Doctors call it hyperhomocysteinemia, but it is better known as “high homocysteine.” What levels should worry you? And how to lower them? 

«I have high homocysteine: should I worry?» Indeed, hyperhomocysteinemia is considered a risk factor for cardiovascular health, and not only that. Some associate it with cystitis and some warn about possible dangers to bones. It could also cause significant problems during pregnancy. Let’s try to understand when it is necessary to take action and how to do it.

What is homocysteine?

Homocysteine is an amino acid, but not one of the “classic” amino acids – those with which proteins are synthesized. Rather, it is a derivative of one of these, methionine.

The process of producing homocysteine from methionine involves the removal of a methyl group, that is, a set of carbon and hydrogen atoms. The addition of a methyl group allows methionine to be obtained again from homocysteine; this process, called “remethylation,” closes a true 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, we speak of:

• 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.

The causes that can lead to an increase include:

• genetic factors;
• pathological conditions (for example, kidney diseases);
• lifestyle (including diet).

In particular, there is a close association between increased homocysteine and the 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 converting homocysteine into methionine.

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

Vitamin B6, on the other hand, is important because it participates in the conversion of homocysteine into cysteine – another reaction that influences blood homocysteine levels.

Furthermore, since the production of 5-methyl THF requires the activity of the MTHFR enzyme (methylenetetrahydrofolate reductase), which transforms dietary folates, mutations in this enzyme can also lead to increased homocysteine in the blood.

The symptoms of high homocysteine vary depending on its cause. Sometimes, the condition is completely asymptomatic; in the presence of B vitamin deficiencies, it may be associated with fatigue, numbness or tingling in the limbs, weight loss, and dementia. Additionally, hyperhomocysteinemia may be linked to osteoporosis and hip fractures, cognitive decline, chronic renal failure, hypothyroidism, Alzheimer’s disease, and schizophrenia, and associations have been found between high homocysteine and anxiety, headaches, or muscle problems.

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

High homocysteine: consequences

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

In particular, having high homocysteine means a greater risk of atherosclerosis. This means that in hyperhomocysteinemia it is easier for so-called atherosclerotic plaques to form, that is, deposits of cholesterol and inflammatory cells in the walls of blood vessels that can grow to block or rupture, generating clots that, carried by the blood, can block blood flow far from the site of formation. 

The consequences of such events can be very serious, such as heart attacks or strokes. High homocysteine increases these risks by damaging the endothelium, the layer of epithelial cells lining the inner walls of blood vessels. Moreover, excessive homocysteine levels in the blood promote inflammation and increase oxidative stress – two other factors involved in atherosclerosis. As if this were not enough, hyperhomocysteinemia is also associated with hypertension.

So, having high homocysteine means more risks for blood vessels, heart, and brain. Regarding the latter, some studies also suggest a link between high homocysteine and neurological problems; in particular, some evidence suggests a direct relationship between high baseline homocysteine and brain atrophy, and an association between hyperhomocysteinemia and cognitive decline has been reported. 

In fact, some doubt remains about the link between hyperhomocysteinemia and cognitive decline (it is thought that vitamin deficiency might be involved); nevertheless, high homocysteine is considered by many also a risk factor for dementia and Alzheimer’s disease.

Furthermore, still on diseases more frequent in old age, high homocysteine is considered an independent risk factor for fractures due to 'osteoporosis both in women and men.

Finally, high homocysteine may lead to complications in pregnancy, such as fetal development difficulties, placental abruption, preterm birth, and miscarriages (including recurrent ones). Moreover, high homocysteine in pregnancy may be associated with disorders linked to hypertension, especially preeclampsia.

High homocysteine in pregnancy: what to do?

In this particular phase of a woman’s life, the blood vessels of the placenta may suffer from hyperhomocysteinemia; the placenta is the organ that supplies blood (and thus nutrients and oxygen) to the embryo first and the fetus later.

The hypothesis is that in this case too, the dysfunction of the endothelium lining the blood vessels – in this case those of the placenta – plays a role. And here too, the baby’s brain could suffer.

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

Therapy for high homocysteine

Treatment for high homocysteine is based on the intake of folic acid. Effective doses range between 0.2 and 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 used in the same way by the body. For example, to be used, the synthetic form dihydrofolate (DHF) must first be converted into tetrahydrofolate (THF), which is then converted into 5-10-methyltetrahydrofolate (5-10-MTHF). Finally, 5-10-MTHF is used by the MTHFR enzyme to produce methyl-tetrahydrofolate needed to convert homocysteine into methionine and thus reduce hyperhomocysteinemia. 

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

When taking a folic acid supplement, it is important to consider all these factors even just to understand the most suitable dosage.

It should also be said that although folic acid is considered the main nutrient responsible for homocysteine levels, supplementation with vitamin B12 and vitamin B6 may also be useful. According to data reported in scientific literature, supplementation with folic acid doses between 0.5 and 5 mg per day reduces plasma homocysteine levels by 25%; adding 0.4 mg per day of vitamin B12 helps reduce them by another 7%, while adding vitamin B6 may be useful after a methionine load test.

High homocysteine: recommended diet

Regarding the diet recommended in case of high homocysteine, it is important to ensure a varied and balanced diet paying attention to include sources of B vitamins, which, being water-soluble, are not stored by the body and therefore must be constantly consumed with foods.

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

Vitamin B12, instead, is present only in animal foods, particularly liver, herring, salmon, sea bass, sole, cod, mussels and clams, white and red meat (chicken and rabbit thighs, beef, lamb). Among cheeses, mozzarella, fontina, gruyere, and provolone are rich sources.

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

Attention should also be paid to cooking methods: it is better, when possible, to reduce cooking times or temperatures to avoid large losses of these precious nutrients. The ideal? Steam cooking!

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