Causes of
Hyperhomocysteinemia
How does Homocysteine
cause Atherosclerosis
Role of Vitamins in Treatment
Homocysteine is an amino acid which is mainly synthesised in the body from Methionine. When Kilmer McKully in 1969 for the first time tried to link atherosclerosis with Homocysteine, he was severely castigated and had to lose his job for the ‘outlandish’ hypothesis proposed by him. Today after thirty years we have realised the importance of his pathbreaking observations. Now we know that 5 to 7 % population have atleast mild homocysteinaemia.
Diet contains negligible amount of homocysteine, most of it being derived from demethylation of Methionine. So the blood levels are dependent mainly on the indigenous synthesis.Once formed in the body it can be metabolised by one of the two routes viz. remethylation to Methionine and trans-sulfuration to Cystathionine.
Methionine------------> Homocysteine
Folic acid + B12
Homocysteine------->Cystathionine
Vit B6
So Vitamin B12, Vitamin B6 and Folic acid are important coenzymes for the reactions involved in metabolism of Homocysteine.When serum Homocysteine is measured its metabolites are also measured along with.
Serum measurements are not easily measurable so far. Studies have shown an inverse relationship between serum homocysteine and levels of Folic acid, Vtamin B12 and Vitamin B6. Back to Top
Causes of Hyperhomocysteinemia
Congenital:
-
Enzyme deficiencies
Nutritional:
- Folic Deficiency
- Vitamin B6 Deficiency
- Vitamin B12 Deficiency
Drug Induced:
- Methotrexate
- Phenytoin, Carbamezapine
- Nitrous Oxid
- Theophylline
- Cholestyramine,niacin
- Contraceptive pills
Systemic Illness:
- Chronic Renal Failure
- Systemic Lupus Erythematosus
- Hypothyroidism Back to Top
Association between hyperhomo-cysteinemia and atherosclerosis is well established as can be gauged from the following bar diagram. Incidence of hyperhomocysteinemia is quite high in the three major types of atherosclerosis. Relative risk of Cerebrovascular atherosclerosis, Coronary atherosclerosis and Peripheral Vascular atherosclerosis is much higher in persons with hyper-homocysteinemia.
How does homocysteine cause atherosclerosis:
Exact mechanism of association of Hyperhomocysteinemia and atherosclerosis remains to be fully elucidated. however the following observations have been made:
Effect on Vascular Endothelium:
- Homocysteine gets auto-oxidised to homocystine in plasma producing several reactive oxygen species which cause endothelial damage
- It supports oxidation of LDL through generation of superoxide amino radiacals.
- Reduced synthesis of Prostacycline could predispose to thrombosis.
Effect on Platelets:
- It increases platelet adhesiveness.
Effects on Clotting factors:
- Reduced Amtithrombin activity has been reported
- It also enhances activities of factor XII and factor V and depressed the activation of protein C.
- It also inhibits the expression of thrombomodulin, induces the expression of tissue factor and suppressed the expression of heparin sulfate by the endothelium. Back to Top
Role of Vitamins in Treatment
It is desirable to bring down the level of Homocysteine to 9 to 10 micromols/L. As much as fourteen interventions have shown decrease in the levels after administration of folic acid in a wide range of doses.400 micrograms of folic acid seems to be sufficeint to achieve the desired effect. Diet alone is seldom sufficient achieve this intake.
Vitamin B12 is generally given along with folic acid for treatment and is known to be effective. It should be given to patients with homozygous hyper-homocysteinemia. Persons with B12 malabsorption should be given injectable form.
Vitamin B6 is also useful for treatment either alone or with Folic acid and Vitamin B12.
So combined Vitamin therapy seems an attractive treatment option. Back to Top