Methylation and homocysteine

Methylation and homocysteine

http://www.foodforthebrain.org/alzheimers-prevention/methylation-and-homocysteine.aspx

Homocysteine is a naturally occurring amino acid produced as part of the body's methylation process. The level of homocysteine in the plasma is increasingly being recognised as a risk factor for disease and seen as a predictor of potential health problems such as cardiovascular disease and Alzheimer's.

The complex metabolism of homocysteine within the body is highly dependent on vitamin derived cofactors, and deficiencies in vitamin B12, folic acid and vitamin B6 are associated with raised homocysteine levels. Other factors thought to raise levels are poor diet, poor lifestyle - especially smoking and high coffee and alcohol intake, some prescription drugs (such as proton pump inhibitors), diabetes, rheumatoid arthritis and poor thyroid function.

There is no consensus about the upper reference limits for plasma homocysteine concentrations although the 'normal' range for healthy individuals is considered to be between 5 and 15 µmol/L. However levels as low as 6.3 µmol/L are thought to confer an increased risk and each 5 µmol/L can increase the risk of coronary heart disease events by approximately 20%.

The good news is that homocysteine levels can be tested and high homocysteine levels can, in many cases, be normalised through diet and vitamin supplementation. The most important nutrients that help lower homocysteine levels are folate, the vitamins B12, B6 and B2, zinc and trimethylglycine (TMG).

This article discusses the causes and impacts of high homocysteine levels and the importance of homocysteine measurement, whilst highlighting some of the limitations associated with sample handling and homocysteine testing, and vitamin supplementation to normalise homocysteine levels.

Measurement of Homocysteine

written by Dr Gillian Hart BSc (Hons), PhD, Cert Mgmt (Open), MIBMS

Background

The importance of homocysteine as a risk factor is becoming much more familiar to us. A constantly increasing number of studies have been published that show homocysteine to be a predictor of potential health problems. It is clear now that raised plasma homocysteine concentrations both predict and precede the development of cardiovascular disease including stroke. A study published in the British Medical Journal showed clearly homocysteine level in blood plasma predicts risk of death from cardiovascular disease in older people even better than any conventional measure of risk including cholesterol, blood pressure or smoking.

Raised levels of homocysteine are also linked to Alzheimer's, dementia, declining memory, poor concentration and judgment and lowered mood. Women with high homocysteine levels find it harder to conceive and are at risk from repeated early miscarriage. High homocysteine has also been linked to migraines, and those with conditions such as diabetes and osteoporosis are at increased risk of raised homocysteine levels. Homocysteine has therefore been shown to play a crucial role as a key marker for disease development determining longevity and health throughout a person's life.

Why is homocysteine harmful?

Homocysteine is a naturally occurring amino acid produced as part of the methylation process. It has the formula C4H9NO2S and is a derivative of protein that is found in blood plasma when body chemistry is out of balance. It is a homologue of the amino acid cysteine, differing by an additional methylene (-CH₂-) group. Homocysteine is not obtained from the diet, instead, it is biosynthesized from methionine via a multi-step process that probably occurs in every cell of the body (Figure 1).

Figure 1: Methionine Metabolism

Methionine is an amino acid, ingested as a component of food protein, and is found primarily in meats, eggs, dairy products, fish, chicken, seeds, nuts and some vegetables. Methionine is activated to S-adenosylmethionine (SAM) by the enzyme methionine adenosyltransferase. Circulating levels of homocysteine are usually low due to its rapid metabolism via one of two pathways: a cobalamin (vitamin B12) and folate dependent re-methylation pathway that regenerates methionine, or a pyridoxal 5' phosphate (PLP, vitamin B6) dependent trans-sulphuration pathway that converts homocysteine into cysteine.

The complex metabolism of homocysteine within the body is highly dependent on vitamin derived cofactors, and deficiencies in vitamin B12, folic acid and vitamin B6 are associated with hyperhomocysteinaemia. The reason homocysteine accumulates in the body causing cell damage and the onset of major disease, is because the biochemical transformation process is not working properly, usually due to lack of these needed vitamins. If these pathways are lacking the required vitamins and minerals, dangerous homocysteine levels and potential ill health can result.

The proposed mechanisms by which hyperhomocysteinaemia can cause harm such as vascular damage, cognitive impairment, neurological complications, congenital defects and pregnancy complications are common to all these conditions. A detailed review of these mechanisms is outside the scope of this article, however, raised homocysteine is associated with damage to the arteriesand one mechanism by which homocysteine is thought to cause this damage is by interfering with the way cells use oxygen, resulting in a build-up of damaging free radicals. Oxidation triggers many diseases including heart disease, strokes, cancers and autoimmune diseases.

Reactive chemical forms such as free radicals can oxidize low-density lipoproteins producing oxy-cholesterols and oxidized fats and proteins within developing arterial plaques. This oxidation injury, along with changes in nitric oxide metabolism, an important regulator and mediator of numerous processes in the nervous, immune and cardiovascular systems, and decreased methylation, appears to contribute to the damage caused. Indeed, methylation defects and impaired DNA repair caused by disturbed folate metabolism are suggested to contribute to carcinogenesis.

Homocysteine also stimulates the growth of smooth muscle cells, causing deposition of extracellular matrix and collagen, which causes a thickening and hardening of artery walls. Overall though, the exact mechanisms involved in the increased risk of ill health with raised homocysteine still remain a mystery in many respects, and more studies are needed to elucidate the exact associations.

What causes raised homocysteine levels?

Many factors are thought to raise levels of homocysteine; among them are poor diet, poor lifestyle especially smoking and high coffee and alcohol intake, some prescription drugs, diabetes, rheumatoid arthritis and poor thyroid function. Raised levels are also associated with chronic inflammatory diseases in general, and some intestinal disorders such as coeliac and Crohn's diseases. Levels increase with age and higher levels are more common in men than women. Levels of homocysteine can increase with oestrogen deficiency and with some long term medications, including corticosteroids. Strict vegetarians and vegans may also be at risk and people who suffer from stress. As with cholesterol, family history and genetic make-up can play a part in causing raised levels as can obesity and lack of exercise. Even people with an active, healthy lifestyle may still be at risk, if there is a family history of high levels of homocysteine or disease.

A rapidly increasing number of variations of the genes that regulate the enzymes that are involved in methionine metabolism have been identified. Reduction in the activity of genes such as the one that regulates the enzyme methyl-enetetrahydrofolate reductase (MTHFR) increases mean homocysteine levels. This gene is present in its homozygous form in about 10% of most European populations but the frequency varies widely geographically and between different ethnic populations.

Testing for homocysteine...Test methods...

"Normal" reference ranges

There is no consensus about the upper reference limits for plasma homocysteine concentrations. Among apparently healthy individuals "normal" concentrations commonly range from 5 to 15µmol/L. However, studies on targeted segments of the population have shown that the upper limit of 15µmol/L is far too high in well-nourished populations without obvious vitamin deficiency. It is clear now that each increase of 5µmol/L in homocysteine level increases the risk of coronary heart disease events by approximately 20%, independently of traditional coronary heart disease risk factors. In addition it is well documented that risk for coronary artery disease is represented by a continuum of homocysteine concentrations with a substantial risk occurring between 10 and 15µmol/L. Some report that any homocysteine measurement over 6.3µmol/L represents an increased risk.

Treatment

The good news is that high homocysteine levels can, in many cases, be normalised, and the advice regarding diet and vitamin supplementation have been shown to be very effective in reducing plasma homocysteine levels. It is clear though that vitamin supplementation can normalize homocysteine levels even when serum vitamin levels are within the normal range, or even in the high range. Metabolic, environmental and genetic factors make it virtually impossible to determine individual nutritional requirements without first carrying out a homocysteine test; the test result can then define the diet and supplementation regime required. The most important nutrients that help lower homocysteine levels are folate, the vitamins B12, B6 and B2, zinc and trimethylglycine (TMG).

Conclusion

This article has provided an overview of the importance of homocysteine measurement, whilst highlighting some of the limitations associated with sample handling and homocysteine testing. There will always be people who are at high risk of raised homocysteine, but the only way to find out definitively is to perform a validated homocysteine test, and then monitor levels during treatment.

Dr Gill Hart is a Biochemist with over twenty-five years’ experience in the development and evaluation of hospital standard tests and testing services. Gill joined the YorkTest team in 2005, and has applied her scientific and regulatory knowledge to all YorkTest services.