Controlling High Homocysteine Levels… And The Diseases They Cause
Homocysteine is a byproduct of the metabolism of the essential amino acid methionine, which is found principally in red meat and dairy products. High homocysteine levels have been associated with increased risk of coronary artery disease, high blood pressure, hip and other bone fractures, rheumatoid arthritis, diabetes, and other serious chronic diseases. Although these are all very dangerous diseases, to the degree that they are caused or aggravated by elevated homocysteine levels, they can be remarkably easy to treat by consuming adequate amounts of foods and especially supplements containing folic acid (folate), vitamin B12 (cobalamin), vitamin B6 (pyroxidine), and betaine (trimethylglycine),* all of which combine to minimize homocysteine levels.
It should come as no surprise that homocysteine levels tend to increase with age. At least part of the reason for this may be nutritional. Absorption of both folate and vitamin B12 from food sources, which is the body’s primary defense against rising homocysteine levels, is dependent on the presence of normal quantities of stomach acid to free them from their food carriers. Unfortunately, stomach acid secretion tends to decline with age1 due to atrophic gastritis (or gastric atrophy), a condition in which the stomach cells that secrete digestive acid die off. As the pH in the stomach and intestines rises (and acid levels decline), folate and vitamin B12, which would normally be absorbed via the small intestine, simply pass through the colon and out of the body in the feces.
About 20% to 50% of elderly people are affected by nutrient deficiencies resulting from naturally occurring atrophic gastritis. In addition, many people take drugs such as proton pump inhibitors (PPI), including Nexium®, Prilosec®, Prevacid®, and others, which reduce the secretion of stomach acid to near zero, further impeding the absorption of folate, vitamin B12, and other nutrients.2, 3 If you’re taking any of these drugs, you can be fairly certain you’re not absorbing enough folate, vitamin B12, and many other nutrients, which may make you vulnerable to a wide range of serious diseases, as described below. (For a complete discussion on the detrimental effects of low stomach acid levels on nutrient absorption and other health issues, please see the book by Drs. Jonathan V. Wright and Lane Lenard, Why Stomach Acid is Good for You.2)
The key to controlling runaway homocysteine levels is to convert the amino acid back to the harmless amino acid methionine, from whence it came, a normal process known as remethylation. To accomplish remethylation, the body requires adequate amounts of folic acid (folate), vitamin B12 and vitamin B6, and sometimes betaine (trimethylglycine). In the absence of these cofactors, homocysteine can easily accumulate to toxic levels.
Elevated homocysteine levels have now been clearly identified as a risk factor for coronary heart disease, putting it in the same class as more familiar risk factors, such as cholesterol, obesity, smoking, and a sedentary life style. While high levels of homocysteine have been linked to heart attacks and strokes, even mild elevations can significantly increase the risks of cardiovascular events.4
Numerous studies have examined the role of folic acid in countering homocysteine-induced cardiovascular damage. For example, in patients with coronary heart disease, folate improves the functioning of the endothelial lining of coronary arteries, the smooth, delicate tissue where dangerous plaque can form. At least some of the benefits of folate ingestion in heart disease patients may be independent of its effects on homocysteine. For example, some research suggests it may reduce intracellular levels of superoxide, an especially dangerous oxygen free radical.5-7
Not surprisingly, high homocysteine levels have also been linked to hypertension (high blood pressure), possibly due to endothelial cell injury caused by homocysteine, among other factors.8-12 A recent study has confirmed that intake of relatively large amounts of folate significantly decreased the risk of hypertension.13 This study, which was published in the Journal of the American Medical Association, drew upon data from two very large prospective cohort studies: the Nurses’ Health Study II, which included 93,803 younger women aged 27 to 44 years and the Nurses’ Health Study I, which included 62,260 older women, aged 43 to 70 years. None of these women had a history of hypertension at the start of the study. Using questionnaires, the researchers assessed the nurses’ intake of dietary and supplemental folic acid every 4 years.
After 8 years of follow-up, they found that younger women who consumed at least 1000 µg (1 mg) per day of folic acid (dietary + supplements) had about half (0.54) the relative risk of hypertension compared to those who consumed less than 200 µg per day. Among the older women, the relative risk reduction was even greater (0.82) for the same comparison (³1000 µg/day vs £200 µg/day). Thus, the greater the folate intake, the less likely the nurses were to develop hypertension. While the study participants consumed folate from both food and supplements, the authors pointed out that the statistically significant association between folate intake and reduced hypertension risk only occurred when the nurses used folate supplements. Thus, diet alone was not sufficient to produce this beneficial effect.
Recent studies have shown that mild elevations in plasma homocysteine levels were associated with increased the risk of osteoporotic bone fractures.14, 15 Now, the results of a Japanese study published in a recent issue of the high-profile Journal of the American Medical Association16 strongly suggests that, not only do high homocysteine levels increase the risk of hip and other bone fractures, but that ingestion of folate plus vitamin B12,which combine to inhibit homocysteine production, significantly reduces that risk. The researchers administered daily doses of either folate (5 mg/5,000 µg) + vitamin B12 (1.5 g/1500 µg), or placebo to 559 patients who had one-sided paralysis (hemiplegia) due to a stroke. The patients were then monitored for 2 years.
Hip fractures in elderly people, especially those who have suffered a stroke, often occur due to frequent falls combined with osteoporosis, the bone thinning disease that results from a variety of factors, including hormonal changes, diet, and disuse. Although the number of falls was similar in both treatment groups in this study, the folate + vitamin B12group had one-quarter as many fractures as the placebo group. The number of hip fractures per 1000 patient-years was 10 in the vitamin-treated group vs. 43 in the placebo control group.
Previous studies have identified increased plasma homocysteine levels as an important risk factor for osteoporosis-related fractures.14, 15 For example, in data from the famous, long-running Framingham Study, homocysteine concentrations were nearly 4-fold higher in the highest quartile of fracture risk patients than in the lowest quartile for men and nearly twice as high for women.15
It should come as no surprise, then, that the Japanese researchers in the present study noted that plasma homocysteine levels significantly decreased from baseline in the low-fracture folate + vitamin B12 group compared to the high-fracture placebo group, where homocysteine levels significantly increased.
While osteoporotic fractures are usually associated with a thinning of the bone, as reflected in a reduction in bone mineral density (BMD), homocysteine concentrations seem to be unrelated to BMD.14, 17 The solution to this apparent paradox seems to lie in homocysteine’s ability to interfere with collagen cross-linking in bone tissue. Collagen cross-links are important for the stability and strength of the collagen network that helps hold bone tissue together. By interfering with the formation of this network, homocysteine increases bone fragility, even though BMD remains normal.18, 19 By reducing homocysteine levels, folate + vitamin B12 helps prevent the collagen network from deteriorating.
This study also clearly demonstrates the inadequacy of the US government’s recommendations (RDAs/DRIs**) for dietary folate and vitamin B12. According to the RDA/DRI, adults should be able to survive on 400 µg of folate per day and 2.4 µg of vitamin B12 per day.20 Note, however, that the doses used in this study to retard bone fractures were many times higher: 5,000 µg of folate and 1,500 µg of vitamin B12. It’s doubtful that lower doses in the RDA/DRI range, as are offered by many commercial multivitamin formulations or dietary fortifications, would be very useful for preserving bone strength. As in the hypertension study noted above, supplemental nutrients are required to produce the beneficial effects on bone health.
Homocysteine and Cognitive Function
Numerous studies have linked elevated levels of homocysteine to both vascular dementia and Alzheimer’s disease. In one recent study, increased homocysteine levels were found in 62.5% of patients with mixed dementia, 22.2% of patients with vascular dementia, 54.2% of patients with cardiovascular disease, and 41.2% of patients with other neurological diseases.21 Another study also found homocysteine levels to be a significant factor in both Alzheimer’s and vascular dementia.22
Moreover, dementia has also been associated with reduced levels of folate and in some cases vitamin B12.23-26 While considerable research needs to be done to completely understand the relationships among these factors, it appears certain that elevated homocysteine can be destructive to cognitive function in the brain and that much can be done via nutritional interventions, such as folic acid, vitamin B12, vitamin B6, and other nutrients to ward off these disastrous effects.
* Folic acid is less bioavailable from food than from supplements. Moreover, it is practically impossible to obtain enough of vitamins B6 and B12 from food short of becoming obese in the process, so sparsely concentrated are these nutrients in the food supply.
** RDA = Recommended Daily Allowance; DRI = Dietary Reference Intake
- Krentz K, Jablonowski H. In: Hellemans J, Vantrappen G, eds. Gastrointestinal Tract Disorders in the Elderly. Edinburgh: Churchill Livingstone; 1984:62-69.
- Wright J, Lenard L. Why Stomach Acid Is Good for You. New York: M. Evans; 2001.
- Wolters M, Strohle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med. Dec 2004;39(6):1256-1266.
- Mangoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. May 2002;112(7):556-565.
- Doshi S, McDowell I, Moat S, Lewis M, Goodfellow J. Folate improves endothelial function in patients with coronary heart disease. Clin Chem Lab Med. Nov 2003;41(11):1505-1512.
- Ashfield-Watt PA, Moat SJ, Doshi SN, McDowell IF. Folate, homocysteine, endothelial function and cardiovascular disease. What is the link? Biomed Pharmacother. Oct 2001;55(8):425-433.
- Doshi SN, McDowell IF, Moat SJ, et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol. Jul 2001;21(7):1196-1202.
- Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. May 13 1999;340(19):1449-1454.
- Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA.Dec 8 1993;270(22):2693-2698.
- Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. May 1 1996;143(9):845-859.
- Wall RT, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. Apr 1-15 1980;18(1-2):113-121.
- Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. Jan 1993;91(1):308-318.
- Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate intake and the risk of incident hypertension among US women. JAMA. Jan 19 2005;293(3):320-329.
- van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. May 13 2004;350(20):2033-2041.
- McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. May 13 2004;350(20):2042-2049.
- Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA.Mar 2 2005;293(9):1082-1088.
- Browner WS, Malinow MR. Homocyst(e)inaemia and bone density in elderly women. Lancet. Dec 7 1991;338(8780):1470.
- McKusick V. Heritable Disorders of Connective Tissue, 3rd ed. St. Louis, MO: Mosby; 1966.
- Jackson SH. The reaction of homocysteine with aldehyde: an explanation of the collagen defects in homocystinuria. Clin Chim Acta. May 18 1973;45(3):215-217.
- Food and Nutrition Information Center. Dietary Reference Intakes: Vitamins. US Department of Agriculture [Accessed March 21, 2005.
- Briani C, Cagnin A, Gallo L, et al. Anti-heparan sulphate antibodies and homocysteine in dementia: markers of vascular pathology? J Neurol Sci. Mar 15 2005;229-230(1):215-218.
- Gallucci M, Zanardo A, De Valentin L, Vianello A. Homocysteine in Alzheimer disease and vascular dementia. Arch Gerontol Geriatr Suppl. 2004(9):195-200.
- Campbell AK, Jagust WJ, Mungas DM, et al. Low Erythrocyte Folate, but not Plasma Vitamin B-12 or Homocysteine,is Associated with Dementia in Elderly Latinos. J Nutr Health Aging. 2005;9(1):39-43.
- Glaso M, Nordbo G, Diep L, Bohmer T. Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging. 2004;8(5):407-413.
- Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr. Jul 2004;80(1):114-122.
- Whalley LJ, Starr JM, Deary IJ. Diet and dementia. J Br Menopause Soc. Sep 2004;10(3):113-117.