Homocysteine

Homocysteine level is one of the most important indicators of our health, and it is essential to keep it within the normal range. Both elevated and low blood homocysteine can potentially disrupt important processes in the body. When elevated, homocysteine begins to damage the vascular wall, increases inflammation, promotes blood clots and impairs nervous system function. This raises the risk of heart attacks, strokes, cognitive impairment, depression and pregnancy complications. Low homocysteine also carries risks: increased oxidative stress, impaired detoxification, poor fat digestion and more. We will go into more detail below.

Biochemistry and metabolism of homocysteine

Homocysteine is a sulphur-containing amino acid that is not obtained from food but is produced in the body as a by-product of the metabolism of the essential amino acid methionine.

Foods high in methionine:

• Egg white
• Various meats (beef, turkey, chicken, etc.) and offal
• Fish and seafood
• Dairy products
• Legumes
• White cabbage and spinach
• Gelatin

Homocysteine is released during methionine metabolism—specifically when it participates in various body reactions (e.g. methylation). The body’s task is to prevent its accumulation, as in large amounts homocysteine becomes toxic. Elevated homocysteine in the body can cause apoptosis of endothelial cells by interfering with protein synthesis. Because of its similarity to methionine it is incorporated into the protein chain but does not complete its formation, leading to defective and toxic proteins. These proteins can trigger an immune response, being perceived by the body as foreign. In addition, homocysteine damages the cellular structure responsible for protein synthesis, activates glutamate receptors and disrupts DNA structure. Thus, our body’s homeostasis strives to maintain intermediate levels of this amino acid, continually converting homocysteine into less toxic compounds and preventing its harmful effects. This is possible via two pathways: remethylation and transsulphuration.

Remethylation is the process by which homocysteine is converted back to methionine with the enzyme methionine synthase. That is, the body effectively “resets” homocysteine, returning it to its initial state. This mechanism helps keep blood homocysteine levels down and prevents accumulation.

For homocysteine to be successfully converted back to methionine, the following are needed:

• The active form of vitamin B9 (5-methyltetrahydrofolate), whose formation is ensured by the MTHFR enzyme. Defects in this enzyme (including due to genetic mutations) impair the remethylation process.
• Vitamin B12
• Betaine, derived from choline

High homocysteine level

The main causes of elevated homocysteine are considered to be B-vitamin deficiencies (such as B6, B9 and B12) and the presence of various genetic mutations. In addition, excessive intake of protein (high methionine) and insufficient greens (a source of folate and vitamins) in the diet disrupt homocysteine metabolism balance: the amino acid is produced in excess but the body lacks resources to process and neutralise it. The situation can be worsened by smoking, alcohol abuse, chronic stress, liver and kidney dysfunction, and certain medications (e.g. metformin).

Consequences of high homocysteine:

• Increases the risk of cardiovascular disease (damages arterial endothelium, causes inflammatory response in the vascular wall, promotes atherosclerosis, ischaemic stroke, etc.)
• Adversely affects bone tissue (impairs collagen synthesis, increases the risk of osteoporosis, etc.)
• Damages the blood–brain barrier and contributes to neurodegeneration
• Increases the risk of pre-eclampsia and other pregnancy complications
• Reduces insulin sensitivity, increasing the risk of type 2 diabetes
• Lowers choline levels in the body
• Causes oxidative stress

Low homocysteine level

Excessive lowering of homocysteine is less common than elevation. However, it can also have adverse health effects.

Causes of low homocysteine:

• Deficiency of methionine and cysteine in the diet
• Digestive and absorption disorders
• Increased use of homocysteine for glutathione synthesis (e.g. in inflammation or oxidative stress, high oxalate levels)
• Enhanced taurine synthesis, especially with alcohol or fatty food consumption
• Folate and vitamin B12 deficiency
• High demand for methyl groups (e.g. during accelerated creatine synthesis)

Consequences of low homocysteine:

• Reduced glutathione synthesis, worsening many pathological conditions (including susceptibility to oxidative stress and chronic inflammation)
• Impaired detoxification and liver function
• Reduced fat metabolism
• Development of cognitive impairment
• Worsening of chronic kidney disease
• Reduced methylation

Besides diet and lifestyle, genetics significantly influence homocysteine level, as its metabolism depends on a number of enzymes encoded by specific genes. If these genes have mutations or polymorphisms, homocysteine metabolism can be disrupted, leading to its accumulation (or less often, to decrease). One of the best-known and clinically significant genes affecting homocysteine level is MTHFR. This gene encodes an enzyme involved in converting folate to its active form—5-methyltetrahydrofolate—required for remethylation of homocysteine to methionine. Our report also includes other genes involved in homocysteine metabolism, such as MTR, MTRR, CBS, BHMT and others. After a detailed analysis of each gene, the report provides personalised recommendations for correction and possible directions for laboratory testing.