vessels in the eye. Elevated homocysteine levels are associated with serious eye conditions, including glaucoma and macular degeneration. A study showed that homocysteine levels of 11.6 µmol/L were the average concentrations in patients who had central retinal vein occlusion.

•       Why Homocysteine Levels Rise?

 

They rise naturally as we age.

Genes also play a large role in the body's metabolism of homocysteine.

Coffee and alcohol consumption increase homocysteine levels.

Eating foods that contain large amounts of methionine, such as red meat and chicken, increase blood levels of homocysteine.

low intake of foods rich in vitamin B, such as green leafy vegetables, may also increase homocysteine levels.

In addition, the following pharmaceuticals are associated with elevated homocysteine levels:

 

–      Fenofibrate—Used in the treatment of high cholesterol.

–      Niacin—Used in the treatment of lipid management.

–       

–      Metformin—Used to treat diabetes.

–       

–      Antiepileptic drugs—Used to control seizures.

–       

–      Levodopa—Used to manage Parkinson's disease.

–       

–      Methotrexate—Used to treat cancer, psoriasis, arthritis, and lupus.

•       . The Life Extension Foundation's approach to lowering homocysteine relies on several principles:

–      Directly addressing high homocysteine levels by increasing metabolization of homocysteine. Nutrients that increase metabolization of homocysteine fall into two categories:

•       those that increase the remethylation of homocysteine back into SAMe, and

•       those that act along the transsulfuration pathway to remove excess homocysteine from the body.

–      Routine blood testing to monitor homocysteine levels. This should include genetic testing to check for abnormalities. Slight genetic defects in as few as two enzymes may cause moderate hyperhomocysteinemia. the most serious form of hyperhomocysteinemia (homocystinuria) is caused by an extremely rare genetic disorder.

–      Addressing the damage directly caused by homocysteine. This may mean supplementing with antioxidants and other nutrients to reduce damage caused by homocysteine.

–      Managing underlying conditions—including high blood pressure, coronary artery disease, diabetes, and hypothyroidism—that are associated with a high homocysteine level.

•       The B Vitamins: A Powerful Weapon:

                 

–        Management of hyperhomocysteinemia begins with folic acid, vitamin B6, and vitamin B12. To varying degrees, folic acid and vitamin B12 increase the remethylation of homocysteine back into SAMe. Vitamin B6 is necessary for the conversion of homocysteine into glutathione along the transsulfuration pathway.

 

 

 

•        TMG and Zinc: Bringing Homocysteine Under Control:

–      TMG (trimethylglycine) and zinc, both of which enhance the action of B vitamins.

–      TMG operates along a different pathway than the B vitamins. its activity is limited to the liver and kidneys.

–      Zinc acts in concert with vitamin B6 to promote remethylation of homocysteine to methionine.

–      Zinc is also needed for the conversion of homocysteine to cysteine and glutathione.

•       Inhibiting the Formation of Homocysteine:

–    Not all the homocysteine created is released directly into the bloodstream as free homocysteine. In fact, less than 1 percent of the homocysteine in the blood is free. The majority, about 98 to 99 percent, is bound to proteins in the blood and considered stored.

–    This store of homocysteine may be released in response to decreased methylation or oxidative damage, or in response to other influences.

–    Nutrients that have been shown to inhibit the release of homocysteine include:

–    Creatine—Somewhere between 50 and 90 percent of the SAMe required by the body goes into the production of creatine. Supplementation with creatine diminishes the need for SAMe, reduces formation of homocysteine, and the need for homocysteine remethylation.

–    Choline-producing nutrients—SAMe is involved in the production of choline. By taking choline-producing nutrients, your body produces less SAMe, which reduces the amount of homocysteine needed. Choline-producing nutrients include cytidine diphosphate (CDP) choline, lecithin, alpha-glycerylphosphorylcholine, and choline chloride.

•       Recommendations

•         It is important to begin your homocysteine-lowering program by working with a qualified physician and taking the necessary blood tests to evaluate your risk. To help lower your homocysteine level, the Life Extension Foundation suggests:

–     Folic acid—4000 to 8000 mcg daily

–     Vitamin B12—1 to 2 mg daily

–     Vitamin B6—100 to 200 mg daily

–     SAMe—400 mg two to four times daily

–     TMG—2 to 4 grams daily

–     Zinc—30 to 90 mg daily

–     CDP choline—250 to 500 mg daily

–     Micronized creatine—500 mg (in capsule form) four to eight times daily

–     N-acetyl-cysteine—600 mg (in capsule form) one to two times daily on an empty stomach