Homocysteine is a naturally occurring, sulphur-containing substance 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. A rare serious inherited metabolic error, homocystinuria, results in very high levels and early onset of strokes.
Hyperhomocysteinemia is a medical condition characterised by high levels of homocysteine in the blood. Patients with hyperhomocysteinemia have an increased risk of developing coronary artery disease (CAD), because high levels of homocysteine alter metabolism in the vascular tissue in a way that the vessel may tear and set up clotting.
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 vitamin(s).
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 homocysteine testing in patients who have high risks of developing heart disease.
Hyperhomocysteinemia is diagnosed after a blood test, called a homocysteine test. Since homocysteine can be formed after the taking of the blood, special precautions are necessary, including placing the blood on ice. Patients who have greater than 15 micromoles of homocysteine per liter of blood are considered to be at risk. High levels are more commonly seen with severe vitamin deficiencies. In the rare condition of homocystinuria with very high risk, the blood levels are typically higher than 100 micromol/ltre.
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.
Inherited variants in the gene for methylenetetrahydrofolate reductase (MTHFR) 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 homocysteine testing in patients who have a high risk of developing heart disease.
Hyperhomocysteinemia is diagnosed after a blood test, called a homocysteine test. The diagnosis is made if an eight-hour fasting blood test reveals greater than 15 micromoles of homocysteine per liter of blood.
Homocysteine damages and degrades the endothelial lining of the arteries, which causes the artery walls to become weaker. 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 build-up 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).
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 daily allowance (RDA) for adults is 400 micrograms 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. Such folate intake lessens the risk for malformations in the baby. 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 anaemia and seizure disorders. It is recommended that pregnant women consume 400 micrograms of folate daily in order to reduce the risk of fatal 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.
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 you are pregnant or breastfeeding.
Vitamin B12: Vitamin B12 supplementation can reduce total homocysteine levels. 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 anaemia. Vitamin B12 is generally considered safe when taken in amounts that are not higher than the RDA. There are not enough scientific data available about the safety of larger amounts of vitamin B12 during pregnancy and breastfeeding.
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 fibre, 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 as well. Most people should aim for a low-density lipoprotein (LDL, or "bad") cholesterol level 3mmol/L. If additional risk factors are present, the target LDL level may be below 2.5mmol/L 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 1.8mmol/L may be optimal.
• 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 millimetres 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.