Doctors call it hyperhomocysteinemia, but it is better known as "high homocysteine." What are the values to be concerned about? And how to lower them? 

"I havehigh homocysteine: should I be worried?" Indeed, hyperhomocysteinemia is considered a risk factor for cardiovascular health and beyond. Some associate it with cystitis and some warn about the possible dangers to the bones. Even during pregnancy it could create not insignificant problems. Let's try to understand when to take corrective action and how to do it.

What is homocysteine?

Homocysteine is an amino acid, but it is not one of the "classic" amino acids-the ones from which proteins are synthesized. Rather, it is a derivative of one of the latter, methionine.

The process of producing homocysteine from methionine involves the removal of a methyl group, that is, an inseime of carbon and hydrogen atoms. The addition of a methyl group, on the other hand, allows methionine to be re-obtained from homocysteine; this process, called "remethylation," closes what is a real cycle that must be kept well functioning to avoid health risks.

High homocysteine: causes and symptoms

Homocysteine levels are considered normal when between 5 and 15 micromoles per liter (µmol/l). Instead, they are referred to as:

• Borderline hyperhomocysteinemia for values between 10 and 12 µmol/l;
• Moderate hyperhomocysteinemia for values between 13 and 30 µmol/l;
• Intermediate hyperhomocysteinemia for values between 31 and 100 µmol/l;
• Severe hyperhomocysteinemia for values above 100 µmol/l.

Causes that can lead to an increase include:

• genetic factors;
• Pathological conditions (e.g., kidney disease);
• Lifestyle (including nutrition).

In particular, there is a close association between increased homocysteine and deficiency of three B vitamins: vitamin B6, vitamin B9 (or folic acid), and vitamin B12. This link depends on the role of these vitamins in the conversion of homocysteine to methionine.

Specifically, folic acid, in the form of 5-methyltetrahydrofolate (5-methyl THF), gives up a methyl group to homocysteine to convert it to methionine. This reaction is catalyzed by the enzyme methionine synthase, which needs the presence of vitamin B12 to work well. Therefore, both folic acid and vitamin B12 deficiency can lead to hyperhomocysteinemia.

Vitamin B6, on the other hand, is important because it is involved in the conversion of homocysteine to cysteine-another reaction on which blood homocysteine levels depend.

In addition, since the production of 5-methyl THF requires the activity of the enzyme MTHFR (methylenetetrahydrofolate reductase), which converts folates found in food, mutations in this enzyme can also lead to increased blood homocysteine.

Symptoms of high homocysteine vary depending on its cause. Sometimes, the condition is totally asymptomatic; in the presence of B-vitamin deficiencies, however, it may be associated with fatigue, numbness or tingling in the limbs, weight loss, and dementia. In addition, hyperhomocysteinemia may be associated with osteoporosis and hip fractures, cognitive decline, chronic royal failure, hypothyroidism, Alzheimer's disease, and schizophrenia, and associations between high homocysteine and anxiety, headaches, or muscle problems have been found.

Finally, high homocysteine may also be associated with specific symptoms in pregnant women, such as recurrent miscarriages.

High homocysteine: the consequences

High homocysteine has been associated with several consequences due to problems with the blood vessels: cardiovascular, cerebrovascular, and thromboembolic diseases. Not surprisingly, as mentioned, homocysteine is considered a cardiovascular risk factor.

In particular, having high homocysteine means running a higher risk of atherosclerosis. This means that in the case of hyperhomocysteinemia, it is easier for so-called atherosclerotic plaques to form, that is, those deposits of cholesterol and inflammatory cells in the wall of blood vessels that can grow to occlude or rupture, generating thrombi that, carried by blood, can block the flow of blood in places even far away from where they were formed. 

The consequences of such events can be very serious, for example, heart attacks or strokes. High homocysteine increases the risk of this by damaging theendothelium, which is the layer of epithelial cells that lines the inner wall of blood vessels. Not only that, excessive levels of homocysteine in the blood promoteinflammation and increase oxidative stress-two other factors involved in atherosclerosis. As if that were not enough, hyperhomocysteinemia is also associated withhypertension.

Here, then, is what having high homocysteine entails: more risks to blood vessels, the heart, and the brain. About the latter, some studies also suggest a link between high homocysteine and neurological problems; in particular, some evidence suggests that there is a direct relationship between high basal homocysteine and brain atrophy, and an association between hyperhomocysteinemia and cognitive decline has been reported. 

In fact, there still remains some doubt about the link between hyperhomocysteinemia and cognitive decline (it is thought, in fact, that a vitamin deficiency might come into play); nevertheless, high homocysteine is also widely considered a risk factor for dementia and Alzheimer's disease.

In addition, still on the subject of diseases that affect more frequently in old age, high homocysteine is considered an independent risk factor for fractures due toosteoporosis in both women and men.

Finally, high homocysteine can lead to complications in pregnancysuch as difficulties in fetal development, placental abruption, pre-term delivery, and miscarriages (as mentioned, including recurrent miscarriages). In addition,high homocysteine in pregnancy may be associated with disorders in turn associated with hypertension, particularly preeclampsia.

High homocysteine in pregnancy: what to do?

At this particular stage of a woman's life, those at the expense of hyperhomocyteinemia can be the blood vessels of the placenta, the organ that supplies blood (and thus nutrients and oxygen) first to the embryo and then to the fetus.

The hypothesis is that malfunction of the epithelium lining the blood vessels-in this case those of the placenta-is also at play here. And in this case, too, the baby's brain may also be at the expense.

In particular, high levels of homocysteine during the third trimester of pregnancy could limit oxygenation of the brain, affecting its structure. In addition, the fetus' central nervous system could pay the consequences of oxidative stress induced by high homocysteine, associated with increased inflammation of blood vessels.

Therapy for high homocysteine

Treatment of high homocysteine is based ontaking folic acid. Effective doses range from 0.2 to 15 mg per day, also in the form of dietary supplements. But what is the best supplement for high homocysteine?

In fact, not all forms of folic acid are equally bioavailable and not all are utilized in the same way by the body. For example, to be utilized, the synthetic form dihydrofolate (DHF) must first be converted to tetrahydrofolate (THF), which only later will be converted to 5-10-methylenetetrahydrofolate (5-10-MTHF). Finally, 5-10-MTHF will be used by the enzyme MTHFR to produce methyl tetrahydrofolate, which is used to convert homocysteine to methionine and thus reduce hyperhomocysteinemia. 

From this point of view, the new generation folic acids may offer advantages. For example, Quatrefolic® corresponds to methylfolate, thus the biologically active form of folic acid; moreover, its bioavailability is three times higher than that of classical folic acid. 

When taking a folic acid supplement, it is important to take all these factors into consideration if only to figure out what dosage is most appropriate.

It should also be mentioned that although folic acid is considered the main nutrient responsible for homocysteine levels,supplementation with vitamin B12 and vitamin B6 could also be beneficial. According to data reported in the scientific literature, supplementation with between 0.5 and 5 mg of folic acid per day reduces plasma homocysteine levels by 25 percent; the addition of 0.4 mg per day of vitamin B12 helps reduce them by another 7 percent, while the addition of vitamin B6 could be helpful after the methionine loading test.

High homocysteine: the recommended diet

Regarding the most suitable diet in cases of high homocysteine, it is important to ensure avaried and balanced diet by making sure to include sources of B vitamins, which, being soluble, are not stored by the body and therefore must be constantly taken in food.

Folic acid is present in foods in the form of folates. The main sources are green leafy vegetables, such as spinach, chicory, and broccoli, but it is also present in red lettuce, peppers, porcini mushrooms, legumes, nuts, and some cereals (barley) or pseudocereals (quinoa). Sources of animal origin include liver, duck meat and chicken (thighs), eggs, salmon, mussels, shrimp, and some cheeses (e.g., gorgonzola and the like).

In contrast, vitamin B12 is found only in foods of animal origin, particularly liver, herring, salmon and sea bass, sole and cod, mussels and clams, white and red meat (chicken and rabbit thighs, beef, lamb). Among cheeses, mozzarella, fontina, gruyere and provolone, for example, are rich in it.

Finally, vitamin B6 is found in nuts, legumes, liver, poultry, fish and shellfish, and some cheeses (such as feta, camembert, and brie).

Beware also of cooking methods: best, as much as possible, to reduce the time or temperature to avoid heavy losses of these valuable nutrients. The ideal? Steam cooking!

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