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
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
. 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.
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.
Lowering homocysteine blood levels is linked to increasing the intake of folic acid and vitamins B6
. The healthiest way to increase intake is by eating more foods that are high in these substances. Good sources of folic acid, vitamin B6
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
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.
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.
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
McCully, Kilmer S. The Homocysteine Revolution. 2nd ed. New York: McGraw Hill 1999.
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〉.
American Heart Association. 7272 Greenville Ave., Dallas, TX 75231. (800)242-8721. http://www.americanheart.org.
Homocysteine.net, May 10, 2004. [cited March 23, 2005]. http://www.homocysteine.net
— A degenerative brain disease of unknown origin that is a common cause of dementia in older individuals.
— A nitrogen-containing building block of protein molecules.
— Loss of minerals from the bones, causing bones to break more easily.
— The liquid part of the blood in which cells are suspended.
ho·mo·cys·te·ine (Hcy), (hō'mō-sis'tē-ēn, -sis'tēn), Distinguish this word in spelling and pronunciation from homocystine.
A homologue of cysteine, produced by the demethylation of methionine, and an intermediate in the biosynthesis of l
-cysteine from l
-methionine via l
-cystathionine. Elevated levels of homocysteine have been associated with certain forms of heart disease.
See also: folic acid
Elevation of the level of homocysteine in the plasma is an independent risk factor for cardiovascular disease (including myocardial infarction, congestive heart failure, stroke, thromboembolic disease, and intermittent claudication) and (in pregnant women) for fetal neural tube defects such as spina bifida and meroanencephaly. Approximately 25% of people with atherosclerosis are found to have elevation of plasma homocysteine above 15 mmol/L. Because homocysteine rises after myocardial infarction and remains elevated for months, some have questioned the causal role assigned to it in vascular disease. Several prospective studies have failed to establish a connection between homocysteine levels and coronary disease risk. Homocysteine appears to exert a direct toxic effect on the intima of arteries, besides inducing oxidation of low-density lipoproteins and predisposing to thrombus formation by activating platelets and coagulation factors. In animal reproduction studies it promotes neural tube defects, cardiac anomalies, and failure of ventral closure. Elevation of plasma homocysteine occurs in various conditions, including genetic disorders, nutritional deficiencies, and chronic diseases. The level is higher in men and tends to rise with advancing age. Premature cardiovascular disease was first linked to elevation of homocysteine in people with homocystinuria, a rare genetic disorder in which deficiency of the enzyme cystathionine β-synthase leads to elevation of homocysteine in plasma and of its oxidation product, homocystine, in urine. A more common genetic disorder associated with abnormally high levels of homocysteine results from mutation of the gene that encodes the enzyme methylene tetrahydrofolate reductase. The marked increase in homocysteine levels after menopause may play a role in the increased incidence of vascular disease, cancer, and osteoporosis in postmenopausal women. Dietary deficiency of folic acid, vitamin B6 (pyridoxine), and vitamin B12 is also associated with elevation of homocysteine, as are chronic renal failure, hypothyroidism, and some malignancies. Lowering the serum concentration of homocysteine by administration of folic acid has been shown to reduce the risk of adverse cardiovascular events in patients with homocystinuria. In animal studies, administration of folic acid prevents the teratogenic effect of homocysteine. Screening for elevated homocysteine levels is advised for patients with coronary artery disease that is out of proportion to known risk factors, or with a family history of premature atherosclerotic disease. Administration of folic acid in a dose of 1 mg/day or more reduces homocysteine levels nearly to normal and protects against both vascular disease and birth defects. see also folic acid