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NORMOCIS 400

Is a nutraceutical composed of Folic acid, vitamins B2, B6 and B12, Zinc and Betaine useful in homocysteine control. It is also suggested in the pre-conceptional period and during pregnancy to reduce Neural Tube Defect risks

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Hyperhomocysteinemia

Hyperhomocysteinemia

What is it?

Hyperhomocysteinemia consists in an excessive concentration of homocisteine in our bloodstream.Homocisteine is an amino-acid whose metabolism is regulated by the action of certain enzymes and vitamins such as vitamins B6 and B12. A lack in these vitamins may result in a buildup of homocisteine which may in turn damage the walls of our blood vessels. When the plasmatic levels of homocisteine reach elevated concentrations (higher than 12 µmol/L), we are witnessing a case of hyperhomocysteinemia.Elevated levels of this amino-acid negatively influence the functions of our nervous system, of our cardiovascular system and of our bone structure. This negative influence may take the form of an increase in the production of free radicals and of the oxidative stress which may occur because of this increase. For this reason, hyperhomocysteinemia is considered a risk factor for the development of cardiovascular diseases, cerebral diseases (it has been associated to a higher possibility of developing Alzheimer’s dementia) and bone fractures of an osteoporotic nature.

 

Hyperhomocysteinemia can be prevented?

Among the causes of hyperhomocysteinemia  are genetic and environmental factors, renal pathologies and specific conditions such as pregnancies, menopause, oral contraceptive pharmacological therapies, anti-epileptics, diuretics and major eating disorders. Many of these factors may not be modified. The patient’s lifestyle is a different story: smoking, alcohol and caffeine abuse, scarce physical activity and a diet which lacks in fruits and vegetables are considered as causes of hyperhomocysteinemia. It has been proven that the assumption of folates and of vitamins B6 and B12 can prevent the buildup of homocisteine even if the other risk factors are present. This is a valid preventive system.

 

HYPERHOMOCYSTEINEMIA: AN IN-DEPTH ANALYSIS

 

WHAT IS HOMOCYSTEINE?

Homocysteine is a non-proteic amino acid which derives from the metabolism of methionine which is in turn an essential sulfurated amino acid our organism absorbs by means of our diet (proteins). Homocysteine derives from S-adenosylmethionine (SAM) and from S-adenosylhomocysteine (SAH). The regulation of the methionine-homocysteine metabolism is based on the SAM/SAH ratio. In well functioning organisms, homocysteine is transformed back into methionine or into simple amino acids which are then easily eliminated through urine discharge. 80% of the homocysteine in our blood is related to proteins, especially to albumin. The remaining 20% of non-complex homocysteine is called “free” homocysteine. This includes both the reduced form (SH) and the oxidative form (S-S).

The produced homocysteine enters the blood stream and is mostly eliminated through urinary discharges, generally in the form of homocysteine. Homocysteine is not completely soluble in acid environments and an excess amount of it may cause radio-opaque stones in the urinary tract or dark red hexagonal crystals which may be found in the urinary discharge. If there is a reduction of the kidney functions, a reduced elimination of homocysteine through urinary discharges will occur and its plasmatic levels will increase.

The metabolism of homocysteine (and the subsequent elimination of excess amounts of it) may also occur through 2 different elimination processes:

  • Remethylation: homocysteine  may be remethylated to methionine by means of two processes which involve folic acid, vitamins B2 and B12, bethaine and zinc
  • Trans-sulfuration: homocysteine is degraded to cysteine by means of a series of processes which involve vitamin B6

A number of group B vitamins such as folic acid (vitamin B9), cyanocobalamin (vitamin B12), pyridoxine (vitamin B6), riboflavin (vitamin B2), bethaine and zinc are co-factors in the transformation process of homocysteine and are essential substances for the reduction of the plasmatic levels of this amino acid.

 

THE PLASMATIC LEVELS OF HOMOCYSTEINE

The plasmatic levels of homocysteine on an empty stomach are higher in men than in pre-menopause women by 10-20% and are then equal after menopause.Homocysteine levels increase with age by 7-12% every 10 years and increase by 2-4 times in cases of chronic renal failure (values >28 μmol/L). This increase is due more to an alteration in the metabolism rather than to a reduction in discharges and is reduced after dialysis. Homocysteine levels increase in alcoholics and in smokers (+ 20%) based on the number of cigarettes consumed every day. Certain prescription drugs (mostly anti-epileptics and diuretics) may cause an increase in the global levels of homocysteine.

Hyperhomocysteinemia occurs when there are elevated levels of homocysteine in the blood stream. It may be of 4 kinds:

  • Mild/borderline: the plasmatic level of homocysteine are of 10-12 µmoli/l
  • Moderate*: the levels are of 13-30 µmoli/l
  • Intermediate*: the levels are of 30-100 µmoli/l
  • Severe: the plasmatic level of homocysteine is higher than 100 µmoli/l. Severe cases are due to defects in the homozygote state of the genes that codify the enzymes involved in the metabolism of homocysteine (especially CBS – homocysteinuria) or to specific deficiencies in vitamin B6.

*Moderate or intermediate levels of homocysteine on an empty stomach may occur in cases of ether zygotic genetic defects in the enzymes involved in the remethylation or in case of vitamin deficits caused by nutritional deficiencies.

 

THE CAUSES OF HYPERHOMOCYSTEINEMIA

The plasmatic concentration of homocysteine is the result of a strong connection between the patient’s dietary habits and his/her genetic factors.

Nine times out of ten, elevated levels of homocysteine occur in patients due to diets which are poor in folic acid and in other group B vitamins, whereas one patient every ten shows elevated levels of homocysteine due to genetic factors.

Genetic alterations cause deficiencies in the enzymes involved in the elimination process of homocysteine. Aside from the deficit of the CBS enzyme which is due to a very rare genetic mutation (Homocystenuria*), high levels of homocysteine may be due to a mutation in the gene responsible for the production of the MTHFR enzyme (methylenetetrahydrofolate-reductase).A pretty common genetic polymorphism has also been identified as a cause of an increase in the levels of homocysteine. This polymorphism is characterized by C677T and 1298A/C mutations. Of these, the former seems to be the most important one with regards to possible thrombosis risks because it causes a 50% reduction in the enzymatic activity of MTHFR. Other genetic anomalies which may cause hyperhomocysteinemia are extremely rare such as methionine synthase deficiencies, cobalamine reductase deficiencies, methyltransferase associated with cobalamine reductase deficiencies, γ-cysthiationine deficiencies.

*Homocysteinuria is a hereditary recessive autosomal disease which is caused by a buildup of homocysteine (homocysteine dimer) as a result of alterations in the metabolism of homocysteine and methionine. It is a metabolic disease which causes early onset multi-dimensional vascular damage because of a deficiency in cystathionine-beta-synthase (CBS), a pyridoxine-dependent enzyme which is involved in the metabolic transsulphurating paths and in the metabolism of methionine. This brings on a significant increase in the haematic levels of homocysteine (>100 mcMol/L) and of methionine and reduced levels of cysteine. The typical form of homocysteinuria must be distinguished from hyperhomocysteinemia which is characterized by lower levels of homocysteine in the blood stream without genetic alterations in the CBS enzyme. The registered cases of homocysteinuria range from 1 case in 65.000 in Ireland to 1 case every 344.000 in the rest of the world.

In conclusion, many factors may be responsible for elevated plasmatic levels of homocysteine. These are:

  • genetic factors
  • physiological factors such as gender, aging, reductions in the kidney functions and hyperthyroidism
  • unbalanced diets which bring on vitamin deficiencies, vegetarian diets, vegan diets, smoking, caffeine and alcohol abuse
  • certain prescription drugs such as proton-pump inhibitors, anti-epileptics, oral birth control pills, anti-Parkinson’s drugs, methotrexate (anti-cancer drug)

 

HYPERHOMOCYTEINEMIA: RISK FACTORS AND CONNECTED PATHOLOGIES

A homocysteine buildup may cause vascular damage which involves the vascular structure and the blood coagulation process.

 

VASCULAR WALL DAMAGE

Arteries are basically composed of 2 functional parts: the smooth muscular cells and the endothelia. The smooth muscular cells can contract after a nervous impulse or because of direct influences deriving from certain substances or even because of indirect mechanisms of endothelia-dependant vessel reactivity.

In the latter case, the endothelia produces vasoactive substances. The most important vasodilatator is nitric oxide (NO) and it is produced by the endothelia by means of the metabolism of arginine thanks to a NO-synthase (NOS). Even though the data is still limited, certain studies have proven that homocysteine influences the vascular functions by means of an indirect action on the vascular tone which induces a more significant vascular contraction which is mediated by the connection between the reduced homocysteine and the nitric oxide and by the resulting production of nitrous oxide. Chronically elevated levels of homocysteine may cause a depletion of the nitric oxide and a production of nitrous oxide which circulates in the organism for 14 minutes. As a consequence, the patient will be in constant vasospasms.

By means of a direct influence, an atherosclerotic plaque is formed and the smooth muscular cells reproduce causing damage to the endothelia and a reduction in vein elasticity. This occurs because homocysteine buildups create a homocysteine-tiolactone complex which, by interacting with the LDL (low density lipoprotein), create an insoluble complex called LDL-tiolactone which is in turn phagocytized by macrophages. These macrophages are unable to divide the LDL-tiolactone complex so they turn into spongy cells which will then constitute the core of the atheroma.Homocysteine buildups may also act like oxygen-free radicals causing:

  • endothelia dysfunctions
  • necrosis of the endothelia cells with a subsequent detachment of these from the blood vessels walls
  • proliferation of smooth muscular cells with a subsequent fibrosis and fibro-calcification of the vessels
  • oxidation of the membrane lipids with a subsequent loss in functionality of these structures
  • oxidation of the LDLs which then become strongly atherogenous

 

CONSEQUENCES ON THE BLOOD PLATELETS: homocysteine buildups increase the adhesiveness and the platelet aggregation force.

 

CONSEQUENCES ON THE COAGULATION FACTORS: homocysteine buildups influence the factors which regulate blood coagulation.

Due to the above mentioned factors, hyperhomocysteinemia is considered an important risk factor for the development of some really severe pathologies.

 

HOMOCYSTEINE AND THE CARDIOVASCULAR SYSTEM

Cardiovascular pathologies: chronic atherosclerosis and myocardial strokes. Patients who have undergone cardiac transplants are sensitive to cardiovascular risk factors and are especially sensitive to risk factors related to elevated levels of homocysteine. The hyperhormocysteinemia which develops after heart transplants might favor the atherosclerosis of the graft and this is one of the most important factors which seem to limit the survival rate of transplant patients.

Cerebrovascular pathologies: cerebrovascular ictus

Peripheral vascular pathologies: such as arterial thrombosis and venous thrombosis and, more specifically, profound venous thrombosis (a disease which generally interests the lower limbs with a subsequent risk of the clot reaching the lungs causing pulmonary embolisms).

 

HOMCYSTEINE AND PREGNANCIES

Homocysteine seems to play an important role in certain pregnancy-related pathologies. Elevated levels of this amino acid have been identified in women who are subject to pre-eclampsia, premature placenta detachments and miscarriages. Moreover, elevated levels of homocysteine have been found in women who have birthed underweight newborns and in 20% of women who have birthed newborns with neural tube defects (the most common neural tube defect is spina bifida).

 

HOMOCYSTEINE AND DEMENTIA

As early as in 1998, certain studies have highlighted a possible connection between homocysteine and dementia. Elevated levels of homocysteine have been found in patients who have been diagnosed with Alzheimer’s disease. Radiological proof of white matter lesions, of silent cerebral ictus, of cerebral cortex atropism and of hippocampus atropism have been positively associated with elevated levels of homocysteine and with cognitive damage. A 2002 study also pointed out that hyperhomocysteinemia is a strong risk factor for the development of dementia and of Alzheimer’s disease. It has also been pointed out that hyperhomocysteinemia is particularly common in elderly patients who have been subject to therapies which could interfere with the metabolism of sulfurated amino acids or who have pathological conditions or even in those who live in social and environmental conditions which could be held responsible for the bad dietary habits which are quite often the main cause for vitamin deficiencies which in turn cause increases in the level of homocysteine. Clinical data and epidemiological data prove that elderly patients with first stage cognitive deficiencies (MCI - Mild Cognitive Impairment) commonly have hyperhomocysteinemia which is also related to cerebral microangiopathies.  Elderly cerebropathic patients with cognitive deficiencies (memory problems, attention deficits, dyslexia) may present lacks in group B vitamins which are to be held responsible for the degeneration of the nervous cells.Studies have proven that a dietary integration with group B vitamins (mainly B6, B12 and B9) may reduce neuro-degenerations. A 2002 study has also shown that hyperhomocysteinemia is a strong risk factor in the development of dementia and Alzheimer’s disease.

 

HOMOCYSTEINE AND DIABETES

The epidemiological data available as of today seems to show that diabetes (both of type 1 and 2) does not influence the plasmatic levels of homocysteine. The presence of nephropathies, on the other hand, is almost always associated with hyperhomocyteinemia because of the reduced excretions of this amino acid and/or because of its catabolism. This could explain the high cardiovascular risks in nephropathic diabetes patients.The connections between retinopathy and diabetic neuropathy and homocysteine are still not clear, although it seems as though macroangiopathies may be related to elevated levels of tHcy and that hyperhomocysteinemia may increase the risk of vascular thrombosis and the mortality risk in patients with diabetes.

 

HOMOCYSTEINE AND BONE FRACTURES

Hyperhomocysteinemia is also one of the causes of bone fractures due to osteoporosis. A 2004 study assesses the connection between the plasmatic levels of homocysteine and the risk of osteoporotic bone fractures. The study shows that: 1) elevated levels of plasmatic homocysteine constitute a strong and independent risk factor for osteoporotic fractures in elderly men and women and 2) the connection between hyperhomocysteinemia and fractures seems to be independent from the mineral density of the bones and from other potential risks for bone fractures.

 

Inpha2000 and the University of Pavia -Italy- have created the booklet  GUIDELINES FOR PATIENTS WITH HYPERHOMOCYSTEINEMIA which is full of information and good advice for a healty diet and a correct life-style

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