Hyperhomocysteinemia (in blood) and Homocysteinuria (in urine) has been known for approximately 30 years.(1,3) Hyperhomocysteinemia, which will be discussed here extensively, is elevated blood plasma level of total homocysteine (tHcy). The tHcy is considered elevated when levels are >15umol/L in blood serum. Patients with hyperhomocysteinemia commonly have tHcy levels of 250umol/L.(2) Normal levels of tHcy has been determined to range from 6.1-15.0umol/L.(6)
Patients with elevated blood levels of tHcy, in several studies, has indicated in having an increased risk in cardiovascular, peripheral vascular and cerebrovascular disease.(1,2,4) Hyperhomocysteinemia has been estimated to be in 5% of the general population, and 13-47% of patients with diagnosed symptomatic atherosclerotic vascular disease, also have hyper- homocysteinemia.(1) The causative agents for hyperhomocysteinemia are deficiencies in folate (folic acid), vitamin B12, vitamin B6, a genetic disposition or even kidney problems.(1) This paper will discuss the metabolism of homocysteine and how hyperhomocysteinemia causes an increased risk in cardiovascular, peripheral vascular and cerebrovascular disease.
Homocysteine (Hcy) is a sulphydryl-containing amino acid by-product that comes from the demethylation of methionine. The major source of methionine is from animal protein.(1,3) In the plasma, Hcy is available in four forms. Hcy can circulate as a free thiol, is disulphide-bound to plasma proteins such as albumin, combined with itself to form a dimer, or bound with other thiols such as a cysteine. These four forms of homocysteine will be referred to as total homocysteine (tHcy).(1) tHcy is metabolized by remethylation or trans-sulphuration.(5)
Methionine is converted to homocysteine through two intermediates: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH).(5,7,8) Methionine demethylation begins with its reaction with ATP and the presence of methionine adenosyltransferase to form SAM.(8) This sulfonium ion is highly reactive and makes it an important biological methylating agent by donating its methyl group to a variety of acceptors such as guanidinoacetate, nucleic acids, neurotransmitters, phospholipids, and hormones.(9) With the presence of methyltransferase, SAM transfers the methyl group to one of many acceptors just mentioned, and is converted into SAH. SAH is then hydrolyzed into adenosine and homocysteine, with the presence of homocysteine hydrolase and water. Homocysteine is then ready for remethylation or trans-sulphuration. This process of remethylation or trans-sulphuration, is carried out in the liver, the kidneys or other tissue cells.(5,7,8,9)(See Figure 1)
In remethylation, a methyl group is donated to homocysteine and is converted to methionine. This reaction is catalyzed by an enzyme called homocysteine methyltransferase. The enzyme requires two cofactors, these are vitamin B12 and N5-methyltetrahydrofolate (N5-MTHF), which is the methyl donor. N5-MTHF depends on the concentrations of N5,N10-MTHF, which comes from the dietary intake of folate (folic acid), and the enzyme N5,N10-MTHF reductase (MTHFR).(1,5,6,7,8,9)(See Figure 2)
Trans-sulphuration, the other tHcy metabolism pathway, occurs when the methylation pathway is saturated or when levels of the amino acid cysteine is required. tHcy is condensed with serine to form cystathionine and gives off a water molecule, by the enzyme cystathionine beta-synthase (CbS). An essential cofactor for CbS is vitamin B6. Cystathionine is then hydrolyzed to cysteine and alpha-ketobutyrate by gamma-Cystathionase.(1,5,6,7,8,9) This reaction uses a water molecule and gives of an amino group. Alpha-ketobutyrate continues along a degradative pathway to propionyl-CoA and then to succinyl-CoA.(7)(See Figure 2)
There is a genetic disposition that inhibits the metabolism of tHcy. This includes a homozygous autosomal recessive genetic defect in the CbS structure. This genetic defect occurs 1 in 100,000 births and has resulted in increased levels of tHcy as high as 40 times from normal in patients. Symptoms include, lens dislocation and other ocular complications, intellectual disability, skeletal deformations, premature atherosclerosis and premature vascular (atherothrombotic) events (1,4). When untreated, vascular events occur in half of the affected people before age 30. Another form is an asymptomatic heterozygous defect in the CbS structure, which occurs 1 in 150 people. In this asymptomatic condition, tHcy serum levels are normal and the risk factors involved are still under investigation. Genetic defects can also occur in the enzyme MTHFR, in homocysteine methyltransferase, or in the intrinsic factor for vitamin B12 absorption.(1)
There are many other factors that inhibits the metabolism of tHcy. One of the factors is dietary deficiencies. When dietary intake of folate, vitamin B12, and vitamin B6 are low or absent, there is a higher risk for hyperhomocysteinemia. Studies have shown that when hyperhomocysteinemia exists, two-thirds are related to a deficiency in one or more of these vitamins. Chronic renal disease is another factor that can be a cause of hyperhomocysteinaemia. The excretion of tHcy has a minor effect in the kidney. However, the kidneys play a major role in the metabolism of tHcy. When the kidneys are diseased, it can cause an increase in tHcy, which causes cardiovascular complications. Levels of tHcy are also affected by various drugs or diseases that corrupt the cofactor metabolism. These effects can increase the tHcy levels.(1)
Studies have shown that there are high levels of tHcy in patients with a preexisting cardiovascular disease, as compared with people without cardiovascular disease.(2) Many studies linked conditions such as atherosclerosis, arteriosclerosis, atherothrombotic vascular events, cardiovascular disease and coronary heart disease to elevated levels of tHcy.(1,2,4) The mechanism to which tHcy may cause vascular damage is unclear, and still need further testing. tHcy may directly promote the proliferation of vascular smooth muscle, by increasing DNA synthesis of Cyclin A Gene synergistically. There are two types of cells that constantly replace themselves in the lining. An A type cell and a B type cell, which both replicate alternately. The increased DNA synthesis by tHcy induces only one cell type to replicate. This uncontrolled replication may be located in one area, which causes the build-up of cells within the lining of the blood vessels. Thus, promoting atherosclerosis. tHcy also alters the coagulation cascade by shortening the life of platelets. tHcy also impairs the endothelium vasomotor regulation of nitric oxide (NO) by forming S-nitroso-homocysteine. This formation of S-nitroso-homocysteine takes away form the NO pool and doesn't allow normal vasodilation of smooth muscle. This also inhibits sulfhydryl-dependent, which is a protective factor against tHcy, from generation of free oxygen radicals. However, after extreme and chronic exposure to tHcy, this action eventually promotes disease by causing oxidative injury to endothelial lining of blood vessels by production of peroxides, from free oxygen radicals.(1,4,8,9,10,11)
Hyperhomocysteinemia can be treated with a multivitamin supplementation. More than 90% of patients have positive response and signs of improvement can be seen in 2-6 weeks. The vitamins involved are folate(folic acid), vitamin B12 and vitamin B6. Folate can be found in fortified cereals, bread, fruits and vegetables. Folic acid is the single most effective treatment for hyper-homocysteinaemia. This vitamin is needed in the synthesis of N5-methyltetrahydrofolate(MTHF). MTHF is needed as a cofactor to homocysteine methyltransferase, which methylates homocysteine into methionine.(1) Vitamin B12 can be found in meats, seafood and dairy products(3). Vitamin B12 is needed in the proper function of the enzyme homocysteine methyltransferase. Vitamin B6 can be found in vegetables and whole grains (3). Vitamin B6 is a cofactor with the enzyme, cystathionine beta-synthase(CbS), which is involved in the metabolism of homocysteine to cysteine.(1,5,7) Dosages of vitamin supplement in the treatment of moderate hyperhomocysteinaemia is about 400ug/day of folic acid, about 400ug/day of vitamin B12 (only 1-3% of recommended 2ug/day is absorbed orally by simple diffusion), and about 10-50mg/day is recommended for vitamin B6. High doses of vitamin B6 for extended period of time can cause neurological disorder, which causes symptoms such as night restlessness and too vivid dream recall. Therefore supplementation of these vitamins should be carefully monitored by the healthcare physicians of the patient with hyperhomocysteinaemia.(1,2)
In conclusion, high levels of homocysteine plays a major role in cardiovascular disease. This increased level of homocysteine can be caused by genetic defects or dietary deficiencies. Treatment of vitamin supplementation reduces the levels of homocysteine and thus lowers the risk of cardiovascular disease.(1,2) Although, this homocysteine theory was founded almost 30 years ago by Kilmer McCully(3), the idea is relatively new to the scientific community and has sparked an interest in many research groups around the world.
1) Hankey, G.J and Eikelboom, J.W. July 31, 1999. Homocysteine and vascular disease. The Lancet 354(9176): p407.
2) Christen, W.G.; Ajani, U.A.; Glynn, R.J. and Hennekens, C.H. February 28, 2000. Blood Levels of Homocysteine and Increased Risks of Cardiovascular Disease. Arch. of Int. Med. 160(4): p422-434.
3) Wright, Karen. Dec 1999. The Clot Thickens. Discover 20(12): p40.
4) Langman, Loralie J. Et Al. April 10, 2000. Hyperhomocysteinemia and the Increased Risk of Venous Thromboembolism. Arch. of Int. Med. 160(7): p961-964.
5) Bender, David A. (1985) Amino Acid Metabolism, 2nd Edition. John Wiley & Sons, Inc., New York.
6) The Merck Manual, 17th Edition (1999), Merck Research Laboratories, Division of Merck & Co., Inc., Whitehouse Station, N.J.
7) Voet, Donald and Voet, Judith G., (1995) Biochemistry, 2nd Edition. John Wiley & Sons, Inc., New York.
8) Fonseca, V; Guba, S.C and Fink, L.M., 1999, Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis. Endocrine Reviews. 20(5):738
9) D'Angelo, A and Selhub, J. July 1, 1997. Homocysteine and Thrombotic Disease. Blood 90(1): 1-11
10) Ling, Q. and Hajjar, K.A. 2000, Inhibition of Endothelial Cell Thromboresistance by Homocysteine. Journal of Nutrition. 130:373S-376S
11) Tsai, Jer-Chia, et al. January 1996. Induction of Cyclin A Gene Expression by Homocysteine in Vascular Smooth Muscle Cells. J. Clin. Invest. 97(1): 146-53
Copyright © 2001 James Graham and Koni Stone
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