What is homocysteine? What is MTHFR? Homocysteine is a chemical found in the blood. It is produced by the metabolism of methionine (an amino acid that is a component of food and protein in our organism) and is excreted in the urine. During the metabolic process, homocysteine can be reused by the body to synthesize other proteins. In the process of reuse, vitamins B12, B6 and folic acid are required. If a person is deficient in vitamin B12, B6 or folic acid, homocysteine cannot circulate efficiently and thus accumulates in the blood. Also, efficient circulation depends on the enzyme formyltetrahydrofolate reductase (MTHFR). A mutation in the gene that forms the MTHFR enzyme can lead to a decrease in enzyme activity, resulting in elevated homocysteine levels. Mild to moderate elevations in homocysteine levels are common; severe elevations are rare. There is a rare genetic disorder called homocystinuria, in which people with the disease have high levels of homocysteine due to a defect in an enzyme that causes homocysteine to build up in the blood. This disease was first reported in 1962. Patients with this disease develop severe cardiovascular disease in their late teens or early twenties, as well as various skeletal-neurodevelopmental abnormalities and eye disease. This reveals that elevated homocysteine levels are a risk factor for the development of arteriovenous thrombosis and atherosclerosis. Many people have mild to moderate elevated homocysteine levels, called homocysteinemia. The cause may be a mutation in the MTHFR gene, which is very common. Elevated levels can also be seen for other reasons. Over the past 20 years there has been a large body of research examining the relationship between mild to moderate elevations of homocysteine, MTHFR mutations and cardiovascular disease and blood clots. How is homocysteine measured? What are normal levels? Homocysteine levels can be measured by a blood test. Fasting is not usually required. Normal levels vary slightly from laboratory to laboratory. Usually <15 umol/L is considered normal; sometimes the upper limit of normal is set at 14 or 13 umol/L. 15-30 umol/L is mildly elevated, 30-60 umol/L is moderately elevated, and >60 umol/L is severely elevated. Elevations are common, with up to 5% to 7% of the population having mildly elevated homocysteine levels. Patients with homocystinuria are usually >100 umol/L. What are the risks of elevated homocysteine levels? 1. Cardiovascular disease. Increased homocysteine levels increase the risk of cardiovascular disease. The more severe the elevation, the greater the risk. Cardiovascular disease includes coronary heart disease, myocardial infarction, and stroke. However, the data show only a mild increase in risk; in 2010, the American Heart Association (AHA) issued a statement saying that elevated homocysteine levels are not considered a major risk factor for cardiovascular disease. 2., Venous thrombosis. Elevated homocysteine levels are associated with an increased risk of venous thrombosis. Venous thrombosis can be seen in the extremities, especially the lower extremities, as deep vein thrombosis (DVT), or in the lungs, as pulmonary embolism (PE). The higher the homocysteine level, the greater the risk. However, (1) the risk of DVT and PE is only slightly increased, and (2) although an elevated homocysteine level is a risk factor for the first episode of DVT and PE, it does not predict recurrence after discontinuation of anticoagulants. Therefore, elevated homocysteine levels were found not to affect the course of anticoagulation therapy. 3. Pregnancy complications. Elevated homocysteine levels are common in women with certain pregnancy complications, including pre-eclampsia, placental abruption, and recurrent miscarriage. However, it is possible that elevated homocysteine levels are the result of these complications rather than their cause. Elevated homocysteine levels are more common in women who have children with neural tube abnormalities (about 20%). Neural tube abnormalities include spina bifida and anencephaly. A multivitamin containing 0.4 mg of folic acid daily is recommended for women of childbearing age to reduce the chance of fetal neural tube abnormalities. This recommendation is independent of homocysteine levels. If there is a history of fetal neural tube abnormalities, a higher dose of folic acid, usually 4 mg, is recommended. 4. Others. Possibilities include autism, cognitive impairment or dementia, depression, Down syndrome, osteoporosis, movement disorders, migraine, multiple sclerosis, and polycystic ovary syndrome. It is still only being studied. How do elevated homocysteine levels contribute to cardiovascular disease and venous thrombosis? It is unclear whether elevated homocysteine levels lead to a predisposition to thrombosis or whether it is simply a marker of increased risk of thrombosis. The observation that vitamin B6, vitamin B12 and folic acid are effective in reducing homocysteine levels, but not the risk of cardiovascular disease and venous thrombosis, suggests that homocysteine may be a marker of increased risk rather than a cause. Therefore, the American Heart Association (AHA) statement of 2010 concluded that there is no clear causal relationship between homocysteine levels and atherosclerosis. Can homocysteine levels be lowered? If so, how can they be lowered? Yes. Folic acid, vitamin B6 and vitamin B12 can lower blood homocysteine levels. Sources of folic acid are fruits and vegetables (especially leafy greens) and fortified breads and cereals. Who needs to have their homocysteine levels tested? Young people (under 20 or 30 years of age) who have unexplained myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism. There is currently no evidence of possible benefit from testing homocysteine levels in others. Both the U.S. Preventive Services Expert Committee and the American Academy of Family Physicians agree that there is no evidence to screen asymptomatic adults in the absence of coronary artery disease. If homocysteine levels are elevated, do I need treatment? No. Although daily supplementation with folic acid, vitamin B6 and vitamin B12 is effective in reducing blood homocysteine levels, it does not reduce the risk of cardiovascular disease, deep vein thrombosis and pulmonary embolism. Therefore, for now, supplementation with folic acid, vitamin B6 or vitamin B12 is not recommended as primary prevention of cardiovascular disease. In some individuals, elevated homocysteine levels are due to a genetic predisposition. Milder elevations may be due to mutations in the MTHFR gene. Under normal circumstances, the MTHFR gene produces an enzyme that regulates homocysteine levels in the body. Each of us has two MTHFR genes, inherited from our father and mother. Some people may have mutations in one or two MTHFR genes; a mutation in one MTHFR gene is called a heterozygote; if both genes are mutated, the person is a pure or compound heterozygote. Are MTHFR mutations common? The most common MTHFR gene mutation is the MTHFR C677T mutation. Individuals heterozygous for the MTHFR C677T mutation have enzyme function at approximately 65% of normal levels. For pure heterozygotes, only 30% of normal function is present. Another mutation is MTHFR A1298C, for which the pure heterozygous enzyme function is 60% of normal. There can also be both an abnormal MTHFR C677T gene and an abnormal MTHFR A1298C gene; called double heterozygotes. Their enzyme function is also diminished. What can be caused by MTHFR mutations? 1. cardiovascular disease, deep vein thrombosis and pulmonary embolism, pregnancy complications. Although mutations in the MTHFR gene can lead to diminished enzyme function, this is not always the case. The MTHFR mutation itself (in the absence of elevated homocysteine levels) is not a risk factor for cardiovascular disease or deep vein thrombosis and pulmonary embolism, and does not lead to pregnancy complications. 2. Other diseases. Over the past 15 years, there have been a large number of studies examining the relationship between MTHFR mutations and various diseases, involving 615 diseases, most of which are associated with homocysteine levels, blood clots, cardiovascular disease risk, cancer risk, neural tube abnormalities, pregnancy complications, and psychiatric disorders. So far, most of these studies have had inconsistent results, with some showing that MTHFR mutations are associated with these diseases, while others show no association. Who should be tested for MTHFR mutations? In 2013, the American College of Medical Genetics recommended that genetic testing for MTHFR should not be performed in individuals at risk for thrombosis and recurrent miscarriage. It also recommended 0.4 mg of folic acid daily for all women of gestational age (regardless of MTHFR status) to reduce the risk of neural tube abnormalities. Similarly, in 2013 the American College of Obstetricians and Gynecologists did not recommend screening women for homocysteine and MTHFR. Do I need treatment if I have a mutation in the MTHFR gene? No. Patients with deep vein thrombosis and pulmonary embolism, cardiovascular disease, and complications of pregnancy who have been tested for one or two mutations in the MTHFR gene should be treated in the same way as patients without mutations. The presence of an MTHFR mutation does not require specific treatment (e.g., folic acid, vitamin B12, or vitamin B6 supplementation).