Heart Disease caused by homocysteine
What is homocysteine?
Homocysteine is an amino acid that is produced by the body by chemically altering adenosine. Amino acids are naturally made products, which are the building blocks of all the proteins in the body.
Can elevated homocysteine levels be genetic?
In 1969, Dr. Kilmer S. McCully reported that children born with a genetic disorder called homocystinuria, which causes the homocysteine levels to be very high, sometimes died at a very young age with advanced atherosclerosis in their arteries. Homocysteine levels in the blood may be elevated for many reasons. More specifically, these reasons can be divided into severe genetic causes and other milder causes.
In the genetic condition called homocystinuria, there is a deficiency or lack of an important mediator molecule (enzymes) in the complicated homocysteine breakdown pathway. This leads to severely elevated levels of homocysteine. In this rare and serious condition, there is a constellation of symptoms that include developmental delay, osteoporosis (thin bones), visual abnormalities, formation of blood clots, and advanced atherosclerosis (narrowing and hardening of blood vessels). This condition is mainly recognized in childhood.
Milder genetic variations are more common causes of elevated homocysteine levels (hyperhomocysteinemia). In these conditions, the mediator molecules malfunction and are less efficient because of minor abnormality in their structure. They also lead to elevation of homocysteine levels, although much milder than in homocystinuria, by slowing down the breakdown of homocysteine.
How common is hyperhomocysteinemia?
Mild elevation in homosysteine levels (hyperhomocysteinemia) are common, and seen in about 5% to 12% of the general population. In specific populations such as, alcoholics (due to poor vitamin intake) or patients with chronic kidney disease, this may be more common. The severe genetic form, homocystinuria, is rare (0.02%).
How can homocysteine levels be lowered?
The consumption of folic acid supplements or cereals that are fortified with folic acid, and to a lesser extent vitamins B6 and B12, can lower blood homocysteine levels. These supplements may even be beneficial in people with mild genetic hyperhomocysteinemia to lower their homocysteine levels. However, it is noteworthy that so far there is no compelling data to support the treatment of hyperhomocysteinemia for prevention of heart disease or treatment of known heart disease or blood clots. Homocysteine levels are not routinely measured in indivduals with heart disease (atherosclerosis) or other diseases.
Does a lowering homocysteine level prevent heart attacks and strokes?
Currently, there is no direct proof that taking folic acid and B vitamins to lower homocysteine levels prevents heart attacks and strokes. However, in a large population study involving women, those who had the highest consumption of folic acid (usually in the form of multivitamins) had fewerheart attacks than those who consumed the least amount of folic acid. In this study, the association between dietary intake of folate and vitamin B6 and risk of heart disease was more noticeable than between dietary intake of vitamin B12 and heart disease, which was minimal.
Many other observational studies have been performed to assess the effect of folate and the other B vitamins on heart disease. Most of these studies have concluded that oral intake of folate has been associated to lower risk of heart disease, possibly because due to lowering of homocysteine levels. The relation between oral intake of vitamin B12 and B6 and heart disease was not as obvious in many of these studies. In one study, it was concluded that even in people with elevated homocysteine levels due to genetic reasons, oral intake of folate and possibly the other B vitamins was related to lower incidence of heart disease.
Most of these data, however, are obtained from observational studies rather than purely controlled scientific data. Therefore, it is important to mention that despite these studies suggesting an association between the intake of these vitamins and the lower incidence of heart disease, in general, there is no compelling clinical evidence to treat hyperhomocysteinemia other than homocystinuria (the severe genetic form) in regards to heart disease, stroke, or blood clots. As stated previously, homocysteine levels are not routinely measured in individuals with these problems.
Who should undergo testing for homocysteine blood levels?
Currently, there are no official recommendations as to who should undergo testing for homocysteine blood levels. Before more scientific data become available from the currently ongoing studies, many experts do not recommend a screening test for blood homocysteine levels, even in patients with unexplained blood clot formation. In addition, the consensus recommendation is against treating elevated homocysteine levels with vitamins to prevent heart disease. Rarely, a few specialists may test for elevated homocysteine levels in patients with early onset of blood clot formation, heart attacks, strokes, or other symptoms related to atherosclerosis, especially if these patients do not have typical risk factors, such as smoking cigarettes, diabetes, high blood pressure, or high LDL cholesterol levels and they suspect genetic causes
There is also no consensus as to the optimal dose of folic acid and other B vitamins for the treatment of elevated blood homocysteine levels. (For example, treatment of patients with high homocysteine levels may require higher doses of folic acid and other B vitamins than the amounts contained in a multivitamin.) Therefore, a decision regarding testing should be individualized after consulting with your doctor and/or a specialist in genetic diseases.
Dr. Andrew Weil
Dr. Andrew Weil
What are the causes of elevated homocysteine?
An inadequate intake of B vitamins, as well as genetic factors that affect the body's absorption and use of folic acid, can lead to elevated homocysteine levels. If this is the case, your intake of folic acid has to be higher than the RDA of 400 mcg. Other contributors to elevated homocysteine levels include stress and coffee consumption: the more coffee you drink, the higher your homocysteine levels are likely to be. The stress-induced neurotransmitters epinephrine and norepinephrine are metabolized in the liver via a process that uses methyl groups. This can also increase the need for folic acid. In addition, elevated homocysteine levels may be due to low levels of thyroid hormone, kidney disease, psoriasis and some medications.
An inadequate intake of B vitamins, as well as genetic factors that affect the body's absorption and use of folic acid, can lead to elevated homocysteine levels. If this is the case, your intake of folic acid has to be higher than the RDA of 400 mcg. Other contributors to elevated homocysteine levels include stress and coffee consumption: the more coffee you drink, the higher your homocysteine levels are likely to be. The stress-induced neurotransmitters epinephrine and norepinephrine are metabolized in the liver via a process that uses methyl groups. This can also increase the need for folic acid. In addition, elevated homocysteine levels may be due to low levels of thyroid hormone, kidney disease, psoriasis and some medications.
How is elevated homocysteine diagnosed?
Homocysteine levels are checked via blood tests. Physicians may order the test for patients who have a family history of heart disease but no other risk factors, such as high blood pressure or high cholesterol. These tests aren't done routinely, are not widely available, and their cost (about $100) may not be covered by health insurance. A normal homocysteine level is between 4.4 and 10.8 micromoles per liter of blood.
Homocysteine levels are checked via blood tests. Physicians may order the test for patients who have a family history of heart disease but no other risk factors, such as high blood pressure or high cholesterol. These tests aren't done routinely, are not widely available, and their cost (about $100) may not be covered by health insurance. A normal homocysteine level is between 4.4 and 10.8 micromoles per liter of blood.
What is the conventional treatment of elevated homocysteine?
There is no treatment for elevated homocysteine apart from efforts to lower your levels by increasing your intake of B vitamins through the eating of more green leafy vegetables, fruits and more grain-based foods fortified with folic acid. So far, studies to determine whether lowering homocysteine levels can reduce the risk of heart disease haven't shown a benefit, but this may be because the studies were too small or because homocysteine levels weren't lowered enough.
There is no treatment for elevated homocysteine apart from efforts to lower your levels by increasing your intake of B vitamins through the eating of more green leafy vegetables, fruits and more grain-based foods fortified with folic acid. So far, studies to determine whether lowering homocysteine levels can reduce the risk of heart disease haven't shown a benefit, but this may be because the studies were too small or because homocysteine levels weren't lowered enough.
What therapies does Dr. Weil recommend for elevated homocysteine?
To lower homocysteine levels, Dr. Weil recommends increasing your intake of B vitamins, particularly folate, and moderating stress. The richest food sources of folate (the form of folic acid found in food) are green vegetables, orange juice and beans. Dr. Weil also recommends taking a multivitamin that gives you 400 micrograms of folic acid in addition to what you might get from your diet. (Some people might absorb this vitamin better in supplement form, which Dr. Weil considers good insurance.) To reduce stress, Dr. Weil advises practicing breathing exercises, meditation and mind-body exercises such as yoga.
To lower homocysteine levels, Dr. Weil recommends increasing your intake of B vitamins, particularly folate, and moderating stress. The richest food sources of folate (the form of folic acid found in food) are green vegetables, orange juice and beans. Dr. Weil also recommends taking a multivitamin that gives you 400 micrograms of folic acid in addition to what you might get from your diet. (Some people might absorb this vitamin better in supplement form, which Dr. Weil considers good insurance.) To reduce stress, Dr. Weil advises practicing breathing exercises, meditation and mind-body exercises such as yoga.
Reducing foods high in animal protein can also help lower homocysteine levels. For optimum health, Dr. Weil recommends following his anti-inflammatory diet, which limits total protein intake to between 80 and 120 grams (three to four ounces) daily, and emphasizes protein sources such as fish, beans, whole soy and dairy products.
Homocysteine is not obtained from the diet.[3] Instead, it is biosynthesized from methionine via a multi-step process. First, methionine receives an adenosine group from ATP, a reaction catalyzed by S-adenosyl-methionine synthetase, to give S-adenosyl methionine (SAM). SAM then transfers the methyl group to an acceptor molecule, (i.e., norepinephrine as an acceptor during epinephrine synthesis, DNA methyltransferase as an intermediate acceptor in the process ofDNA methylation). The adenosine is then hydrolyzed to yield L-homocysteine. L-Homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine or conversion to L-cysteine.[4]
Mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine β-synthase catalyses the condensation of homocysteine and serine to give cystathionine. This reaction uses pyridoxine (vitamin B6) as a cofactor. Cystathionine γ-lyase then converts this double amino acid to cysteine, ammonia, and α-ketobutyrate. Bacteria and plants rely on a different pathway to produce cysteine, relying on O-acetylserine.[5]
Homocysteine can be recycled into methionine. This process uses N5-methyl tetrahydrofolate as the methyl donor and cobalamin (vitamin B12)-related enzymes. More detail on these enzymes can be found in the article for methionine synthase.
Homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle. Because of this "self-looping" reaction, homocysteine-containing peptides tend to cleave themselves by reactions generating oxidative stress.[6]
Common levels in Western populations are 10 to 12, and levels of 20 μmol/L are found in populations with low B-vitamin intakes or in the older elderly (e.g., Rotterdam, Framingham).[citation needed] Women have 10-15% less homocysteine during their reproductive decades than men, which may help explain the fact they suffer myocardial infarction (heart attacks) on average 10 to 15 years later than men
Abnormally high levels of homocysteine in the serum, above 15 µmol/L, are a medical condition calledhyperhomocysteinemia. This has been claimed to be a significant risk factor for the development of a wide range of diseases, including thrombosis, neuropsychiatric illness, and fractures.[citation needed] It is also found to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.[13]
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