Introduction
Risk factors to predict the likelihood of
heart attacks are heredity, age, cigarette smoking, hypertension, diabetes, obesity, lack of physical activity, and abnormal cholesterol levels. Increasingly newer risk factors like high levels of LDL – cholesterol, Vit E, high levels of triglycerides, insulin resistance and homocysteinaemia.
The idea that high levels of Homocysteine may be associated with heart disease started right from the late 1960’s when a pathologist Kilmer Mc Kully investigated children with homocysteinaemia, having advanced arteriosclerosis, suggested a possibility of a link between the two.
Homocysteine Metabolism
Homocysteine is a sulphur containing amino acid produced during methionine metabolism. The levels of homocysteine (Hcy) in the blood depends upon how much methionine is eaten (mainly present in animal protein) and how much is metabolized.
Homocysteine is then metabolized by remethylation or by a transulphuration pathway.
Remethlyation pathways
- The methyl group from 5 methyl Tetrahydrofolate is transferred to homocysteine. This reaction is catalyzed by Vit B12 dependant methionine synthetase.
- Methyl group from betaine is transferred to homocysteine.
Transulphuration pathways
Homocysteine is transulphurated to cystathionine. Vit B dependant cystathionine b synthase catalyzes this reaction. Cystathionine is a source of cysteine, which is required for synthesis of many major biological compounds including glutathione.
Total mean Homocysteine (tHcy) = Protein bound homocysteine + free homocysteine
The mean values for (tHcy) are about 10 mmol/l in normal subjects. The values are 10% higher in the men as compared to women and the concentration progressively rises with age.
Homocysteine measurements should be obtained while the patient is in the fasting state.
Mild Homocysteinaemia = 16 to 30 mmol/l
Moderate Homocysteinaemia = 31 to 100 mmol/l
Severe Homocysteinaemia > 100 mmol/l 1
Consequences of Hyperhomocysteinaemia
1) Homocysteine is identified as a risk factor for coronary, peripheral and cerebral vascular disease. Patients with homocysteine values in the top 5 % have a higher risk of cardiovascular or cerebral diseases than those in the lower 90 % after adjustment of other risk factors.2 Increased Hcy levels are associated with higher risk regardless of aetiology. Recent studies suggest a graded risk even in high normal range of Homocysteine, thus reduction in these subjects may also be advantageous.
It contributes to arteriosclerosis by the following mechanisms:
- It generates super oxide and hydrogen peroxide, which have been linked with damage to arterial endothelium.
- Homocysteine changes coagulation factor levels so as to encourage clot formation.
- Homocysteine prevents the small arteries from dilating so that they are more vulnerable to obstruction.
- Homocysteine cause smooth muscle cells to multiply.
- One of the reactive products of homocysteine thiolactone interacts with low-density lipoproteins causing them to precipitate and cause endothelial damage.
- Homocysteine thiolactone also causes platelet aggregation.
2) Homocysteine also causes neural damage by both excitoxicity and different apoptotic processes. There is also lot of clinical evidence available to suggest a strong relationship between high plasma Hcy levels and brain atrophy in healthy elderly subjects, as well in elderly patients with Alzheimer’s disease.3,4
Homocysteine and Women
Homocysteine levels increase in postmenopausal women. The lower homocysteine levels in pre menopausal women could be because of efficient handling of methionine through the transulphuration pathway. The higher plasma levels of oestrogen could also account for lower plasma homocysteine levels.5
In normal pregnancy homocysteine levels fall to some extent during pregnancy. Hyperhomocysteinaemia if present is an important risk factor for venous thromboembolism and is associated with adverse pregnancy outcomes such as pre-eclampsia, placental abruption, early pregnancy loss and neural tube defects.6
Aetiology of HyperHomocysteinaemia
- Genetic factors: Patient deficient in cysthathionine beta synthetase is the most common genetic basis for hyperhomocysteinaemia. Mutation in yet another enzyme i.e. 5-10 methylene tertahydrofolate reductase (MTHFR) is seen in 4-10 % of the general population.7 Patients who receive medication that interferes with folate and methionine metabolism in combination with this mutation can also cause high levels of homocysteine.
- High Homocysteine levels are also seen in malignancies of breast, ovary, and psoriasis.
- Increased Homocysteine levels are also seen because of relative dietary deficiency of folic acid. Increased levels are also seen with other factors like cigarette smoking, physical inactivity and hypertension.
Correcting Hyperhomocysteinaemia
homocysteine level of less than 10 mmol/l is usually recommended. Based on various calculation models, reduction of plasma Hcy levels may theoretically prevent 25 % of cardiovascular events.
- Eating fruits, and vegetables, cutting down on animal protein, avoiding refined carbohydrates, and consuming alcohol in moderation also hold the key to treatment. There are few randomized controlled trials where supplementation with Folic acid and Vitamin B12 intake stops the increase in atherosclerotic plaque, some data is also available that moderate to high Folate concentrations levels are associated with reduced incidence of coronary events.8
- Supplemtation of Folic acid (0.5 – 5 mg/day) reduces risk of cardiovascular disease by 25%. Additional Vitamin B12 supplementation induces further reduction by 7%. Further intake of Vitamin B6 and the combination of the above reduces further, the risk of acute myocardial infarction.9
- Trimethylglycine is a nutrient with remarkable role in tackling homocysteinaemia. It is involved in Hcy metabolism as an alternative methyl donor. Some studies recommend that use of trimethylglycine since it also improves metabolic control in B6 non-responsive patients with Homocysteinaemia even after optimum dietary control. It also increases the plasma serine and cysteine levels.10
Conclusion
There is convincing evidence that tHcy contributes to development of arteriosclerosis, probably as a casual role. Determining Homocysteine levels in our country is not routinely available and is quite expensive. Folate, B6, B12 are inexpensive. It therefore seems reasonable to supplement all patients of Coronary artery disease with B12, B6, folic acid and probably even trimethylglycine.
References
- Malinow MR, Boston AG, Krauss M. Homocysteine. Diet, and Cardiovascular Disease. A Statement From Health Care Professionals From The Nutrition Committee: American Heart Association. Circulation 1999; 99 : 178-82.
- Alfthan G, Aro A, Gray KF. Plasma Homocysteine and Ischaemic heart disease. Lancet 1997; 349-97.
- Wendell U, Bremer J.Relation of plasma Homocysteine to cerebral infarction and cerebral atherosclerosis. Stroke 1998; 2478-83.
- Bleich Sdegner D, Speling. Homocysteine as neurotoxin in chronic Alcoholism. Prog Neuropsyhopharmacol Biol Psychiatry 2004; 28 (3) : 453-64.
- Vander M, Wounter MG, Schllekens, et al. Hormone replacement decrease serum homocysteine in menopausal women. Eur J Clin Investigation 1994; 24 : 733-36.
- Sctene S, HyperHomocytenemia and pregnancy complications. Grinetol Pol 2004; 75(4): 317-25.
- Veland PM, Histad S Schneed J, et al. Biological and Clinical Implication of MTHFR 677 T polymorplism. Trends Pharmac Sci 2001; 22 (4) : 195-201.
- Tacani A, Peluchi C, Parpind M, et al. Folate & Vit B6 intake and risk of acute Myocardial infarction in Italy. Euro J Clin Nutr 2004; 58(9) : 1266-72.
- Koutolibi S Huffman Fg. Serum total homocysteine levels, folate, vit B intake and Coronary artery disease risk factors among triethnic students. Ethn Dis 2004 winter; 14 (1) : 64-72.
- Singh RH, Kruger WD, Wang L, et al. Cystathionine beta Synthase deficiency: Effects of betaine supplementation after methionine restriction in B6 non-responsive homocystinuria. Genet Med 2004; 6(2) : 90-5.
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