Hyperhomocysteinaemia

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 and genetic defects) may cause homocysteine levels to rise. A rare, serious, inherited metabolic error called homocystinuria results in very high levels of homocysteine, and early onset of strokes.

People with hyperhomocysteinaemia (high levels of homocysteine in the blood) have an increased risk of developing coronary artery disease (CAD), because high levels of homocysteine alter metabolism in the vascular tissue in such a way that the vessel may tear and lead to clotting.

Risk factors and causes of hyperhomocysteinaemia

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

People with kidney failure who are undergoing dialysis also have an increased risk of developing the condition. The exact mechanism remains unclear.

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 doesn’t 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 of hyperhomocysteinaemia

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.

How is hypermonocysteinaemia diagnosed?

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.

What are the complications of hypermonocysteinaemia?

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).

How is hypermonocysteinaemia treated?

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 0.5-2.0g 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 1.5g 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 US 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.

How can hyperhomocysteinaemia be prevented?

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

Regular exercise improves the overall health of your blood vessels and heart. It also helps to control weight, diabetes, blood pressure and stress. Aim for at least 150 minutes of exercise per week.

If you have risk factors for hyperhomocysteinemia and cardiovascular disease, you should have your blood cholesterol levels checked as well. Most people should aim for a low-density lipoprotein (LDL or "bad") cholesterol level of 3mmol/L. If additional risk factors are present, your target LDL level may be below 2.5mmol/L of blood. If you’re at a very high risk for heart disease (e.g. if you’ve had a heart attack before), an LDL level below 1.8mmol/L may be optimal.

Other preventive steps include:

• Controlling your blood pressure. This will reduce stress on the arteries and help 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. Keep your heart healthy by consuming alcohol in moderation. Men should have no more than two drinks containing alcohol daily, and women should have no more than one drink containing alcohol daily.
• Quitting smoking and other tobacco products. Nicotine constricts blood vessels, increases blood pressure, and even damages the lining of the blood vessels.

Making healthy dietary and lifestyle choices reduces your risk of developing hyperhomocysteinemia and helps prevent cardiovascular disease, diabetes and other medical conditions.

Reviewed by Prof David Marais, FCP(SA), Head of Lipidology at Groote Schuur Hospital and the University of Cape Town. January 2018.