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 is it used?
The homocysteine test may be used a few different ways:
A health practitioner may order a homocysteine test to determine if a person has a vitamin B12 or folate deficiency.
The homocysteine concentration may be elevated before B12 and folate tests are abnormal.
Some health practitioners may recommend homocysteine testing in malnourished individuals, the elderly, who often absorb less vitamin B12 from their diet, and individuals with poor nutrition, such as drug or alcohol addicts.
Homocysteine may be ordered as part of a screen for people at high risk for heart attack or stroke. It may be useful in someone who has a family history of coronary artery disease but no other known risk factors, such as smoking, high blood pressure, or obesity.
However, the exact role that homocysteine plays in the progression of cardiovascular disease has not been established, so the utility of the screening test continues to be questioned.
Routine screening, such as that done for total cholesterol, has not been recommended.
Tests for both a urine and blood homocysteine may be used to help diagnose homocystinuria if a health practitioner suspects that an infant or child may have this inherited disorder.
In the U.S., all babies are routinely tested for excess methionine, a sign of homocystinuria, as part of their newborn screening.
If a baby’s test is positive, then urine and blood homocysteine tests are often performed to confirm the findings.
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 fewer heart 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.
When is it ordered?
This test may be ordered when a health practitioner suspects that a person may have a vitamin B12 and/or folate deficiency.
Signs and symptoms are initially subtle and nonspecific. People with an early deficiency may be diagnosed before they experience any overt symptoms. Other affected people may experience a variety of mild to severe symptoms that can include:
- Fatigue, weakness
- Loss of appetite
- Rapid heart rate
- Shortness of breath
- Sore tongue and mouth
- Tingling, numbness, and/or burning in the feet, hands, arms, and legs (with B12 deficiency)
Homocysteine testing may be ordered as part of assessing a person’s risk of cardiovascular disease, depending on the individual’s age and other risk factors.
It may also be ordered following a heart attack or stroke to help guide treatment.
This test is may be ordered when newborn screening detects an elevated level of methionine or if an infant or child has signs and symptoms of homocystinuria.
Babies with this condition will appear normal at birth, but if not treated, they will, within a few years, begin to develop signs such as a dislocated lens in the eye, a long slender build, long thin fingers, and skeletal abnormalities.
What does the test result mean?
In cases of suspected malnutrition or vitamin B12 or folate deficiency, homocysteine levels may be elevated.
If an individual does not get enough B vitamins and/or folate through diet or supplements, then the body may not be able to convert homocysteine to forms that can be used by the body.
In this case, the level of homocysteine in the blood can increase.
Studies from the mid- to late-1990s suggested that people who have elevated homocysteine levels have a much greater risk of heart attack or stroke than those with average levels.
Investigating the link between high homocysteine levels and heart disease remains an active area of research.
At present, however, the use of homocysteine levels for risk assessment of cardiovascular disease (CVD), peripheral vascular disease, and stroke is uncertain given that several trials investigating folic acid and B vitamin supplementation indicate no benefit or lowering of CVD risk.
Additionally, a 2012 study of multiple datasets, including 50,000 people with coronary heart disease, called the potential for a cause-and-effect relationship between homocysteine levels and heart disease into question.
The American Heart Association (AHA) does acknowledge the relationship between homocysteine levels and heart attack/stroke survival rates but doesn’t consider elevated homocysteine a major risk factor for CVD.
While the AHA does not recommend widespread use of folic acid and B vitamins to reduce risk of heart attack and stroke, it does promote a balanced, healthy diet and advise health practitioners to consider overall risk factors and diet in managing cardiovascular disease.
In newborn testing, greatly increased concentrations of homocysteine in the urine and blood mean that it is likely that an infant has homocystinuria and indicates the need for further testing to confirm the cause of the increase.
Is there anything else I should know?
When test results suggest homocystinuria, liver or skin biopsy samples are sometimes tested to determine whether the enzyme cystathionine beta synthase (CBS) is present.
The absence of this enzyme is the most common cause of homocystinuria. Genetic tests may be ordered to test for one or more of the most common gene mutations.
If someone has a strong family history of early atherosclerosis or a family member has been diagnosed with homocystinuria, then that person should be tested for the gene mutation that was found in the family member.
Homocysteine levels can increase with age, when a person smokes, and with the use of drugs such as carbamazepine, methotrexate, and phenytoin.
Homocysteine levels are lower in women than in men. Women’s concentrations increase after menopause, possibly due to decreased estrogen production.
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.