Related Terms

• Atherosclerosis, betaine, betaine anhydrous, cardiovascular disease risk, cerebral artery disease, choline, cocamidopropylbetaine, coronary artery disease, dialysis, fasting blood test, folate (vitamin B9), folic acid (vitamin B9), homocysteine, homocysteine test, homocystinuria (cystathionine beta-synthase deficiency), hyperhomocysteinemia, kidney failure, methylenetetrahydrofolate reductase (MTHFR) enzyme, methylenetetrahydrofolate reductase (MTHFR) gene, niacin, vitamin B6 (pyroxidine), vitamin B12.

Background

• Homocysteine is a naturally occurring, sulfur-containing amino acid in the blood that requires enzymes, vitamin B12, folic acid, and other vitamins to be converted to the essential amino acid methionine. Several conditions (such as deficiencies of certain vitamins in the body, kidney failure, hypothyroidism, or genetic defects) may cause homocysteine levels to rise.

• Hyperhomocysteinemia is a medical condition characterized by high levels of homocysteine (an amino acid) in the blood. Patients with hyperhomocysteinemia have an increased risk of developing coronary artery disease (CAD), because high levels of homocysteine may irritate blood vessels, and this may then lead to blockages in arteries. In addition, clots become stronger and less likely to break down naturally. Such changes make vessels vulnerable to clots, obstructions, and disease.

• Deficiencies in folic acid (folate), vitamin B6, vitamin B12, or betaine may lead to hyperhomocysteinemia. The concentration of homocysteine in the blood will decrease after appropriate supplementation with the deficient vitamins.

• Patients with kidney failure who are undergoing dialysis also have an increased risk of developing hyperhomocysteinemia. However, researchers have not discovered exactly why this condition sometimes develops in dialysis patients.

• Hyperhomocysteinemia does not cause any symptoms. Therefore, the American Heart Association recommends regular homocysteine testing in patients who have high risks of developing heart disease.

• Hyperhomocysteinemia is diagnosed after a blood test, called a homocysteine test. Patients who have greater than 15 micromoles of homocysteine per liter of blood with a fasting blood test are diagnosed with the condition.

Risk Factors and Causes

• Deficiencies in folic acid (folate), vitamin B6, or vitamin B12 may lead to hyperhomocysteinemia.

• Patients with kidney failure who are undergoing dialysis also have an increased risk of developing hyperhomocysteinemia. However, researchers have not discovered exactly why this condition may develop in dialysis patients.

• Other conditions that may increase an individual's risk of developing hyperhomocysteinemia include hypothyroidism, liver disease, metabolic disorders (especially those leading to nutritional deficiencies), genetic abnormalities, and certain types of cancer. Some medications may also elevate homocysteine levels in the blood.

• A condition known as homocystinuria (cystathionine beta-synthase deficiency) may cause elevated levels of homocysteine in the blood. This is a rare genetic (inherited) disorder that affects the enzyme cystathionine beta-synthase. This enzyme is involved in the metabolism of homocysteine. In homocystinuria, cystathionine beta-synthase does not work properly. As a result, homocysteine accumulates in the blood.

• Inheritable differences in the methylenetetrahydrofolate reductase (MTHFR) gene may also lead to increased levels of homocysteine in the blood. This gene contains the instructions for making the MTHFR enzyme, which is involved in the conversion of homocysteine to methionine. Genetic differences in the MTHFR gene are quite common, and certain variations that cause the gene to be defective have been linked to increased risk of cardiovascular disease.

Signs and Symptoms

• Hyperhomocysteinemia usually does not cause any obvious symptoms. Therefore, the American Heart Association recommends regular homocysteine testing in patients who have a high risk of developing heart disease.

Diagnosis

• Hyperhomocysteinemia is diagnosed after a blood test, called a homocysteine test. A positive diagnosis is made if an eight-hour fasting blood test reveals greater than 15 micromoles of homocysteine per liter of blood.

Complications

• Homocysteine damages and degrades the endothelial lining of the arteries, which causes the artery walls to become weaker and narrower. Homocysteine also prevents small arteries from dilating, making them more vulnerable to obstruction by a clot or plaque formation. Homocysteine also promotes blood clot formation by changing the structure of the clot itself.

• A high level of homocysteine in the blood is an independent risk factor for atherosclerosis (a disease involving progressive plaque buildup and hardening of the arteries), cerebral artery disease (a disease affecting the arteries supplying the brain), coronary artery disease (a disease affecting the arteries supplying the heart), and peripheral artery disease (a disease affecting the arteries supplying the extremities).

Treatment

• Patients with hyperhomocysteinemia receive betaine, folate, vitamin B6, and/or vitamin B12 until homocysteine levels are normal. However, it is not clear if lowering homocysteine levels results in reduced cardiovascular morbidity and mortality. Reducing homocysteine does not seem to help with secondary prevention of death or cardiovascular events such as stroke or myocardial infarction in people with prior stroke. More evidence is needed to fully explain the association of total homocysteine levels with vascular risk and the potential use of vitamin supplementation. Until definitive data are available, the current recommendation is screening of 40 year-old men and 50 year-old women for hyperhomocysteinemia.

• Betaine anhydrous: Dietary betaine intake is about 0.5-2.0 grams daily. Higher betaine intake is associated with reduced levels of plasma homocysteine, and betaine supplementation is a standard treatment for hyperhomocysteinemia. Overall, betaine supplementation has shown significant reductions in both fasting and postmethionine-load homocysteine. For hyperhomocysteinemia, betaine is usually given at a dose of six grams daily. However, decreases in plasma homocysteine have been shown with lower doses (similar to normal dietary levels), such as 1.5 grams daily.

• Avoid if allergic or hypersensitive to betaine anhydrous or cocamidopropylbetaine, a form of betaine. Use cautiously with renal disease, obesity, and psychiatric conditions. Avoid if pregnant or breastfeeding.

• Folate: Folic acid (vitamin B9) supplementation lowers homocysteine levels and might reduce the risk of cardiovascular disease. The U.S. recommended dietary allowance (RDA) for adults is 400 micrograms daily for males or females aged 14 years and older. For breastfeeding adult women, the RDA is 500 micrograms daily. For pregnant women, the RDA is 600 micrograms daily. Higher folate intake is associated with reduced levels of plasma homocysteine, and betaine supplementation is a standard treatment for hyperhomocysteinemia.

• Avoid if allergic or hypersensitive to folate or any folate product ingredients. Use cautiously if receiving coronary stents and with anemia and seizure disorders. It is recommended that pregnant women consume 400 micrograms of folate daily in order to reduce the risk of fetal defects. Folate is likely safe if breastfeeding.

• Vitamin B6: Taking vitamin B6 (pyridoxine) supplements alone or in combination with folic acid has been shown to be effective for lowering homocysteine levels.

• The RDAs for vitamin B6 for adults are as follows: males (19-50 years old), 1.3 milligrams; males (51 years old and older), 1.7 milligrams; females (19-50 years old), 1.3 milligrams; females (51 years old and older), 1.5 milligrams; pregnant women, 1.9 milligrams; and lactating women, 2 milligrams. Some researchers think the RDA for women 19-50 years old should be increased to 1.5-1.7 milligrams daily. The RDAs for vitamin B6 for children are as follows: infants (0-6 months), 0.1 milligrams; infants (7-12 months), 0.3 milligrams; children (1-3 years), 0.5 milligrams; children (4-8 years), 0.6 milligrams; children (9-13 years), 1 milligram; males (14-18 years), 1 milligram per day; females (14-18 years), 1.2 milligrams per day.

• Avoid vitamin B6 products if sensitive or allergic to any of their ingredients. Some individuals seem to be particularly sensitive to vitamin B6 and may have problems at lower doses. Avoid excessive dosing. Vitamin B6 is likely safe when used orally in doses not exceeding the recommended dietary allowance (RDA). Use cautiously if pregnant or breastfeeding.

• Vitamin B12: Hyperhomocysteinemia is a risk factor for coronary, cerebral, and peripheral atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction (heart attack), and ischemic stroke. Vitamin B12 supplementation can reduce total homocysteine levels.

• Recommended dietary allowances (RDAs) for vitamin B12 are 2.4 micrograms daily for adults and adolescents aged 14 years and older, 2.6 micrograms daily for adult and adolescent pregnant females, and 2.8 micrograms daily for adult and adolescent lactating females. Because 10-30% of older people do not absorb food-bound vitamin B12 efficiently, those over 50 years of age should meet the RDA by eating foods fortified with B12 or by taking a vitamin B12 supplement. Supplementation of 25-100 micrograms daily has been used to maintain vitamin B12 levels in older people. A doctor and pharmacist should be consulted for use in other indications. Vitamin B12 has been taken by mouth and given by intramuscular (IM) injection by healthcare professionals. One clinical trial tested patients' acceptance of intranasal vitamin B12 replacement therapy (500 micrograms per week).

• Avoid vitamin B12 supplements if allergic or hypersensitive to cobalamin, cobalt, or any other vitamin B12 product ingredients. Avoid with coronary stents (mesh tube that holds clogged arteries open) and Leber's disease. Use cautiously if undergoing angioplasty and with anemia. Vitamin B12 is generally considered safe when taken in amounts that are not higher than the recommended dietary allowance (RDA). There are not enough scientific data available about the safety of larger amounts of vitamin B12 during pregnancy and breastfeeding.

Integrative Therapies

• Unclear or conflicting scientific evidence:

• Choline: Choline is an essential nutrient related to the water-soluble B-complex vitamins folate, pyridoxine, and B12, and to the essential amino acid methionine. It is synthesized in the body, as well as consumed in the diet. The largest dietary source of choline is egg yolk. Choline can also be found in high amounts in liver, peanuts, fish, milk, brewer's yeast, wheat germ, soy beans, bottle gourd fruit, fenugreek leaves, shepherd's purse herb, Brazil nuts, dandelion flowers, poppy seeds, mung beans and other beans, and a variety of meats and vegetables, including cabbage and cauliflower. Higher choline intake is associated with reduced levels of plasma homocysteine, and choline supplementation has been suggested as a treatment for hyperhomocysteinemia.

• The "average" diet supplies 400-900 milligrams of choline daily, which is presumed to be adequate. According to the Institute of Medicine, although the adequate intake (AI) has been set for choline by the Institute of Medicine's Food and Nutrition Board, there are few data to assess whether a dietary supply of choline is needed at all ages. It may be that the choline requirement can be met by the body's own synthesis of choline at some of these stages.

• The recommended daily intake by the U.S. Food and Nutrition Board of the Institute of Medicine for men 18 years old or older is 550 milligrams daily, not to exceed 3.5 grams daily; for women 19 years old or older, it is 425 milligrams daily, not to exceed 3.5 grams daily; for women 18 years old, it is 400 milligrams daily, not to exceed three grams daily; for pregnant women, it is 450 milligrams daily; and for breastfeeding women, it is 550 milligrams daily.

• Upper intake levels (UL) should not exceed 3.5 grams daily for adults and the elderly. Dosages at the upper limit intake levels are contraindicated (inadvisable) for persons suffering from trimethylaminuria, kidney disease, liver disease, depression, and Parkinson's disease, as they may be at risk for side effects.

• Fair negative scientific evidence:

• Niacin: Niacin decreases blood levels of cholesterol and lipoprotein (a), which may reduce the risk of atherosclerosis ("hardening" of the arteries). However, niacin also can increase homocysteine levels, which may have the opposite effect. Overall, the scientific evidence supports the use of niacin in combination with other drugs (but not alone) to decrease cholesterol and slow the process of atherosclerosis. More research is needed in this area before a firm conclusion can be drawn.

Prevention

• Prevention strategies focus on dietary and lifestyle modifications. A healthy diet includes at least five daily servings of fruits and vegetables; consuming foods rich in fiber, whole grains, calcium, omega-3 fatty acids; and reducing intake of cholesterol and saturated fat.

• Regular exercise improves the overall health of blood vessels and the heart. It also helps control weight, diabetes, and blood pressure, and reduces stress. Thirty minutes of daily exercise is normally recommended.

• Patients with risk factors for hyperhomocysteinemia and cardiovascular disease should have their blood cholesterol levels checked regularly. Most people should aim for a low-density lipoprotein (LDL, or "bad") cholesterol level below 130 milligrams per deciliter of blood. If additional risk factors are present, the target LDL level may be below 100 milligrams per deciliter of blood. If the individual is at a very high risk for heart disease, such as having a previous heart attack, an LDL level below 70 milligrams per deciliter of blood may be optimal. Other cholesterol goals include a total cholesterol level of less than 200 milligrams per deciliter of blood, a triglyceride level less than 150 milligrams per deciliter of blood, and high-density lipoprotein (HDL, or "good") cholesterol level of greater than 40 milligrams per deciliter for men and greater than 50 milligrams per deciliter of blood for women. Patients with high cholesterol levels may be prescribed cholesterol-lowering agents to help maintain healthy cholesterol levels.

• Controlling blood pressure reduces stress on the arteries and helps keep them functioning properly. A healthy blood pressure should ideally be a systolic reading of less than 120 millimeters of mercury (mmHg) and a diastolic reading of less than 80mmHg (that is, less than 120/80mmHg).

• Limiting alcohol consumption is also part of a healthy lifestyle. It is recommended that men should have no more than two drinks containing alcohol daily, and women should have no more than one drink containing alcohol daily.

• Patients who smoke cigarettes or use other tobacco products are advised to quit. Nicotine constricts blood vessels, increases blood pressure, and even damages the lining of the blood vessels. Making healthy dietary and lifestyle choices reduces an individual's risk of developing hyperhomocysteinemia and helps prevent cardiovascular disease, diabetes, and other medical conditions.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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