What is it?

Hyperhomocysteinemia consists in an excessive concentration of homocysteine in our bloodstream. Homocysteine 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 homocysteine which may in turn damage the walls of our blood vessels. When the plasmatic levels of homocysteine 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.

Can hyperhomocysteinemia 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.


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 through 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 that involve vitamin B6.

A number of group B vitamins such as folate (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 kidney 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 caused by 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 folate 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, ?-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 through 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 aaforementioned factors, hyperhomocysteinemia is considered an important risk factor for the development of some really severe pathologies.

Homocysteine and vascular diseases

Clinical and epidemiological studies showed a correlation between high homocysteine and vascular diseases.

Cardiovascular diseases: hyperhomocysteinemia is considered a risk factor for coronary atherosclerosis and myocardial infarction (Wald, 2006). A group of patients with high cardiovascular risk, and worsened further by high values of homocysteine, is the population of subjects who underwent heart transplant; it appears in fact that hyperhomocysteineimia developed after a transplant may facilitate graft atherosclarosis, one of the main limitations for these patients' long term survival (Ambrosi, 1994)

Cerebrovascular diseases: hyperhomocysteinemia is responsible for a damage to small cerebral arteries. A recent study (Martilelli, 2003) has proven that patients with hyperhomocysteinemia show a risk factor 4 times higher than normal to suffer from cerebral venous sinus thrombosis.

Cerebrovascular stroke: many studies proved a significant correlation between this amino acido blood concentration and ischemic cerebral events (Wald, 2006). Homocysteine, in fact, causes cerebral atheromoatosis, also responsible for ischemic events involving not yet well known mechanics, surely increasing the production of free radicals, vases' internal wall lesions and a thickening of the muscle wall. In a more recent study (Lu Hao, 2013) a group of researchers decided to find out if high homocysteine levels and hyperlipidemia in the bloodstream may together have a synergic effect and increase the risk of a stroke. The result of their restrospective analysis lasted 5 years (2007-2012) confirmed the hypothesis: patients with high level of homocysteine and lipids (cholesterol and tryglicerides) in the bloodstream, equal to other risk factors, had a forty percent higher chance of facing a stroke compared to a control group with normal values. The coexistence of hyperhomocysteinemia and hyperlipedimia thus has a negative synergic effect.

Peripheral vascular pathologies such as arterious and venous thrombosis and specifically deep venous thrombosis, a diseases that generally attacks the lower limbs with the following risk that the clot migrates to the lungs causing a pulmonary embolism (Den Heijer, 1996), are also related to hyperhomocysteinemia.

Cardiac small vessel disease (CSVD): in a recent study (Kloppenborg, 2014) it has been proven that homocysteine (which promotes endothelium disfunction through various processes) has a role in the development of the small vessel generalized disease, involving both the brain and kidney. The same authors commented that the function may be regulated with a vitamin treatment and therefore represent a potential target for the therapy. Moreover the significant association of high level of tHcy (total homocysteine) with CSVD progression appears to be stronger in patients with a history of cerebrovascular disease, indicating that these patients are the most vulnerable to the homocysteine effects and CSVD progression.

Abodminal Aorta Aneurysm (AAA): a recent metanalysis study (Takagi, 2014) has shown the link between homocysteine levels and abdominal aorta aneurysm. A series of analysis has demonstrated a substantial increase in global homocysteine levels in the group with AAA compared to the control group and another analysis group proved a statistically significant increase in AAA incidence for subjects with hyperhomocysteinemia

Homocysteine and hypertension

High homocysteine, a cardiovascular risk factor may act, as stated above, as both a direct (helping atherosclerosis) and indirect risk factor, meaning facilitating atherosclerosis complications, one of which is actually arterial hypertension

A few studies suggest that homocysteine may act in the development of hypertension, and as such may provide a potential connection mechanism with homocysteine and vascular diseases. Experimental facts proved that high homocysteine levels cause negative effects on the NO vasodilator, on the proliferation of smooth muscle cell, alter endothelial function, vascular wall elasticity and kidney function. Because physiological factors such as peripheral resistence, arterial stiffness and kidney function are factors determining blood pressure, it would be reasonable to foresee a connection between homocysteine and blood pressure (Wilson, 2010).

Homocysteine and neurodegenerative diseases

Dementia and Alzheimer's disease

Since 1998 it has been speculated that there was a correlation between homocysteine and dementia: in patients with Alzheimer's disease histological diagnosis, global hymocysteine levels actually higher than normal were found. Even the radiological evidence of white matter lesions, silent cerebral infarcation and cerebral cortex and hippocampus atrophia were positevely associated to high homocysteine concentrations and cognitive damages. From a study (Seshadri, 2002) emerged, moreover, that hyperhomocysteinemia is an undesputable risk factor for the development of both dementia and Alzheimer's disease. Furthermore it has been observed that hyperhomocysteinemia is particularly frquent in older subjects, often exposed to therapies capable of interfering with sulfur amino acids metabolism, or suffering from pathological conditions or in case of socio-enviromental situations, responsible for bad nutrition, often the foundation of those vitamin deficit that represent a very common cause of homocysteine plasmatic levels increase. Clinical and epidemiological data prove how, in elderly patients with MCI (Mild Cognitive Impairment) hyperhomocysteinemia linked to cerebral microangiopathy is frequently present. The elderly cerebropathic patient with cognitive impairment (memory, awareness disorders and dyslexia) may represent group B vitamins deficit states responsible for the degeneration of nerve cells. Studies show, in fact, that the supplementation of group B vitamins (especially B6, B12 and B9) reduces neurodegeneration.

Parkinson's disease

Moderate homocysteine plasmatic levels (twice higher than normal) have been observed in patients suffering from Parkinson's disease in treatment with levodopa.

Hyperhomocysteinemia is probably caused by a higher production of S-Adenolsyl-L-homocysteine during the levodopa metabolism. How this represents a vascular risk factor in these patients or determines a cognitive decline is not yet fully clear, even if in a clinical study (Rogers, 2003) it's been observed a signicative correlation between hyperhomocysteinemia and vascular disease in patients treated with levodopa.

Homocysteine and epilepsy

Low plasmatic levels of folic acid and high homocysteiene levels have been observed in epileptic patients in pharmacological treatment with anticonvulsant drugs. It's not yet fully clear, however, how much hyperhomocysteinemia in these patients represents a risk factor for vascular pathologies or defines a lowering of the edge of the convulsive seizure (Paknahad, 2012).

In another recent review (Belcastro, 2012) it's concluded that, for patients who assume antiepileptic drugs, supplementation of 400 mcg of folic acid, low dosages of vitamin B2, B6, and B12 for the treatment of folates deficit and for the reduction of homocysteine serum levels is absolutely recommended.

Homocysteine and menopause

Sexual hormones affect homocysteine concentrations. Men have higher levels of homocysteine than women of the same age. These levels however increase in women in menopause. This makes postmenopausal women face a higher risk of incurring a cardiovascular event. Hormonal therapy and folic adic consumption reduce plasmatic homocysteine by 10-15% (De Leo, 2004).

Homocysteine and diabetes

Epidemiological data available up till today seem to show that the diabetic disease, both type 1 and type 2, does not itself affect homocysteine plasmatic levels. The presence of nephropathies however, because of reduced amino acid extrection and catabolism, almost always goes along with hyperhomocysteinemia and this may explain, at least in part, the elevated cardiovascular risk of nephropathic diabetics. Not yet clear are the connections between diabetic retinopathy and neuropathy and homocysteine, while it seems that macroangiopathy is connected to increased global homocysteine levels and that hyperhomocysteinemia may cause a higher risk of vascular thrombotic disease and mortality in diabetic population compared to non-diabetic subjects. (Russo, 2013). In a recent study (Sudchada, 2012) it's been proven that folic acid supplementation in patients with type 2 diabetes mellitus, compared to placebo, may reduce the global homocysteine levels and is connected to a trend that leads to a better glycemic control.

Homocysteine and kidney failure

Chronic renal insufficiency (CRI) is very frequently connected to an increase in homocysteine plasmatic levels, that may well be considered a new uremic toxin. Uremic patients hold a mortality rate caused by cardiovascular diseases 30 times higher than the general population (the risk varies according to the considered age range). This condition cannot be entirely explained by common tratidional risk factors (hypercholesterolemia, hypertension, smoke, diabetes, etc.) or those factors characteristic of uremia (hyperparathyroidism, anemia, hypoalbuminemia, etc.). Hence the interest of the scientific community in other risk factors, such as hyperhomocysteinemia. Hyperhomocysteinemia is also a cardiovascular risk factor with the highest prevalence: it's found in 90-95% of CRI cases. Homocysteine levels increase when the kidney function declines and progresses to uremia. In CRI hyperhomocysteinemia begins to appear when the glomerular filtration rate decreases under 70 mL/min.

But what are the causes of hyperhomocysteinemia in kidney failure? In theory, causes of an increase of homocysteine may be connected to: 1) increased production 2) reduced metabolism 3) reduced excretion. The most plausible hypothesis, at this stage of the studies, is a reduction of homocysteine removal by the kidney or other organs. (Satta, 2006)

Homocysteine and erectile dysfunction

The correlation is evident and important because hyperhomocysteinemia is connected to a vascular damage which may be the cause of erectile dysfunction.

Erectile deficit mst not be considered a separate “disease” because it may be the sign of a vascular problem meaning it may be the first clinical manifestation that may later show with cardiac ischemic or cerebrovascular events. Endothelial dysfunction caused by hyperhomocysteinemia involves a reduced endothelial secretion of nitroc oxide (NO), the main mediator of vasodilation. Erection requires an NO-mediated vasodilation; hyperhomocysteinemia, by inhibiting NO endothelial synthesis, may be the causal factor of an erectile dysfunction by hypoafflux, which may regress after the normalization of plasmatic homocysteine. Furthermore a study suggests that hyperhomocysteinemia may concurr to the genesis of thrombotic events, like low flow priapism or superficial deep vein thrombosis of the penis. In the last few years it's been highlighted that the urologist may be the first medical figure to obsverve signs and symptoms that lead to suspect and diagnose a polidistrectual arteriopathy, which, adequately examined, may reveal a latent coronaropathy.

Similarly, it may happen that the urologist may be the first physician to diagnose a hyperhomocysteinemia, examining the pathogenesis of an erectile dysfunction or penile thrombotic events. (Chierigo, 2011)

Homocysteine and retinal vein occlusion

The occlusion of the retinal vein circulation (RVO) is a disorder frequently found by retinologists and this pathology is second only to diabetic retinopathy as the cause of secondary vision loss to vascular diseases of the retina. Retinal vein occlusion is a relatively frequent event that may cause anatomic damages and different functionals: from light forms, that involve low caliber vessels, that may cause minimal functionals alterations, to dramatic forms of central ischemic vein occlusion that may compromise the visual function and rsult in devastating complications such as neovascular glaucoma. Risk factors that predispose to RVO are many and generally are the same found in vascular alterations that involve other body districts such as in the case of stroke or coronaropathies. Among these there are those that involve the thrombophilic state and therefore hyperhomocysteinemia as well. Many studies have by now demonstrated that there is a statistically significant connection between hyperhomocysteinemia presence and central retinal vein occlusion, central retinal artery occlusion and non-arteritic anterior ischemic optic neuropathy, disease in which it's been recently found a significant increase of homocysteine levels in the plasma. Similarly the alterations of the fundus oculi consisting in caliber and vessel development variations should be caused by a parietal damage of the vessels caused by the homocysteine's action. In the patients with hyperhomocysteinemia a careful ocular follow-up is essential not only to promptly find retinal artery and vein occlusions but also to diagnose and early treat alterations of the field of view and of the fundus oculi in order to prevent or anyway delay the lesion progession.

Homocysteine and migraine

The connection between migraine and hyperhomocysteinemia involves, in particular, migraine with aura; studies on caucasian populations have hypothesized that the mutation of the C677T gene of the MTHFR may influence the susceptibility of a subject to migraine with aura, The vessel wall disfunction (endothelium), in association with high values of homocysteine, may be the foundation of the activation mechanism and the insurgency of migraine for direct damage caused by homocysteine on the endotheium and on the vascular oxidative state. It appears, in fact, that homocysteine may worsen oxidative stress.

Some experimental data suggest that endothelial dysfunction linked to hyperhomocysteinemia may be involved in the beginning and the upkeeping of the migraine pain during the attack. In fact, it's been observed that the fraction of trigeminal neurons that respond to pain increases in relation to the application of the L-homocysteic acid, a substance that mimics the homocysteine action. It's also suspected a comorbodity migraine/cerebral ischemia, because it's supposed that homocysteine may play an important role in the cerebral circulation disfunction which, during oligoemia spreading, may be responsible for cerebral infarction.

Homocysteine and auditory system disorders

Sudden hypoacusis, dizzines and tinnitus are often referable to lesions happened in one of the areas of anatomic competence of the vestibulocochlear microcircle, with selective or total damage of the receptor areas. Sudden deafness may be caused by vascular disorders that facilitate te alteration of the cochlear perfusion. Several pro-thrombotic risk factors have been considered in the pathogenesis of the vascular damage, and it's been recently suggested the possible role of genetic alterations. Among these, MTHFR gene polymorphisms that lead to a homocysteine increase, may be involved in the pathogenesis of sudden deafness. (Capaccio, 2005)

Homocysteine and psoriasis

It is known that various drugs used for the systemic treatment of psoriasis may influence its prognosis because of several side effects, some of which of cardiovascular nature. Among these it's been demonstrated that the use of methotrexate increases plasmatic homocysteine levels.

Hyperhomocysteinemia, cardiovascular independent risk factor, seems to have a role in the link between psoriasis and cardiovascular diseases. It is known that abnormal values of plasmatic homocysteine promote oxidative stress and the consequent endothelial dysfunction, aside from contributing to a pro-thrombotic state through an increase in plasmatic fibrinogen. A study on patients affected by psoriasis has proven not only higher levels of homocysteine in the bloodstream compared to the controls, but has also shown that hyperhomocysteinemia directly connects with the severity of psoriasis. The same study has also highlighted the inverse correlation between plasmatic homocysteine values and folic acid levels. The authors have therefore theorized that hyperhomocysteinemia in patients with psoriasis is determined by an acid folic deficiency, probabily caused by an excessive consumption in the increased cutaneous turnover. Finally, the psoriatic disease seems to be determined by a platelet hyperactivity, which would facilitate, along with hyperhomocysteinemia, a prothrombotic state. The latter seems to diminish with clinical psoriasis remission. (Vestita, 2010)

Homocysteine and autoimmune rheumatic diseases

High serum levels of homocysteine may be considered risk factors for cardiovascular diseases in patients with rheumatoid arthritis (RA), as well as in patients with systemic lupus erythematosus. Homocysteine may cause an endothelial damage and it's been proven a correlation between increased homocysteine levels and higher ischemic cardiopathy risk, cerebral stroke and carotid atherosclerosis.

Homocysteine has a direct toxic action on endothelial cells, increases LDL oxidation and has a prothrombotic effect. Increased homocysteine levels have been demonstrated in patients with RA. Methotrexate – one of the most used and effective drugs for the treatment of patients with AR - reduces folate plasmatic and erythrocytic levels, with consequent increase of homocysteine levels for a reduction of Methylenetetrahydrofolate reductase. In this respect, during the treatment with methotrexate it's always recommendend an integration with folic acid, as this practice prevents the toxicity by methotrexate and hyperhomocysteinemia. In LES hyperhomocysteinemia is associated with increased effects of arterial thrombosis. (Limonta M.)

Homocysteine and hypothyroidism

If untreated, thyroid disorders may cause significant consequences to the heart: even small variations of thyroid hormone phyiological levels may cause a heart problem. Some thyroid diseases, such as Hashimoto thyroiditis (an autoimmune disease that causes an inflammation of the thyroid and resulting hypothyroidism), have been connected with an increased risk of hypercholesterolemia, arterial hypertension, atherosclerosis, cardiac disease and stroke.

Even atrial fibrillation seems to be strictly linked to thyroid disease. Other complications may be pericardial effusion (liquid gethering in the pericardial sack) and high homocysteine values, an event connected to an increase of cardiovascular risk.

Homocysteine and celiac disease

Celiac disease is a severe and frequent disease caused by gluten intolerance. The disease is caused by an immunitary reaction in the intestine against these proteins with consequent destruction of the intestine cells and malabsorption. Because of malabsorption, in people who suffer from celiac disease there often is a deficit of: iron, zinc, B-group vitamins, vitamin K and other substances. A recent study (Hadithi, 2009) has confirmed the frequent and real deficit of folic acid and vitamin B12 and homocysteine increase in celiac disease even if ignored. It also shows that the integration with folic acid and vitamin B12 actually leads to the “normalization” of the concentrations in the bloodstream of these micronutrients in patients who suffer from celiac disease. Celiac disease represents a clear case in which normal nutrition is unable to assure normal supply of micronutrients, vitamins, iron, oligoelements etc. and in which the integration acquires great clinical and therapeutic importance.

Homocysteine and Crohn's disease

Crohn's disease is a chronic inflammation that may in theory hit all the alimentary canal, mouth to anus, but is mostly localized in the last part of the small intestine called ileum (ileitis) or colon (colitis) or both (ileocolitis).

The intestinal tracts affected show inflammation, swelling and ulcers that affect the whole thickness of the intestinal wall. Because of the malabsorption it is not rare that patients may incur vitamin deficit; especially group B vitamin deficit may lead to an increase in plasmatic homocysteine levels. (Spina, 2008)

Homocysteine and depression

Hyperhomocysteinemia may cause a neurotransmitter alteration with consequent depression. The increase of plasmatic homocysteine, acknowldeged as a functional marker for both folate and vitamin B12, has been recognized in the depressed and, in a vast-scale Norwegian study, it's been linked to a higher risk of depression, but not anxiety. In depression it is safe to acknowledge the substantial evidence of a folate, vitamin B12 reduction and its related plasmatic homocysteine increase. Moreover, to further support what stated above, we must note that MTHFR C6771 polymorphysm, which alters the homocysteine metabolism, has been proven in depressed patients. Finally it should be noted that low folate levels may indicate a poor response to antidepressants and that folic acid treatment is indicated in order to improve their action (Di Lascio, 2012)

Homocysteine and cancer

A study published on the New England Journal of Medicine demonstrated that cancer is more likely caused by diet and lifestyle rather than personal genetic heritage. What role does homocysteine play in this setting? Cancer is provoked by damages to the DNA and the presence of high homocysteine levels makes DNA more vulnerable to damages not easily repairable once damaged. On the other side it's been shown that homocysteine concentration is a great indicator of antitumor therapy effectiveness. Homocysteine increases when the tumor grows and decreases when it regresses. Among the forms of cancer mostly connected to high homocysteine levels are breast, colon cancer and leukemia. By reducing homocysteine levels it is possible to reduce the risk of these diseases by a third. (Holford, 2008)

Homocysteine and drugs

Shown below are drugs that may cause an increase in plasmatic homocysteine levels.

FIBRATE – It has been discovered (Dierkes, 2004) that the consumption of some fibrates (class of hypolipemiant drugs) can cause hyperhomocysteinemia. In particular fenofibrate and bezafibrate increase by 20 to 40% plasmatic homocysteine levels. The problem seems to be caused by an alteration of the creatine-creatinine metabolism and in mutations of the methyl group transfer. This effect has not been found when using gemofibrozil (a hypolipemiant drug) and statins. Homocysteine increase after the intake of fenofibrate may be reduced with the consumption of folic acid, vitamin B6 and B12.

METFORMIN – long term metformin treatment (a drug used for the treatment of diabetes) increases the risk of lack of vitamin B12, which leads to an increase in homocysteine concentrations. Therefore, because vitamin B12 is predictable, during long term metformin treatment regular measuring of vitamin B12 concentrations must be considered, which in case must be supplemented.

Other drugs that may cause a lack of vitamin B12 and therefore risk of an increase in homocysteine plasmatic levels are:

  • Esomeprazole + Lansoprazole, Pantoprazolo + Rabeprazole for the treatment of duodenal and gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome, symptomatic gastroesophageal reflux disease and ulcers connected to prolonged therapies with steroidal anti-inflammatory drugs.
  • Esomeprazole + Naproxen for the treatment of signs and symptoms of arthrosis, rheumatoid arthrtitis and ankylosing spondylitis in patients at risk of developing FANS ulcers.
  • Glibenclamide + Metformin, Linagliptin + Metformin, Metformin + Pioglitazone, Metformin + Sitagliptin and Metformin for the treatment of type 2 diabetes.
  • Octreotide for relief from symptoms related to functional gastroenteropancreatic neuroendocrine tumors.
  • Omeprazole for therapy aimed at gastric pathologies, such as ulcer and gastroesophageal reflux disease (GERD), aside from the prevention from possible gastric lesions caused by the consumption of FANS drugs.
  • Ropinirole for the treatment of Parkinson's disease.


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.


Cattaneo M. Hyperhomocysteina, Atherosclerosis and Thrombosis. Thromb Haemost 1999; 81: 165-76.Cetin I., Berti C., Calabrese S. Role of micronutrientes in the periconceptional period. Human reproduction Update, vol.0, n.0 pp. 1-16, 2009.De Leo V, la Marca A, Morgante G, Musacchio MC, Luisi S, Petraglia F. Menopause, the cardiovascular risk factor homocysteine, and the effects of treatment. Department of Pediatrics, Obstetrics and Reproductive Medicine, Institute of Obstetrics and Gynecology, University of Siena, Siena 53100, Italy.Durga j. at al. Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age. Lancet 2007, Jan 20; 369 (9557); 166-7. Leopardi P, Marcon F., Caiola S., Siniscalchi E., Zijno A., Crebelli R. Il polìmorfismo della metilenetetraidrofolatoreduttasi 677C-T e l’interazione con acido folico e riboflavina. Workshop- Network Italiano Promozione Acido Folico-Prevenzione Primaria di Difetti Congeniti. Istituto Superiore di Sanità Roma, 5 ottobre 2007.Lonn E, Yusuf S, Arnold MJ et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567-77. Erratum in: N Engl J Med 2006;355(7):746.McCaddon A., Hudson P., Davies-G., Hunghes A., Williams J.H. Homocysteine and cognitive decline in healty elderly. Dementia and geriatric cognitive disorders, Sep-oct 2001, vol.12 n.5: 309-13.McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004;350(20):2042-9. Ripa R., Ripa S. Omocisteina: un fattore di rischio cardiovascolare trascurato. Progress Nutrition 2003 Vol. 5, n. 3, 248-261. Russo G.T., Cucinotta D. Iperomocisteinemia e rischio cardiovascolare nel diabete mellito. Ann Ist Super Sanità 2003;39(2):153-163.Van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004;350(20):2033-41.Verhoef P., Stampfer MJ, Buring JE, at al. Homocysteine metabolism and risk of myocardial infarction. Relation with vitamins B6, B12 and folate. Am, J. Epidemiol 1966; 143:845-59.Wald D., J. K. Morris, M. Law, N. J. Wald. Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ vol. 333 25 Nov. 2006.Satta E., Perna A.F., Lombardi C., Acanfora F., Violetti E., Romano M.M., Capasso R.; Pisano M., Paduano F., De Santo N.G. L’iperomocisteinemia nell’insufficienza renale cronica: aspetti clinici, nutrizionali e tossicità. Giornale Italiano di Nefrologia/Anno 23 n. 5, 2006/pp. 480-489.Finocchiaro P., Zoccali C.. Iperomocisteinemia e progressione dellenefropatie. Giornale Italiano di Nefrologia / Anno 22 n. 6, 2005/pp. 590-596.Chierigo P., Dedola S.,. Taccola M.C, Saugo M., Rossetto L., FranzolinN. Quadri clinici andrologici in pazienti con iperomocisteinemia. Journal of Andrological Sciences. Vol. 18, N.1, March 2011. pp 42-43.Bandello F., Varano M. Documento di Consenso: Gestione dei Pazienti con Diagnosi di Occlusione Venosa Retinica. IRCCS Fondazione G.B. Bietti per lo Studio e la Ricerca in Oftalmologia – Istituto Scientifico Universitario San Raffaele.Cretì A., Scenna G., De Notaris M., Brancaccio V., Giuliani C., De Rosa P. Manifestazioni oculari in pazienti con iperomocisteinemia . Fonte: neurologa Elena Guaschinio dell’IRCCS Mondino di Pavia. Pubblicazione 02/2010 su Cefalee Today.Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83. Antonio Siniscalchi. Iperomocisteinemia nelle malattie neurologiche. RpM Programma periodico di Educazione Medica Continua Vol. 95, N. 7-8, Luglio-Agosto 2004. Dierkes J, Westphal S,Luley C. The effect of fibrates and other lipid-lowering drugs on plasma homocysteine levels. Expert Opin Drug Saf. 2004 Mar;3(2):101-11. Hadithi M., Mulder C., Stam F., Azizi .J, Crusius J., Peña A., Stehouwer C., Smulders Y. Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. World J Gastroenterol 2009 February 28; 15(8): 955-960.International Task Force for Prevention Of Coronary Heart Disease: Coronary heart disease and stroke: Risk factors and global risk. Homocysteine, heart disease and stroke http://www.chd-taskforce.de/pdf/sk_homocysteine.pdf. Ding R., Lin s, Chen D. The association of Cystathionine ßSynthase (CBS) T833C polymorphism and the risk of stroke: A meta-analysis. Journal of the Neurological Sciences 312 (2012) 26–30.Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with L-dopa. Arch Neurol 2003. 60:59–64.Siniscalchi A., Gallelli L., Mercuri N. B., Ibbadu G., and De Sarro G. Role of lifestyle factors on plasma homocysteine levels in Parkison’s disease patients treated with levodopa. Nutritional Neuroscience (2006), 9:1, 11 – 16.Sudchada P, Saokaew S, Sridetch S, Incampa S, Jaiyen S, Khaithong W. Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2012 Oct;98(1):151-8. doi: 10.1016/j.diabres.2012.05.027. Epub 2012 Jun 22.Satta E., Perna A.F., Lombardi C., Acanfora F., Violetti E., Romano M.M., Capasso R., Pisano M., Paduano F., De Santo N.G.L’iperomocisteinemia nell’insufficienza renale cronica: aspetti clinici, nutrizionali e tossicità. Giornale Italiano di Nefrologia / Anno 23 n. 5, 2006 / pp. 480-489. Chierigo P., Dedola S., Taccola M.C., Saugo M., Rossetto L., Franzolin N. Quadri clinici andrologici in pazienti con iperomocisteinemia. Journal of Andrological Sciences Vol. 18 No. March 2011. Cretì A., Scenna G., De Notaris M., Brancaccio V., Giuliani C., De Rosa P. Manifestazioni oculari in pazienti con iperomocisteinemia. www.farmigea.it Vento Claudio. Corso di Neuroanatomia: comorbidità malattia cerebrovascolare/emicrania: correlati anatomici. Università Degli Studi Di Roma “La Sapienza” anno 2003-2004.Capaccio P, Ottaviani F, Cuccarini V, Ambrosetti U,Fagnani E, Bottero A, Cenzuales S, Cesana BM, Pignataro L. Le mutazioni del gene della metilentetraidrofolato-reduttasi (MTHFR) quali fattori di rischio per la sordità improvvisa. iAm J Otolaryngol. 2005 Nov-Dec;26(6):383-7.Vestita M., Cassano N., Vena G.A. Associazione tra psoriasi e rischio cardiovascolare: cosa c’è di nuovo? 2010 – http://www.tuttosanita.it/ArchivioDocumenti. Limonta M. Rischio cardiovascolare nelle malattie reumatiche autoimmuni. http://www.cardiometabolica.org. Di Lascio G., Di Lascio S. Depressione come malattia sistemica I° – Folati omocisteina e depressione. Notiziario Gennaio 2012 N°1 http://www.associazioneamec.com/notiziario-amec/anno-2012/272-notiziario-gennaio-2012-nd1-depressione-come-malattia-sistemica.html?start=13. Patrick Holford. Manuale di nutrizione familiare ed. tecniche Nuove 2008. Cap. 16. Ambrosi P, Barlatier A, Habib G, Gargon D. Hyperhomocysteinemia in heart transplanted recipients. Eur Heart J 1994; 15: 1191-1196. Den Heijer M., Koster T. Blom H.J., Bos G. M.J., Briët E., Reitsma P.H., Vandenbroucke J. P. and Rosendaal F.R.. Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis N Engl J Med 1996; 334:759-762March 21, 1996DOI: 10.1056/NEJM199603213341203. C. P. Wilson, H. McNulty, J. M. Scott, J. J. Strain and M. Ward. The MTHFR C677T polymorphism, B-vitamins and blood pressure. Proceedings of the Nutrition Society (2010), 69, 156–165. Zamzam Paknahad,1,2 Ahmad Chitsaz,3 Akbar Hasan Zadeh,1,2 and Elham Sheklabadi. Effects of Common Anti-epileptic Drugs on the Serum Levels of Homocysteine and Folic Acid Int J Prev Med. 2012 March; 3(Suppl1): S186–S190.