Homocysteine: the phantom menace

Digging into the science

When we enjoy a meal rich in animal protein we receive some amount of methionine — an essential sulfur-containing amino acid. It is a building block of a lot of proteins, it takes part in angiogenesis (blood vessels formation), moderately lowers the cholesterol blood level, is needed for biosynthesis of some hormones and other amino acids. Once methionine enters the body, it’s being partly converted into another building block — homocysteine. Thus, homocysteine is a breakdown product of protein metabolism. All the time body takes attempts to convert homocysteine back, but some of it remains as it is.

The difference between homocysteine and methionine is only that left-hand methyl group (marked in red). To convert homocysteine back to methionine body needs folates: they provide this methyl group

The question arises: why is it happening? There are a couple of reasons: genetic (due to the presence of mutations in some genes) or dietary (due to the excess of methionine or the lack of vitamin B in one’s diet. Vitamin deficiency also may be caused by bad habits, some meds and gut infections). Another factor that affects homocysteine is the renal malfunction. Because of disease or injury, renal metabolism may be impaired and excretion of homocysteine subsequently reduced.

Throughout the life homocysteine blood level gradually rises. Most adults generally have around 10–11 μmol/L, with lower levels in women. The gradual increase of homocysteine level ​​with age is explained by a decrease in renal function, lower levels of vitamins B6, B12, and folate (B9). Most laboratories report normal blood homocysteine levels below 15 µmol/L. On the other hand, Aging Research Center of Karolinska Institute in Sweden reported in 2010 that the optimal homocysteine range is below 7 µmol/L.

High homocysteine concentration in blood (over 15 µmol/L) is called “hyperhomocysteinemia.” If hyperhomocysteinemia is inherited — such condition is called “homocystinuria.” The latter is a rare disorder. According to U.S. National Library of Medicine, it affects 1 in 200,000 to 335,000 people worldwide. The disorder appears to be more common in some countries, such as Ireland (1 in 65,000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 1,800).

Homocysteine and cardiovascular health — where is the link?

Cardiovascular diseases remain the leading cause of mortality in Western populations. Homocysteine has been considered as an independent risk factor for them. Its increased blood concentration has a direct connection with endothelial dysfunction (endothelium is a thin layer of cells that line the interior surface of blood vessels) and atherosclerosis. In a nutshell, homocysteine damages interior of blood vessels, then cholesterol starts to stick to the damaged areas, forming atherosclerotic plaques and obstructing vascular transport.

According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine raise the risk for cardiovascular disease 2-fold. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia.

To preserve healthy society, eighty countries introduced the mandatory fortification of flour with folic acid following WHO recommendations. Such policy is applied in Sweden, Chile, Canada, United States, Australia, New Zealand, Uzbekistan, Turkmenistan, and many other countries.

So far, The Food and Drug Administration in the United States and the European Food Standards Agency have approved several products containing 5-MTHF: a compound which helps the body to convert homocysteine back to methionine. Maybe one day it will even substitute folic acid supplements.

Homocysteine and reproductive health

Since an impressive (83–91%) decrease in the risk of fetal neural tube defects was shown due to the folic acid supplementation, homocysteine started to be one of the central topics when women’s health is discussed. Women with raised homocysteine levels have an increased risk of having pregnancy complications and an adverse pregnancy outcome. Thus, folic acid preparations are often recommended for women who are preparing for pregnancy or trying to conceive.

Except for reproductive health, it is known that among women, raised homocysteine levels lead to decreased bone mineral density and increased risk of osteoporosis.

Moreover, in 2014 Chinese study found that some mutations coupled with raised homocysteine are associated with a higher risk of breast cancer, especially among women with low folate intake, vitamin B6, and vitamin B12. Such association disappeared among women with moderate and high intake of these vitamins.

There are a lot of similar publications, which link homocysteine to women’s health problems, leaving no doubts that this amino acid should be under thorough monitoring.

Homocysteine and mental health

People with elevated levels of homocysteine are at the greater risk of Alzheimer’s disease, senile dementia, and depression. According to the literature, the homocysteine ​​metabolite — homocysteic acid is a centrally acting neurotoxin. The mechanism through which homocysteine may accelerate dementia most likely is through cerebral microcirculation impairment, endothelial dysfunction, and oxidative stress.

In 2014 study published in Journal of the Neurological Sciences scientists found a startling 10.5-fold greater risk of vascular dementia among people with high homocysteine and uric acid. Treatment with some of B-vitamins resulted in a noticeable 53% lower brain atrophy rate. This finding suggests that patients with elevated levels of homocysteine ​​are more affected by vascular dementia.

Another research found that elderly individuals with homocysteine levels greater than 14 µmol/L were about twice as likely to develop Alzheimer’s disease.

A few studies show that high homocysteine levels correlate with low levels of serotonin. This could contribute to depression, schizophrenia, and affective disorders.

Genetic predictors of elevated homocysteine: dubious MTHFR and others

As it was mentioned above, there are several reasons for homocysteine elevation, some of which are genetic. The most extensively studied and surrounded by a lot of hype is the MTHFR gene. Since decades ago researchers noticed that MTHFR 677TT mutation seems to elevate homocysteine levels, people devote books, movies and websites to this gene. If the MTHFR gene works properly, it produces an enzyme which, in turn, involves folate and vitamin B12 to convert homocysteine back to methionine.

There are two ways in which this gene may be represented: C and T. And people may carry one of three combinations CC, CT, and TT, due to the fact that we inherit two copies of it — one from mother and the other one from father. Those who are CT or TT have correspondingly 40% and 70% less MTHFR enzyme function than those who have the CC. According to the 1000 Genomes Project, only 13–20% of Europeans and Americans carry two T-copies of it.

Numerous studies have found that women with two T-copies have an increased risk of having a child with a neural tube defect. Both men and women, who inherited T-gene variants from both parents may be at a mildly increased risk for blood clots (venous thromboembolism).

Most of such research papers found associations between many conditions and MTHFR — that is, people who had an MTHFR variant might also have one of these other problems. On another hand, this mutation has not yet been demonstrated to be the defining cause for a specific disease. Conducting international clinical trials may provide further evidence supporting the notion that the MTHFR gene may cause all those conditions.

Thus, The American College of Medical Genetics and Genomics (ACMG) suggests not to order MTHFR genetic testing for the risk assessment of hereditary thrombophilia due to the lack of evidence which supports the causal link.

On another hand, Mayo Clinic (a premier health and research institute in the USA) suggests that one should consider testing for the common MTHFR gene mutations if having coronary artery disease, acute myocardial infarction, peripheral vascular artery disease, stroke, or venous thromboembolism, or those who have increased basal homocysteine levels or an abnormal methionine-load test.

Besides MTHFR there are several genetic markers, which may cause hyperhomocysteinemia. A 2013 meta-analysis (scaled and statistically strong review of other researches, which included data from 44,147 individuals of European ancestry) found several more genetic loci, which may contribute to elevated homocysteine.

For example, another gene — CBS — provides instructions for making an enzyme called cystathionine beta-synthase. This enzyme is responsible for using vitamin B6 to convert homocysteine and serine to a molecule called cystathionine. More than 150 mutations that cause homocystinuria have been identified in the CBS gene.

Mutations in other CUBN and FUT2 genes may impair constitutive vitamin B-12 concentrations, indirectly leading to subsequent homocysteine elevation.

There are also mutations in the genes, which are involved in renal functioning. NOX4 is one of such genes. Its exact role in normal physiology is yet to be determined, but the most compelling explanation for the observed genetic association between changes in this gene and plasma homocysteine concentration is regulation of renal handling of homocysteine by NOX4. This association, however, requires further validation.

How to maintain cardiovascular health?

Reducing high homocysteine levels is important for one’s wellness.Currently, prevention is the best strategy in a fight with elevated homocysteine levels. Here are some scientifically-proven insights about how to keep it under control:

1. Decrease consumption of meat. Since homocysteine comes from methionine, which is a constituent of animal proteins, reducing meat consumption will reduce homocysteine biosynthesis as well. This is one of the reasons why many dieticians support the idea, that most of the protein in the diet should come from plant sources.

2. Eat greens. So far, folate (B9), vitamins B6 and B12 are one of the most reliable assistants in lowering homocysteine. However, recent researches demonstrate that B6 and B12 vitamin supplements may increase the risk of cancer (particularly lung cancer) and mortality. Those, before running to a pharmacy you better consider a safer way to stay healthy: maintaining a balanced diet. Term “folic” is from the Latin word “folium”, which means leaf. Folates occur naturally in many foods, especially dark green leafy vegetables, liver, and lentils. Beyond lowering homocysteine, you will receive enough fiber and many other vitamins and minerals crucial for health maintenance. A half a cup of cooked lentils has 179 mcg folate (almost half of the daily value according to Mayo Clinic).

3. Take care of kidneys. There is a direct connection between homocysteine level and renal function. Thus, maintaining kidney health will keep under control excretion of this amino acid.

4. Quit smoking and watch your coffee consumption. Some scientific groups have found that smokers have an increased tendency to elevated homocysteine levels. Moreover, those, who smoke over 20 years are prone to have decreased levels of vitamins B9 and B12. These vitamins are essential for maintaining homocysteine under control, so it’s important to keep their sufficient plasma levels.

Those, who prone to drink too much coffee also should take special care. The link between heavy coffee consumption and increased homocysteine blood level has been confirmed in randomized controlled trials. Coffee, but not caffeine, affects homocysteine metabolism within hours after intake, due to a presence of various compounds, which counteract with homocysteine-converting enzymes. In a Hordaland Homocysteine Study, it was shown that those, who drink ≥9 cups of coffee daily, have >20% higher total homocysteine concentrations than those who drink no coffee. On the other hand, moderate coffee consumption among healthy people doesn’t significantly increase the homocysteine concentration. Similar effect on homocysteine has heavy alcohol consumption.

5. Be active. It’s no secret that many of us are sitting much more than moving which is so bad for cardiovascular health! You don’t necessarily have to schedule a workout session to get more movement into your day: if you’re not one to wake up early for a morning run, simply get off your bus one station before and have a walk towards your work, and take stairs instead of an elevator. A few studies have shown that homocysteine concentrations may increase with a sedentary lifestyle, while moderate physical activity contributes to lowering the level of homocysteine.

5. Do regular checks. By doing so, you increase your chances of preventing maladies before they start harming you. Your health provider can consult you about lowering homocysteine levels if needed and can offer the best solution exactly for you.

The Bottom Line

Let’s sum it up:

  1. An elevated level of homocysteine can be harmful. It’s better to keep it around < 7 μmol/L.
  2. Do not make conclusions based on genetic testing of only one gene. Clinical context is always important. Thus, consult with your practitioner before taking any measures.
  3. If you are genetically prone to have elevated levels of homocysteine you better eat more folate-rich foods. In contrast to the controversial information regarding vitamin B supplementation, more leafy vegetables in the diet surely won’t be harmful.
  4. Do not smoke and watch your coffee consumption. If you follow at least this — it could already be a solid contribution to a healthier future.

Science is growing exponentially, and new articles regarding rational management of homocysteine and cardiovascular health sustenance appear almost monthly. If you don’t want to miss new insights on this topic, follow us: we are constantly gathering new scientifically-based information in this field.