Homocysteine and MTHFR Mutations
2015; Lippincott Williams & Wilkins; Volume: 132; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.114.013311
ISSN1524-4539
Autores Tópico(s)Pregnancy and preeclampsia studies
ResumoHomeCirculationVol. 132, No. 1Homocysteine and MTHFR Mutations Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBHomocysteine and MTHFR Mutations Stephan Moll, MD and Elizabeth A. Varga, MS, LGC Stephan MollStephan Moll From Hemophilia and Thrombosis Center and Clot Connect Program (www.clotconnect.org), University of North Carolina School of Medicine, Chapel Hill (S.M.); Division of Hematology/Oncology/Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, OH (E.A.V.); and The Ohio State University College of Medicine, Columbus (E.A.V.). and Elizabeth A. VargaElizabeth A. Varga From Hemophilia and Thrombosis Center and Clot Connect Program (www.clotconnect.org), University of North Carolina School of Medicine, Chapel Hill (S.M.); Division of Hematology/Oncology/Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, OH (E.A.V.); and The Ohio State University College of Medicine, Columbus (E.A.V.). Originally published7 Jul 2015https://doi.org/10.1161/CIRCULATIONAHA.114.013311Circulation. 2015;132:e6–e9Homocysteine is a chemical in the blood. It is formed when the amino acid methionine, which is a building block of the proteins in our food and body, is naturally broken down (ie, metabolized) to be excreted in the urine (Figure). During this breakdown process, homocysteine can be recycled by our body to be reused to build other proteins. For this recycling, we need vitamins B12, B6, and folate. If a person is deficient in vitamin B12, B6, or folate, homocysteine cannot be efficiently recycled and therefore accumulates in the blood. Also, for recycling to be the most efficient, the enzyme methylenetetrahydrofolate reductase (MTHFR) is needed. Inherited mutations in the gene that make the MTHFR enzyme can lead to an enzyme that is not optimally active and, consequently, may lead to elevated homocysteine levels. Mild to moderate homocysteine elevations are common; extremely high homocysteine elevations are uncommon.Download figureDownload PowerPointFigure. Homocysteine pathway: breakdown and recycling. CBS indicates cystathionine-β-synthase; and MTHFR, methylenetetrahydrofolate reductase.BackgroundPeople with a rare genetic condition called homocystinuria have a defective enzyme that causes homocysteine to accumulate to high levels in the blood. The disorder was first described in 1962. Individuals with homocystinuria develop severe cardiovascular (affecting heart and blood vessels) disease in their teens and twenties, in addition to a variety of skeletal and neurological-developmental abnormalities and eye problems. This led to the discovery that elevated homocysteine levels are a risk factor for developing blood clots in the arteries and veins and atherosclerosis (hardening of the arteries). Many people in the general population have mildly or moderately elevated homocysteine levels, termed homocysteinemia. This may be due to inherited mutations in the MTHFR gene; such mutations are very common. Other causes for elevated levels exist (Table 1). Over the past 20 years, there has been a great deal of research examining the relationship between mild to moderate elevations in homocysteine, and MTHFR mutations and the risk for cardiovascular disease and blood clots, as well.Table 1. Causes of Elevated Homocysteine• Dietary deficiency of folic acid, vitamin B6, and vitamin B12• Genetic abnormalities, including CBS and MTHFR mutations• Low levels of thyroid hormones (hypothyroidism)• Kidney failure• Chronic conditions and diseases (such as obesity, high blood pressure, diabetes mellitus, smoking, physical inactivity, high cholesterol)• Medications (such as atorvastatin, fenofibrate, methotrexate, and nicotinic acid)• UnknownHomocysteineHow Is Homocysteine Measured? What Is a Normal Level?Homocysteine is measured through a blood test. It is typically not required for a person to be fasting for the blood draw. There are slightly variable classifications for what is considered an elevated homocysteine level, because normal and abnormal values are set by individual laboratories. Typically, a level 60 µmol/L is considered severely elevated. Elevated levels are common: up to 5% to 7% of the general population has a mildly elevated homocysteine level. Individuals with the rare homocystinuria typically have levels of >100 µmol/L.What Are the Risks for Someone With Elevated Homocysteine Levels?a. Cardiovascular disease. Elevated homocysteine levels are associated with an increased risk for cardiovascular disease (see Table 2). The higher the level, the higher the risk. Cardiovascular disease can lead to coronary artery disease, heart attacks, and strokes. However, data show that the risk is only mildly increased; in 2010, the American Heart Association issued a statement that it does not consider high homocysteine levels in the blood to be a major risk factor for cardiovascular disease.1b. Clots in veins. Elevated homocysteine levels are associated with an increased risk for blood clots in the veins. Clots in the veins can occur in the extremities, mostly the legs, and are called deep vein thrombosis (DVT); they can also occur in the lung and are called pulmonary embolism (PE). The higher the homocysteine level, the higher the risk. However, (1) overall, the risk DVT and PE is only slightly increased, and (2) although elevated homocysteine is a risk factor for a first episode of DVT or PE, it does not predict a higher risk of recurrent clot once a patient is off blood thinners. Therefore, finding an elevated homocysteine does not influence the duration a patient should be treated with blood thinners.c. Pregnancy complications. Elevated homocysteine levels have been observed more frequently among women with certain pregnancy complications, including preeclampsia (dangerously elevated blood pressure in pregnancy), placental abruption (where the placenta detaches from the uterus), and recurrent pregnancy loss. However, it appears that elevated homocysteine levels may be a consequence of these complications, rather than the cause. Elevated homocysteine levels are observed more commonly among women who have a child with a neural tube defect (an abnormality of the fetal spine or brain). Neural tube defects include spina bifida (an opening in the fetal spine) and anencephaly (a severe birth defect in which the brain and skull do not form properly). Approximately 20% of women who have a child with a neural tube defect have abnormal homocysteine metabolism. It is recommended that all women of childbearing age take a multivitamin containing 0.4 mg of folic acid per day to reduce the chance of neural tube defects in their children. This recommendation is independent of a person's homocysteine level. A higher dosage of folic acid, usually 4 mg, may be recommended if the woman has had a previous child with a neural tube defect.d. Others. Homocysteine has been investigated as a risk factor for several other diseases, including autism, cognitive impairment or dementia, depression, Down syndrome, osteoporosis, movement disorders, migraines, multiple sclerosis, and polycystic ovary syndrome. At this time, testing for homocysteine in these contexts is considered investigational.Table 2. Risks That Have Been Associated With Elevated Homocysteine Levels• Coronary artery disease (atherosclerosis)• Heart attack• Stroke• Peripheral arterial disease• Venous thrombosis Deep vein thrombosis (DVT) Pulmonary embolism (PE)• Having a child with a neural tube defect (ie, spina bifida)• Pregnancy complications (preeclampsia, placental abruption, pregnancy loss)• Role of homocysteine has been investigated in many other diseases (see text)How Does Elevated Homocysteine Cause Cardiovascular Disease and Clots in Veins?It is not clear whether elevated homocysteine causes the blood to clot more easily, or whether it is just a marker of an increased clotting risk. The observations that homocysteine levels can be effectively lowered by vitamin B6, vitamin B12, and folic acid, yet that such lowering does not lead to a decrease in cardiovascular disease or venous disease (DVT and PE), suggest that homocysteine is simply a marker of an increased cardiovascular risk, not the cause of it. Accordingly, the American Heart Association in 2010 stated that a causal link between homocysteine levels and atherosclerosis (hardening of the arteries) has not been established.1Can Homocysteine Levels Be Lowered? If So, How?Yes, it can be lowered. Folic acid (also referred to as folate), vitamin B6, and vitamin B12 can decrease homocysteine in the blood. A good source for folic acid is fruits and vegetables (especially green leafy vegetables), and fortified breads and cereals, lentils, chickpeas, asparagus, spinach, and most beans, as well. 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