The Homocysteine Threat



 

It has been called the mysterious killer, appearing in cases of atherosclerosis that show no signs of elevated serum cholesterol, diabetes mellitus or hypertension—it's homocysteine. (McCully, l 990) Homocysteine is an amino acid that can be deadly if it is not properly metabolized. There are two nutrient dependent enzymes which convert homocysteine to methionine or cysteine, and when there is a defect with these enzymes, homocysteine levels can rise. (Malinow, 1990) In the past 20+ years, research has shown that elevated homocysteine, or hyperhomocysteinaemia, is linked to atherosclerosis, pregnancies complicated by neural tube defects, early pregnancy loss and venous thrombosis. (Bakker, 1997)

The risk of vascular disease is 30 times greater in people with high homocysteine levels. (Ross, 1997) Although it is projected that 5% of the general population has moderately elevated homocysteine (Bakker, 1997), hyperhomocysteinaemia has particularly affected postmenopausal women, the elderly and individuals with folate, vitamin B6, and vitamin B12 deficiencies. (Stabler, 1997; Gupta, 1997; Malinow, 1990)

The Missing Link

Questions began as numerous patients became afflicted with cardiovascular disease even though they lacked the "normal" risk factors, such as high cholesterol, diabetes mellitus, obesity and hypertension. Enter the Homocysteine Theory.

In a 1990 study of 194 consecutive autopsies performed on atherosclerosis victims, researchers concluded that approximately two-thirds of the patients developed severe atherosclerosis without evidence of elevated serum cholesterol, diabetes or hypertension. Their explanation was elevated homocysteine. (McCully, 1990) Another observation was made in Ireland, where mortality rates for coronary heart disease in men is about three times higher than in France. While conventional risk factors did not account for the difference, plasma levels of homocysteine were significantly higher in the Irish than the French. (Manilow, 1996) When homocysteine is elevated, arteriosclerotic lesions can form which can cause intimal injury, calcium deposition and elastin degeneration within the arterial wall. (McCully, 1990)

It has been suggested that supplementation of folic acid could prevent approximately 13,500-50,000 deaths caused by coronary artery disease annually. (Boushey, 1995)


The Role of Folate

Low levels of folate have been found to be inversely correlated with homocysteine. Data shows that high plasma homocysteine levels and low plasma folate and vitamin B12 levels are associated with a higher prevalence of coronary artery disease, especially in older men and women. (Aronow & Ahn, 1997) Numerous publications support the importance of folate in lowering homocysteine levels.

The folate dependent enzyme, methylenetetrahydrofolate reductase (MTHFR), is a crucial enzyme for the remethylation of homocysteine to methionine. (Bostom et al., 1996) In a 1996 study, folic acid supplementation (on patients with chronic renal failure) lowered plasma homocysteine levels significantly. (Chauveau et al., 1996) In a meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid and homocysteine published in JAMA, 1995, researchers concluded that higher folic acid intake reduces homocysteine levels and "promises to prevent arteriosclerotic vascular disease". (Boushey, 1995)

In order for folic acid to be effective, however, levels of vitamin B 12 (cobalamin) must be normal.

Often, patients with a B12 deficiency have elevated homocysteine levels as well as methylmalonic acid levels.

This is especially prevalent in the elderly. (Stabler et al., 1997)

It is believed that vitamin B 12 can correct methionine synthase abnormalities, which is theorized to be a major metabolic pathway that converts homocysteine to methionine. (Mills et al., 1996) A paper published by the National Institutes of Health in 1996 discusses the critical part vitamin B12 plays along with folic acid in regulating the homocysteine levels in periconceptual mothers, thereby preventing neural tube defects. (Mills et al., 1996)

Vitamin B6

Vitamin B6 (pyridoxine) also works to lower homocysteine like vitamin B12 and folic acid. Pyridoxine is necessary for homocysteine to convert to cysteine through the transsulfuration pathway. A 1996 study concluded that patients deficient in vitamin B6 can not convert homocysteine to cysteine causing levels to escalate. Therefore, vitamin B6 deficiency is an independent risk factor associated with vascular disease. (Ubbink, 1996)


Betaine (Tri-methylglycine)

One of the newest focuses of treatment for homocystinuria is trimethylglycine (TMG), also called Betaine (not MCI). TMG is considered a "methylation enhancing compound" which helps homocysteine convert to methionine. In a 1993 study on patients with elevated homocysteine, the therapy with TMG in addition to pyridoxine, folate and cobalamin supplementation significantly reduced homocysteine plasma levels with no side effects during the two years in which treatment was monitored. Interestingly, on the cases where combined folate, pyridoxine and Cobalamin did not dramatically lower homocysteine, adding TMG had significant effects. (Monatero et al., 1993) Along with lowering homocysteine, TMG is said to lower VLDL's increase muscle mass and decrease fat content. (Franker, 1997) Research is ongoing and the results on this beneficial nutrient may be revolutionary in homocysteine maintenance.

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References:
Aronow, W.S. & Ahn, C., "Association between plasma homocysteine and coronary artery disease in older persons." American Journal of Cardiology 80:9 (November 1, 1997): 1216-8.
Bakker, R.C., Brandjes, D.P., "Hyperhomocysteinaemia and associated disease." Pharm World Science 19:3 (June 1997): 126-32.
Bostom, A.G., et al., "Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients" Atherosclerosis 123:1 -2 (June 1996): 193-202.
Boushey, C.J., et al., "A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes [see comments]" JAMA 274:13 (October4, 1995): 1049-57.
Chauveau, P., et al., "Long term folic acid but not pyridoxine supplementation lowers elevated plasma homocysteine level in chronic renal failure" Mineral and Electrolyte Metabolism 22:1-3 (1996): 106-9.
Frankel, Paul, Ph.D., TMG Breakthrough Specialty Laboratories (1997).
Gupta, A. ~ Robinson, K., "Hyperhomocysteinaemia and end stage renal disease" Journal of Nephrology 10:2 (March-April 1997) 77-84.
Koehler, K.M., et al., "Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women" Journal of American College of Nutrition 15:4 (August 1996): 364-76.
Malinow, M.R., M.D., "Hyperhomocysteinemia: A Common and Easily Reversible Risk Factor For Occlusive Atherosclerosis" Circulation 81(1990): 2004-6.
Manilow, M., et al., "Plasma homocysteine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease" Atherosclerosis 126: 1 (September 27, 1996): 27-34.
McCully, Kilmer, S.D., "Atherosclerosis, Serum Cholesterol and the Homocysteine Theory: A Study of 194 Consecutive Autopsies" The American Journal of the Medial Sciences 299:4 (April 1990): 217-221.
Mills, J.L., et al., Journal of Nutrition "Homocysteine and neural tube defects" 126:3 (Marchl996) : 756S-760S.
Monatero Brens, C., et al., "Homocystinuria: effectiveness of the treatment with pyridoxine, folic acid, and betaine" An Esp Pediatr 39: 1 (July 1993): 37-41.
Ross, Gary, M.D., "Deadly Amino is Factor in Health Problems" Journal of Longevity Research 3:8 (1997): 16-17.
Stabler, S.P.; Allen, R.H.; Lindenbaum, J., "Vitamin B-12 deficiency in the elderly: current dilemmas." American Journal of Clinical Nutrition 66:4 (October 1997): 741-9.
Ubbink, J.B., "The role of vitamins in the pathogenesis and treatment of hyperhomocysteinaemia." Journal of Inherit Metabolic Disorders 10:2 (June 1997): 316-25.
Ubbink, et al., "The effect of a subnormal vitamin B-6 status on homocysteine metabolism [see comments]" Journal of Clinical Investigation 98:1 (July 1, 1996): 177-84.

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