What is Homocysteine?
Homocysteine is a sulfur-containing amino acid produced in the body during the metabolism of the essential amino acid methionine, which involves a series of conversions that require enzymes. Homocysteine is a natural substance made by the body, not to be feared, but to be appreciated and controlled. Homocysteine functions at a metabolic crossroad that can affect the methyl and sulfur group metabolism of key enzymes, hormones, and vital nutrients. Many important nutrients, especially B vitamins, are needed for these enzymes.
The Problem with too Much Homocysteine
The circulation of excess homocysteine can damage the lining of arterial walls so they become narrow and inelastic. Research suggests that a raised homocysteine level is an independent risk factor for hardening of the arteries, coronary heart disease, stroke, peripheral vascular disease and other conditions associated with abnormal blood clotting. Elevated homocysteine is also linked with a number of other serious medical conditions, including osteoporosis, Alzheimer’s disease, multiple sclerosis, rheumatoid arthritis, spontaneous abortion, placental abruption, renal failure, and type II diabetes. When homocysteine is elevated it reduces nitric oxide (NO) production via increasing levels of ADMA which can increase the risk of hypertension and erectile dysfunction.
Synergistic nutrients found in Homocysteine Supreme™ facilitate the efficient metabolism of homocysteine, preventing toxic levels of homocysteine from accumulating. This makes it possible for a functioning pathway to provide necessary methyl and sulfur groups for a myriad of biochemical reactions, especially those needed for detoxification, joint and cartilage repair, and brain health.
Warning on Synthetic Folic Acid: Read about the important differences and safety concerns to consider between Synthetic Folic vs Natural Folate (DFH uses Natural Folate in their products).
Many important nutrients, especially B vitamins, are needed for these enzymes. The homocysteine pathway that begins with methionine is a multi-faceted, complicated pathway that results in the production of very important amino acids and necessary neurotransmitters, including the sulfur containing amino acids taurine and cysteine and the catecholamines epinephrine and norepinephrine.
Excess homocysteine in the circulation can damage the lining of arterial walls so they become narrow and inelastic. Research suggests that a raised homocysteine level is an independent risk factor for hardening of the arteries, coronary heart disease, stroke, peripheral vascular disease and other conditions associated with abnormal blood clotting. Elevated homocysteine is also linked with a number of other serious medical conditions, including osteoporosis, Alzheimer?s disease, multiple sclerosis, rheumatoid arthritis, spontaneous abortion, placental abruption, renal failure, osteoporosis, and type II diabetes. When homocysteine is elevated it reduces nitric oxide (NO) production via increasing levels of ADMA which can increase risk of hypertension and erectile dysfunction.
Synergistic nutrients, found in Homocysteine Supreme, facilitate the efficient metabolism of homocysteine, preventing toxic levels of homocysteine from accumulating. This makes it possible for a functioning pathway to provide necessary methyl groups and sulfur groups for a myriad of biochemical reactions, especially those needed for detoxification, joint and cartilage repair, and brain health.
Why should we check homocysteine levels in individuals?
Excess homocysteine in the circulation can damage the lining of arterial walls making them narrow and inelastic. Research suggests that a raised homocysteine level is an independent risk factor for hardening of the arteries, coronary heart disease, stroke, peripheral vascular disease and other conditions associated with abnormal blood clotting.[1,2,19] Elevated homocysteine is also linked with a number of other serious medical conditions including depression, osteoporosis, Alzheimer?s disease, multiple sclerosis, rheumatoid arthritis, spontaneous abortion, placental abruption, neural tube defects (spina bifida, cleft palate, etc) renal failure, osteoporosis, and type II diabetes.[9,11,16]
When homocysteine is elevated it reduces nitric oxide (NO) production which can increase risk of hypertension and erectile dysfunction. Synergistic nutrients, found in Homocysteine Supreme, facilitate the efficient metabolism of homocysteine preventing toxic levels of homocysteine from accumulating. Homocysteine Supreme allows the homocysteine pathway, which begins with methionine, to flow smoothly in any direction producing its necessary and important end products including the sulfur containing amino acids taurine and cysteine and the neurotransmitters epinephrine, dopamine, and serotonin.
What is Homocysteine?
Homocysteine is produced by the demethylation of dietary methionine which comes from protein containing foods. Homocysteine is recycled back into methionine through a pathway that involves vitamin B12 in the form of methylcobalamin (which remethylates it) and folic acid. Homocysteine is simply an intermediate in a very important biochemical pathway. Plasma homocysteine can also travel another route which involves passing of sulfur groups (trans-sulfuration). This is vitamin B6 dependent and results in the production of cysteine which can convert into the most important antioxidant in the body, glutathione.
What causes Homocysteine to become elevated?
Any road block in this pathway can cause homocysteine to elevate. When we intricately study the biochemistry of the homocysteine pathway we can see that it involves a series of conversions that require enzymes. Several nutrients, especially B vitamins, are needed for these conversions to occur. Stress can deplete B vitamins, as can many medications.
The Comprehensive Metabolic Profile (CMP) test offered by Designs for Health can pinpoint B vitamin deficiencies. Testing homocysteine levels is important as well. Performing both tests on women wishing to get pregnant could reduce risk of neural tube defects and pregnancy complications. All individuals with homocysteine levels above 7 are in need of intervention. Two capsules daily of Homocysteine Supreme is an ideal recommendation. Individuals with family history of early heart attacks or depression are also prime candidates for such intervention.
Who should not take Homocysteine Supreme?
Individuals undergoing chemotherapy, radiation, or taking Methotrexate should not take high dose folic acid without consulting with their health care practitioner.
What are ideal homocysteine levels for individuals?
Initially, levels between 8 and 15 micromol/L were considered ideal. Latest research suggests maintaining even tighter control as homocysteine levels above 6.9 micromol/L may be harmful for long-term health. A rise in serum homocysteine of 5 micromol/ L may increase cardiovascular risk by 20% to 30%. Homocysteine levels tend to rise with age. Remember that folic acid and B12 absorption decline in the elderly so they may require higher doses of these nutrients to lower their homocysteine levels effectively. Also, medications commonly taken by these individuals deplete folic acid such as Ibuprofen and other NSAIDS. Folinic acid, the pre-activated form of folic acid like that found in food, was added to Homocysteine Supreme with this in mind to make Homocysteine Supreme more effective. This formula contains 2 mg of folic acid because research shows that supplementing 2-7 mg of folic acid daily reverses plaque and prevents stroke.[12,18,19] Research also shows that doses above 1000 mcg of B12 get absorbed effectively even without intrinsic factor.
|Homocysteine Level||Risk Level|
|7?9.9 micromol/L||Mild risk|
|10.?12.9 micromol/L||Moderate Risk|
|13?20 micromol/L||High risk|
|Over 20 micromol/L||Very high risk|
How and how often should we test homocysteine levels?
Individuals with a personal or family history of coronary heart disease, or other CHD risk factors, or who have the MTHFR (methyltetrahydrofolate reductase) faulty gene should have homocysteine testing at least twice per year. Checking homocysteine levels in all individuals yearly shows we are invested in their health and longevity. Serum homocysteine can be ordered through any standard lab.
Testing for deficiencies of folic acid, B6 and B12 is very easy via bloodspot and/or urine collection. Designs for Health's Comprehensive Metabolic Profile (CMP) and Basic Metabolic Profile (BMP) tests will detect which of these are lacking. Serum or urinary methylmalonic acid (MMA) is the best marker of functional B12 status, while the formiminoglutamate (FIGLU) marker is best for folic acid. Kynurenine and quinolinic acid elevations show a deficiency of B6. Elevations of any of these markers on the CMP test may increase risk of homocysteinemia. Individuals with hypothyroidism are at greater risk of hyperhomocysteinemia because hypothyroidism decreases hepatic levels of enzymes involved in the remethylation pathway of homocysteine.
How do we know that correcting these deficiencies will help longevity?
A meta-analysis of 12 randomized controlled trials suggested that supplementation with 0.5-5.7 mg folic acid per day could reduce elevated homocysteine levels by 25%, while adding 0.02-1 mg per day vitamin B12 produced a further 7% reduction. In a study of 350 elderly people aged 65-75 years, folic acid supplements of 400-600mcg per day were needed to produce significant lowering of homocysteine levels compared to placebo. Due to reduced absorption in the elderly, it was estimated that a total intake of 926mcg per day was needed to avoid folate deficiency and lower cardiovascular risk. The addition of vitamin B12 is doubly important here as folate can mask early signs of vitamin B12 deficiency which might lead to subacute combined degeneration of the spinal cord.
Have researchers yet done large-scale trials to assess whether interventions to lower homocysteine levels will reduce cardiovascular morbidity and mortality?
One recent analysis suggested that supplementation of B vitamins did not reduce risk of cardiovascular events. This conclusion should not be considered valid because the subjects had previous cardiovascular events and the doses were not high enough for positive results considering the age of the subjects, as just discussed. There is adequate evidence that controlling homocysteine, and adequately supplementing folic acid and B12 will improve overall health, reduce cardiovascular risk and increase longevity. Even older women need higher doses of B vitamins. After menopause, some women are less able to process homocysteine7 which may explain the higher risk of coronary heart disease in this group. Hormone replacement therapy, as well as oral contraceptives, deplete B vitamins. A survey in the US suggested that only 40?50% of people obtained enough folic acid from their diet to process homocysteine normally.
Do individuals with the faulty MTHFR genotype need to take 5,10 methyltetrahydrofolate which is more expensive than folic acid?
No. Research shows that supplementation of folic acid gets better homocysteine lowering results than supplementing 5,10 MTHF in individuals with this faulty genotype and in the other genotypes as well. Methylenetetrahydrofolate reductase enzyme (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-MTHF), the methyl donor for the formation of methionine from homocysteine. Research does not support the belief that having this gene polymorphism means these individuals have poor folic acid metabolism. One particular study looked at the ability of homozygotes for the MTHFR C677T (this CT genotype mutates to TT) to convert 5-formyltetrahydrofolic acid (folinic acid) to 5-MTHF, a process that requires the action of the MTHFR enzyme. These researchers concluded that the conversion of oral folinic acid to 5-MTHF is not impaired in persons with the mutated T/T MTHFR genotype. A quote from Kelly in the Alternative Medicine Review says: ?Administration of folinic acid bypasses the deconjugation and reduction steps required for folic acid. Folinic acid also appears to be a more metabolically active form of folate, capable of boosting levels of the coenzyme forms of the vitamin in circumstances where folic acid has little to no effect. Therapeutically, folic acid can reduce homocysteine levels and the occurrence of neural tube defects, might play a role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis, appears to be a rational aspect of a nutritional protocol to treat vitiligo, and can increase the resistance of the gingiva to local irritants, leading to a reduction in inflammation. Reports also indicate that neuropsychiatric diseases secondary to folate deficiency might include dementia, schizophrenia-like syndromes, insomnia, irritability, forgetfulness, endogenous depression, organic psychosis, peripheral neuropathy, myelopathy, and restless legs syndrome.?
Another study involving hemodyalsis (HD) individuals showed folinic acid supplementation significantly reduced hyperhomocysteinaemia, MDA (Malondialdehyde) levels, and oxidized LDL. Quoted here is the authors' conclusion: ?Treatment with folinic acid lowers plasma homocysteine levels and, like vitamin E, affords antioxidant protection, which prevents lipid peroxidation. This lowering of lipid peroxidation may reduce the risk of atherosclerosis and prevent or delay cardiovascular complications in HD individuals.? So, in a nutshell, folinic acid, supplied in Homocysteine Supreme, is an active form of a group of vitamins known as folates. Folinic acid is one of the forms of folate (bound to calcium) found naturally in foods. Folate deficiency is believed to be the most common vitamin deficiency in the world due to food processing, food selection, and intestinal disorders. In the body folinic acid may be converted into any of the other active forms of folate.
Why so much emphasis on converting homocysteine back to methionine?
Many doctors don't realize that the most common block in the homocysteine pathway is the conversion of cystathionine to cysteine which requires B6 to activate the cystathionine beta-synthase enzyme, making B6 an important ingredient in Homocysteine Supreme. B6 is also required in the step that converts homocysteine into cystathionine. Serine, another important ingredient in Homocysteine Supreme, is needed in this step as well. Remember this part of the pathway synthesizes cysteine needed for glutathione synthesis and taurine which has multiple functions including preventing catabolism due to chronic stress and aiding insulin function, both being important for our metabolic syndrome individuals.
Homocysteine Supreme, which includes all needed nutrients and cofactors, will work no matter where the patient's block in the pathway is because of the synergism of the ingredients, and will work in individuals with the faulty genotype because of the high dose of folic acid and folinic acid it contains. This formula (by supplying folates and methylcobalamin B12) does aid the process for homocysteine to be converted back to methionine in case the body is in need of converting methionine into SAMe (S-adenosylmethionine) which is known to improve depression, synthesize neurotransmitters and support joint comfort, function and mobility in the spine, hips and knees. It is important to the joints because of its critical role in cartilage production. If SAMe is supplemented in the absence of adequate B12, homocysteine levels may increase. Designs for Health supplies B vitamins in its SAMe blister packed tablets (protected from light and moisture) in order to prevent this.
Besides faulty enzymes and genes are there chemicals that cause faulty methionine conversion?
Yes, heavy metals. Mercury and lead are known to bind to these sulfur amino acids and interfere with the pathway. Mercury depletes B12 and may interfere also by causing a deficiency of this key methylator. The methylcobalamin form of B12 is responsible for remethylating folic acid so it can convert homocysteine back to methionine. However, too much emphasis on converting the pathway backwards does not allow the body to synthesize more cysteine if needed. Mercury toxicity creates a greater need for cysteine and glutathione. Chronic mercury inhalation from mercury fillings, with its great affinity to bind to sulfur (S) amino acids, methionine and cysteine, can decrease the availability of these amino acids and affect the metabolism of both vitamin B12 and folic acid, making higher supplemental doses crucial. Cysteine, is needed to synthesize glutathione, the most important antioxidant in the human body. High amounts of glutathione are used up to protect the body from heavy metals such as mercury. Glutathione helps the liver to detoxify chemicals. This antioxidant prevents apoptosis, dying of our cells due to excessive oxidative stress caused by heavy metals and chemicals, especially a problem in people who do not consume enough fruits and vegetables which contain antioxidants.
Is methylation important?
Some of the toughest individuals will not get effective lowering of homocysteine until choline is supplemented. Choline converts to betaine (see pathway) with the help of riboflavin, vitamin B2, and aids methylation in this step of the pathway. TMG (trimethylglycine) provides extra methyl groups. Betaine with the help of B2 can convert back to glycine and aid the synthesis of creatine for muscle health. All needed nutrients have been included in Homocysteine Supreme for optimal results as well as magnesium and zinc which are cofactors for enzymes in the pathway.
Bottom Line:Synergistic nutrients, found in Homocysteine Supreme, facilitate the homocysteine pathway, preventing toxic levels of homocysteine from accumulating, and make it possible for a functioning pathway to provide necessary methyl and sulfur groups for a myriad of biochemical reactions, especially those needed for detoxification, immune system support, joint and cartilage repair, brain health and for reducing our risk of cardiovascular and other serious diseases.
- Verhoef P et al. Plasma total homocysteine, B vitamins and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:989-95
- Refsum H et al. Homocysteine and cardiovascular disease Ann Rev Med 1998;49:31-62
- Boushey CJ et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probably benefits of increasing folic acid intakes. JAMA 1995;274:1049-57
- Voutilainen S et al. Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler Thromb Vasc Biol 1999;19:1263-6
- Tsai JC et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994;91:6369-73
- Nappo F et al. Impairment of endothelial function by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999;281:2113-18
- Toprak A, Erenus M, Ilhan AH, Haklar G, Fak AS, Oktay A.The effect of postmenopausal hormone therapy with or without folic acid supplementation on serum homocysteine level. Climacteric. 2005 Sep;8(3):279-86.
- Malinow MR et al. Homocysteine, diet and cardiovascular disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-82.
- Ueland PM et al. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000;72:324-32.
- Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005 Oct;82(4):806-12.
- Richter B, Stegmann K, Roper B, Boddeker I, Ngo ET, Koch MC. Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population. J Hum Genet. 2001;46(3):105-9.
- Hackam DG et al. What level of plasma homocysteine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocysteine levels above and below 14 micromol/L. Am J Hypertens. 2000;13:105-10.
- Laboratory Evaluations in Molecular Medicine?J. Alexander Brally, PhD, CCN and Richard Lord, PhD (Metametrix Biochemistry Textbook).
- Stern LL, Bagley PJ, Rosenberg IH, Selhub J. Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene. J Nutr. 2000 Sep;130(9):2238-42.
- Berlin H BR, and Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinisic factor. Acta Med Scand. 1968; 184:247-248
- Kelly GS. Folates: supplemental forms and therapeutic applications. Altern Med Rev. 1998 Jun;3(3):208-20.
- Bayes B, Pastor MC, Bonal J, Junca J, Romero R. Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E. Nephrol Dial Transplant. 2001 Nov;16(11):2172-5.
- Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006 Mar 14;113(10):1335-43
- Evers S et al. Features, symptoms and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol 1997;54:1276-82
- Catargi B, Parrot-Roulaud F, Cochet C, Ducassou D, Roger P, Tabarin A. Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid. 1999 Dec;9(12):1163-6.
Serving Size 2 Capsules
Servings Per Container 60
Amount Per Serving:
(Vitamin B-2) (as Riboflavin-5-Phosphate)
Vitamin B-6 50mg
(as Pyridoxine Hydrochloride 40 mg; Pyridoxal-5-Phosphate 10 mg)
Vitamin B-12 1000mcg
(TRAACS® Magnesium Glycinate Chelate Buffered)
(TRAACS® Zinc Glycinate Chelate)
Trimethylgylcine (TMG) 500mg
N-Acetyl-Cysteine (NAC) 100mg
Other Ingredients: Microcrystalline cellulose, silicon dioxide, vegetable stearate.
Recommended Use: As a dietary supplement, take two capsules per day with meals, or as directed by your health care practitioner.
This product does not contain: wheat, yeast, soy , gluten, eggs, dairy, corn, artificial colors, flavors, sugars, or preservatives.
*All raw materials have been reviewed and validated by DFH QC to be non-GMO (based on supplier documentation)
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.