**3.2 Other disease states**

Hyperhomocysteinemia occurrs in a wide range of unrelated diseases as depicted in Table 1.

Over the past 15 years, there has been an explosion in the number of scientific articles describing an association between homocysteine and vascular disease. Hyperhomocysteinemia has been linked to an increased risk of cardiac events; sudden death; stroke; coronary- carotid- cerebral- and peripheral-arterial diseases. It is also implicated in transplant coronary artery disease and essential hypertension (Dinesh, 2004). In general, retrospective analyses show that for every 4 µM rise in homocysteine levels, the relative risk for cardio vascular disease increases by 1.3 to 1.4 (Nygard et al. 1997a). Data obtained from (COMAC-European concerted Action Project (Graham et al., 1997), which studied patients with vascular disease and control subjects, confirmed that homocysteine levels more than 12 µM increased the risk for all types of atherotrombotic vascular disease. So, after a thorough review of the available literature, hyperhomocysteinemia should be considered an independent risk factor for cardiovascular disease.


Table 2. Common diseases associated with high homocysteine levels (Hultberg et al., 1993; Pettersson et al., 1998; Bolander-Gouaille, 2001; Hultberg, 1993).

#### **3.3 Lifestyle factors**

Pathophysiology and Clinical Aspects of 22 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

in these homozygotes there is a frequent development of atherothrombotic complications during young adulthood, which often are fatal. Mudd and colleagues estimated that approximately 50 percent of untreated homocystinuria patients will have a thromboembolic event before the age of 30 and that the disease-related mortality is approximately 20 percent

Other abnormalities of the remethylation cycle that are associated with hyperhomocysteinemia include genetic methionine synthase deficiency and genetic

Genetic mutations in MTHFR are the most commonly known inherited risk factor for elevated homocysteine levels. To have any detrimental effect, mutations must be present in both copies of a person's MTHFR genes (Varga et al., 2005). (1) A point mutation in the coding region for the 5,10-MTHFR binding site (C677T), leading to the substitution of an alanine to a valine effectively increases homocysteine levels increase and decreases methionine levels or (2) A1298C another common point mutation of the MTHFR gene, both affect the enzyme activity catalyzing the vitamin B12–dependent remethylation of homocysteine to methionine. C677T homozygotes carry the double TT (thermolabile) allele of the enzyme MTHFR gene of which the enzyme activity is reduced to 35% of the normal (Schriver et al., 1995), and having an average homocysteine level of 19.7 µM. In CT heterocygotes this is 10.3 µM, while for CC unaffected this is 10.0 µM. Further, data show that people with C677T TT have 21% increased risk of ischemic heart disease; in those with

Aproximally 10% to 20% of Caucasians carry the TT allele, whereas the remaining 80% - 90% carry either the CT or CC alleles. Black subjects have a very low frequency of carring the TT allele. The C677T mutation does have different regional incidences in Europe where the German and Italian populations show different incidences of 24.5% and 43.8%

Hyperhomocysteinemia occurrs in a wide range of unrelated diseases as depicted in Table 1. Over the past 15 years, there has been an explosion in the number of scientific articles describing an association between homocysteine and vascular disease. Hyperhomocysteinemia has been linked to an increased risk of cardiac events; sudden death; stroke; coronary- carotid- cerebral- and peripheral-arterial diseases. It is also implicated in transplant coronary artery disease and essential hypertension (Dinesh, 2004). In general, retrospective analyses show that for every 4 µM rise in homocysteine levels, the relative risk for cardio vascular disease increases by 1.3 to 1.4 (Nygard et al. 1997a). Data obtained from (COMAC-European concerted Action Project (Graham et al., 1997), which studied patients with vascular disease and control subjects, confirmed that homocysteine levels more than 12 µM increased the risk for all types of atherotrombotic vascular disease. So, after a thorough review of the available literature, hyperhomocysteinemia should be considered an independent risk factor for

disorders of vitamin B12 metabolism both impairing methionine synthase activity.

CT the risk is increased by only 6% (Dinesh -K, 2004).

(Mudd et al., 1970).

respectively.

**3.2 Other disease states** 

cardiovascular disease.

From a public health viewpoint, it is important to identify modifiable factors that influence the plasma homocysteine concentrations. The next lifestyle factors may have an effect on plasma homocysteine concentration (Bolander-Gouaille, 2001):

#### **3.3.1 Smoking**

Smoking is associated with vascular disease and other complications related to homocysteine (Bolander-Gouaille, 2001). The number of cigarettes smoked a day was one of the strongest determinants of homocysteine levels (Nygard et al., 1995). In women, the increase of plasma homocysteine levels was about 1% per each cigarette smoked, and in men about 0.5%. The mechanisms by which smoking increases the homocysteine levels may be manifold, however there is some experimental evidence that nicotine directly affects the methylation reactions. Besides, in smokers catabolism of folate has been suggested(Godin & Crooks, 1986).

#### **3.3.2 High alcohol intake**

High alcohol consumption is often associated with gastrointestinal disturbances, which may result in decrease absorption of vitamins (the most important is folic acid), thus contributing to elevated homocysteine levels. Alcohol has also been reported to inhibit methionine synthase (MS), to decrease hepatic uptake and increase excretion, mainly via urine (Barak et al., 1993). The decreased concentration of serum folic acid may occur in 80% of alcohol abusers and this can lead to serious clinical consequences.

Hyperhomocysteinemia: Relation to Cardiovascular Disease and Venous Thromboembolism 25

Use drugs: e.g.: phenytoin, carbamazepine, methotrexate, aminoglutethimide

osteoporosis, ulcers, diabetes, heart conditions, high blood pressure, thrombosis, cancer

It has been recognized, since the first description of hyperhomocysteinemia, that arterial and venous thrombosis are common in these patients. Patients with homocysteinuria suffered of thrombotic events, cerebrovascular occlusions, deep vein thromboses, myocardial infarctions and peripheral vascular thromboses (Mudd et al., 1985) of which a quarter of all thrombotic events occured before the age of 16 and half before the age of 28, much earlier in life than would normally be expected for these types of events. Further, patients with CBS deficiency-induced homocysteinuria have high levels of plasma homocysteine (Carey et al., 1968). Interest in the hyperhomocysteinemia condition increased when a large number of studies (mainly retrospective) showed that also mildly elevated homocysteine levels are associated with venous thromboembolism (VTE), thrombotic stroke, and peripheral vascular disease (Wilcken & Wilcken, 1976, Mudd et al.,

To conclude, mild hyperhomocysteinemia can be induced by a variety of risk factors of which the most common genetic factors are heterozygous CBS gene defects and polymorphism in the MTHFR gene at position 677, while as well numerous aquired

Digestive problems, auto-immune diseases, asthma, eczema, arthritis,

Table 3. Common risk factors inducing mild hyperhomocysteinemia

**4. Venous thromoembolism and hyperhomocysteinemia** 

**MOST COMMON RISK FACTORS** 

Deficients of folate, vitamin B6 and B12

 Physical inactivity / sedentary life-style Drinking caffeinated drinks - coffee, tea, coke

 Post menopausal status Drinking alcohol

Often angry or suppress anger

*Inherited*  CBS deficiency MTHFR deficiency MS deficiency Being male *Aquired*  Aged 40 +

Smoking

 Being pregnant Being strict vegetarian High fat/protein diet intake

1985, Moll, 2004).

conditions might be involved (Table 3).

 High diet salt intake Hypothyroidism

Chronic kidney problems

Suffering from chronic illnesses
