High and low homocysteine: normal homocysteinemia values


What is homocysteine?

What's this homocysteine? Homocysteine is an amino acid obtained from methionine, through a process of demethylation (loss of a methyl group). There methionine it is also a sulfur amino acid, called essential, as the body is not able to synthesize it.
The importance of methionine is closely associated with its ability to donate methyl groups, which are necessary for the DNA methylation process.

The metabolism of the homocysteine takes place in 2 ways:

  • Street of transulfuration: which leads to the formation of cysteine and, subsequently, to cystine (requires Vitamin B6).
  • Street of remethylation: which involves the re-conversion of homocysteine into methionine.

For the remethylation process the presence of some B vitamins is essential, in particular the folate, of the vitamin B6 and of vitamin B12.

Why do folate and B vitamins play a key role in homocysteine metabolism? Folate and B Vitamins act like cofactors some enzymes (eg MHTFR or methylene-tetra-hydro-folate reductase) involved in the metabolic processes of homocysteine and therefore have a very important role; in fact, their deficiency leads to hyperhomocysteinemia.

Homocysteinemia - Homocysteine in the blood

In blood there are three forms of homocysteine:

  • Free oxidized form
  • Reduced free form
  • Form constituting the structure of some proteins

The peculiar feature of the homocysteine is that it has both an auto-oxidant and a pro-oxidant action, therefore it itself becomes a radical species and is able to induce the production of oxygen radical species.

Chemical formula of homocysteine.

Chemical formula of homocysteine.

The radical species of oxygen (ROS), also known as free radicals, are highly reactive molecular structures.

Our cells are equipped with anti-oxidant systems (eg catalase, vitamin A, vitamin E etc).
These have the task of removing radical species and containing oxidative stress. When the balance between the oxidizing system (i.e. free radicals) and the anti-oxidant system is altered, then the oxidizing component will prevail which will damage the cells and, in the long run, also the tissues and organs.

It is good to remember that, sometimes, small “stresses” (called hormetines) have a positive action because they stimulate the response of the antioxidant systems, or generate an adaptation of our biological systems to the exposure of small exogenous stimuli.

Several foods have anti oxidant action and therefore they are indicated in case of hyperhomocysteine:

  • Red Wine (without exceeding)
  • Tomato
  • Blueberries
  • Blackberries
  • Avocado
  • Dried fruit (walnuts, almonds etc)

These foods are rich in polyphenols is flavonoids, substances known to be antioxidants.

Curiosity: Red wine, consumed in the right quantities (maximum 1 glass with meals), has an anti-oxidant action and reduces the risk of cardiovascular disease. This was discovered thanks to the phenomenon now known as "French paradox". France has always been famous for its cheeses, which due to their high lipid (fat) content, should lead to a greater risk of cardiovascular mortality in the population that consumes them; however, it has been seen that cardiovascular mortality in the French population is not higher than other populations with the same diet, this is because the consumption of red wine, rich in resveratrol, has an anti-oxidant action and therefore reduces cardiovascular risk.

Factors that can lead to the onset of ROS

  • Hyperhomocysteinemia
  • Ionizing radiation (via water hydrolysis)
  • Inflammations
  • Enzymes
  • Transition metals (which act as catalysts).

Why is hyperhomocysteinemia a parameter to be controlled?
Hyperhomocysteinemia should therefore be monitored because it represents an independent risk factor for cardiovascular disease. Therefore, the mere presence of the condition of hyperhomocysteinemia - regardless of the presence of comorbidities such as hypertension, diabetes, dyslipidemias etc, increases the risk of onset of cardiovascular disease.

How homocysteine is dosed? The homocysteine dosage is carried out through a blood sample. The sample must be taken on an empty stomach for at least 10-12 hours, without having consumed coffee or smoked cigarettes, conditions that could distort the outcome of the examination.

Methionine load curve

The methionine load curve is not performed often. It is performed in subjects who have a predisposition to arterial and venous thrombophilia or who have particular risk factors. It is a dynamic test which consists in the administration of a load of methionine and the subsequent evaluation of how homocysteine is metabolized over time.

Normal values of homocysteine

The reference values of homocysteinemia vary according to both sex and age.
Homocysteine levels increase with age and the higher they are, the greater the cardiovascular risk.

  • Values normal: 7-11 µmol / L
  • Values normal in patients > 65 years: 7-14 µmol / L
  • Hyperhomocysteinemia values moderate:> 50 µmol / L
  • Hyperhomocysteinemia values strict:> 150-200 µmol / L
  • Normal homocysteine values in pregnancy: <6 µmol / L

Values above 150-200 µmol / L represent a serious condition of hyperhomocysteinemia. These cases are generally seen in people who do not respond to therapy.

NB Drugs such as metformin (used to treat diabetes and metabolic syndrome) or omeprazole can increase homocysteine levels in the blood. Folic acid, on the other hand, reduces them.

High homocysteine

Hyperhomocysteinemia is a pathological condition associated with an increase in homocysteine, resulting from both genetic alterations, an unhealthy lifestyle, the use of certain drugs or the coexistence of some pathologies. It is associated with an increased cardiovascular risk.

Causes of hyperhomocysteinemia

We distinguish the causes of hyperhomocysteinemia in:

Congenital causes

  • Mutations of the MHTFR gene (today it is no longer considered a mutation, but a polymorphism since it occurs in more than 1 % of the population). The most common mutation is C677T.
  • Mutations of other enzymes involved in the homocysteine metabolic cycle (both in transulfuration and remethylation; eg Cystathionine Beta Synthase)
  • Homocystinuria: pediatric pathology with self-estimated recessive transmission

 Acquired causes

  • Medicines
  • Predisposing pathologies eg. endocrine pathologies (hypothyroidism)
  • Nutritional deficiencies of vitamins of group B (A reduction of Vitamins B or folic acid can be consequent to an altered intake of the same or to their altered absorption - typical of alcoholic patients, drug addicts, or as a result of chronic intestinal inflammatory diseases such as: celiac disease and Crohn's disease).

The most frequent forms of hyperhomocysteinemia are those related to: nutritional deficiencies is mutations in the gene for MHTFR.

Lifestyle plays a fundamental role in the regulation of homocysteinemia.

Factors that increase homocysteine levels (hyperhomocysteinemia)

  • Smoke
  • Excessive consumption of ethanol
  • Excessive consumption of coffee
  • Sedentary lifestyle
  • Proliferative diseases
  • Hypothyroidism
  • Type II diabetes
  • Kidney failure
  • Congenital causes (MHTFR mutation)
  • Vitamin deficiency (Folate, Vitamin B6 and Vitamin B12)

Mechanisms through which the damage endothelial resulting from hyperhomocysteinemia:

  • Direct damage to the endothelium
  • Production of oxygen radical species
  • Decrease in the activity of eNOS synthetase (endothelial nitric oxide synthetase, normally it causes vasodilation)
  • Increased platelet aggregation induced by homocysteinemia

Risks associated with hyperhomocysteinemia

Increased homocysteine levels carry a greater risk of total mortality.

  • Direct endothelial damage (resulting in coronary heart disease, angina pectoris, heart attack, etc.)
  • Thromboemolism
  • Stroke (cerebrovascular disease)
  • Risk of relapse in subjects who have undergone coronary angioplasty, with values greater than 11 µmol / L
  • Risk of fetal changes in neural tube development (spina bifida or meningocele)
  • Risk of onset of neurodegenerative diseases (e.g. senile dementia)

High homocysteine symptoms

Given that one of the most frequent causes of hyperhomocysteinemia is the lack of folic acid, the symptomalogy, albeit non-specific, is often associated with this condition.

  • Dizziness
  • Asthenia (tiredness)
  • Weakness
  • Pallor
  • Anemia
  • Tachycardia (rapid heartbeat)
  • Dyspnea (difficulty in breathing)
  • Loss of appetite
  • Tingling (paraesthesia)
  • Numbness of the limbs, especially the hands and feet

Hyperhomocysteinemia therapy

Therapy for hyperhomocysteinemia is based on the administration of folic acid supplements. The dosage is often 5 mg per day of folic acid orally for 2-3 months, at the end of which homocysteinemia is dosed again; the therapy is interrupted for 1 month and then eventually, depending on whether the homocysteine values are normalized or not, resumed. Or, you can proceed with the continuous administration of 5 mg of folic acid for 2-3 days a week.

A dietary "therapy" and an improvement in lifestyle must always be associated with drug therapy: it is therefore advisable stop smoking is practice physical activity.

What to eat in case of high homocysteine (hyperhomocysteinemia)?

 The recommended diet to reduce hyperhomocysteinemia is based on:

  • Legumes (especially lentils)
  • Spinach
  • Eggs
  • Meat
  • Fish
  • Whole grains
  • Moderate consumption of red wine (the consumption of one glass of red wine per day is associated with a anti oxidant action, to reduction of the values of homocysteine and toincreased HDL - also known as good cholesterol)
  • Reduction in the consumption of foods rich in saturated fats
  • Reduction in the consumption of simple and refined sugars

Homocysteine and pregnancy

During pregnancy the homocysteinemia values are reduced physiologically, to compensate for the condition of increased venous stasis.

The homocysteine values in pregnancy, therefore, generally reach 4-5 µmol / L.

In the pregnancies of women with increased homocysteinemia, for example due to genetic problems, in addition to the risk of fetal alterations, as mentioned above, there is also the risk of:

  • placental rupture,
  • pre - eclampsia,
  • increased risk of miscarriages,
  • low weight of the newborn at birth.

Hypomocysteinemia or low homocysteine

Low homocysteine is a physiological condition that is associated with the reduction of homocysteine values, linked both to the consumption of antioxidant substances, and following a healthy lifestyle, and in para-physiological conditions (e.g. pregnancy) to compensate hemodynamic alterations.

 Causes of low homocystenine

  • Pregnancy
  • Type I diabetes
  • Alcohol (in modest quantities)
  • Physical activity

Low Homocysteine Symptoms

This condition does not present typical clinical symptoms. It is generally not clinically relevant, as it is not associated with pathological conditions.


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