Homocysteine

Definition

Homocysteine is a naturally occurring amino acid found in blood plasma. High levels of homocysteine in the blood are believed to increase the chance of heart disease, stroke, Alzheimer's disease, and osteoporosis.

Description

Homocysteine is a sulfur-containing amino acid that occurs naturally in all humans. It is broken down in the body through two metabolic pathways. The chemical changes that must occur to break down homocysteine require the presence of folic acid (also called folate) and vitamins B⁶ and B¹². The level of homocysteine in the blood is influenced by the presence of these substances.

Homocystinuria is a rare genetic disorder that occurs in about one in every 200,000 individuals. This congenital metabolic disorder causes large amounts of homocysteine to be excreted in the urine. Homocystinuria is associated mental retardation and the development of heart disease before age 30.

In the late 1960s, doctors documented that individuals with homocystinuria developed narrowing of the arteries at a very early age, sometimes even in childhood. Although homocystinuria is rare, this finding stimulated research on whether people who did not have homocystinuria but who did have unusually high levels of homocysteine in their blood were at greater risk of developing heart disease or stroke.

Many risk factors, including family history of heart disease, smoking, obesity, lack of exercise, diabetes, high levels of low-density lipoprotein cholesterol (LDL or "bad" cholesterol), low levels of high-density lipoprotein cholesterol (HDL or "good" cholesterol), and high blood pressure have been documented to increase the risk of stroke and heart disease. With so many other risk factors, it has been difficult to determine whether high levels of homocysteine are an independent risk factor for the development these diseases. However, a substantial number of controlled, well-designed, and well-documented studies have shown that individuals who have high levels of homocysteine in the blood are at increased risk of developing blocked blood vessels, a condition known as occlusive arterial disease or at risk to worsen atherosclerosis ("hardening of the arteries").

In the 2000s, studies also suggested that high levels of homocysteine were associated with poorer mental functioning, leading to ongoing investigations into the role of homocysteine in Alzheimer's disease. Additional studies have also suggested that high levels of homocysteine can lead to osteoporosis and an increased risk of broken bones in the elderly. As of 2005, homocysteine was being tested in half a dozen clinical trials to determine its role in these and several other conditions. Information on clinical trials that are enrolling patients can be found on-line at 〈http://www.clinicaltrials.gov〉.

Causes and symptoms

Homocysteine is thought to irritate the lining of the blood vessels causing them to become scarred, hardened, and narrowed. This increases the work the heart must do, leading to heart disease. High levels of homocysteine also cause increased blood clotting. Blood clots can decrease or block the flow of blood through blood vessels, resulting in strokes and heart attacks. If and how homocysteine directly plays a role in osteoporosis and Alzheimer's disease is not clear as of 2005.

The level of homocysteine in the blood naturally varies with age, gender, diet, hereditary factors, and general health, but it is estimated that 5-10% of the population has homocysteine levels that are considered high. With the exception of rare individuals who have congenital homocystinuria, people with high blood levels of homocysteine do not have any obvious signs or symptoms.

Diagnosis

The American Heart Association and the American College of Cardiology do not recommend routine screening of homocysteine levels, but they do recommend screening as part of a cardiac risk assessment for individuals who have a family history of coronary artery disease but no obvious symptoms of heart disease. The level of homocysteine in the blood can be measured with a simple blood test that is often, but not always, done after fasting. Homocysteine levels of 12 mmol/L are considered normal and levels below 10 mmol/L are considered desirable.

Treatment

Lowering homocysteine blood levels is linked to increasing the intake of folic acid and vitamins B₆ and B₁₂. The healthiest way to increase intake is by eating more foods that are high in these substances. Good sources of folic acid, vitamin B₆ and B₁₂ include green leafy vegetables, fortified breakfast cereals, lentils, chickpeas, asparagus, spinach, and most beans. Taking a daily multivitamin is also a way to increase the levels of these substances. However, megadoses of folic acid, vitamin B₆ and B₁₂ are not recommended. Individuals should discuss dosage with their doctor before beginning any supplements. It is important to note that a direct link between increased intake of folic acid, vitamin B₆, and vitamin B₁₂ and decreased incidence stroke and heart attack has not been proved. However, one study published in the Journal of the American Medical Association found that women whose folic acid levels were in the lowest 25% were 69% more likely to die of coronary problems than women whose folic acid levels were in the top 25%.

Individuals with homocystinuria are treated with the drug betaine (Cystadane). This is a powder dissolved in water, juice, or milk and drunk usually twice a day with meals. This drug is not normally used simply to lower high levels of homocysteine in the absence of congenital disease.

Prognosis

Individuals who increase the folic acid, vitamin B₆ and B₁₂ in their diet are expected to see a decrease in blood levels of homocysteine and as a result decrease their risk of heart disease and stroke.

Prevention

Certain drugs are suspected of increasing the level of homocysteine in the blood. People using these drugs should discuss with their doctor the advisability of increasing their intake of folic acid, vitamin B₆, and vitamin B₁₂. These drugs include:

• lipid-lowering drugs such as fenofibrate (Tricor) and bezafibrate (Bezalip)
• metformin (Glucophage), a drug to modify insulin resistance
• anti-epileptic drugs such as phenobarbital, phenytoin (Dilantin), primidone (Mysoline) and carbamazepine (Tegretol)
• levadopa (Sinemet) for treatment of Parkinson's disease
• methotrexate (Rheumatrex, Trexall) for treatment of cancer, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus
• androgen treatment
• nitrous oxide ("laughing gas"), a mild anesthetic

Resources

BOOKS

McCully, Kilmer S. The Homocysteine Revolution. 2nd ed. New York: McGraw Hill 1999.

PERIODICALS

McLean, Robert R., et al. "Homocysteine as a Predictive Factor for Hip Fracture in Older Persons." New England Journal of Medicine, 350 (May 13, 2004): 2042-49 [cited 23 March 2005]. 〈http://content.nejm.org/cgi/content/abstract/350/20/2042〉.

Morey, Sharon S. "Practice Guidelines: AHA and ACC Outline Approaches to Coronary Disease Risk Assessment." American Family Physician, 61, no. 8 (April 15, 2000): 2534-44 [cited March 23, 2005]. 〈http://www.aafp.org/afp/2000415/practice.html〉.

ORGANIZATIONS

American Heart Association. 7272 Greenville Ave., Dallas, TX 75231. (800)242-8721. 〈http://www.americanheart.org〉.

OTHER

Homocysteine.net, May 10, 2004. [cited March 23, 2005]. 〈http://www.homocysteine.net〉

KEY TERMS

Alzheimer's disease— A degenerative brain disease of unknown origin that is a common cause of dementia in older individuals.

Amino acid— A nitrogen-containing building block of protein molecules.

Androgens— Male sex hormones.

Congenital— Present at birth.

Osteoporosis— Loss of minerals from the bones, causing bones to break more easily.

Plasma— The liquid part of the blood in which cells are suspended.

homocysteine An amino acid formed as an intermediate in the metabolism of methionine, and in the formation of cysteine from methionine; it is demethylated methionine. Does not occur in foods to any significant extent, and is not generally considered to be of nutritional importance. High blood concentrations of homocysteine (occurring as a result of poor folic acid, vitamin B6, and B₁₂ status) have been implicated in the development of atherosclerosis, heart disease, and stroke.

homocysteine (hoh-moh-sis-ti-een) n. a sulphur-containing amino acid that is an intermediate in the synthesis of cysteine. Elevated levels of homocysteine in the blood are a risk factor for vascular disease independent of diabetes, hypertension, elevated levels of cholesterol in the blood, and smoking. See also homocystinuria.