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Elevated levels of homocysteine have been associated with a number of disease states.
Elevated homocysteine is a known risk factor for cardiovascular disease and thrombosis. It has also been shown to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Homocysteine degrades and inhibits the formation of the three main structural components of arteries: collagen, elastin and proteoglycans. In proteins, homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues, affecting structure and function.
Elevated levels of homocysteine have also been linked to increased fractures in elderly persons. Homocysteine auto-oxidizes and reacts with reactive oxygen intermediates, damaging endothelial cells and increasing the risk of thrombus formation.
A study on elderly Japanese individuals who had experienced a stroke found that folate and B12 reduce the incidence of osteoporotic hip fractures.
Deficiencies of the vitamins B6, B9 and B12 can lead to high homocysteine levels.
- About 50% of homocysteine is converted back to methionine by remethylation via the methionine synthase major pathway. This requires active folate and vitamin B12, in order to donate a methyl group. Active folate is known as 5-methyltetrahydrofolate (5-MTHF).
- Another pathway for the conversion of homocysteine back to methionine also exists, involving methylation with trimethylglycine (also called betaine or abbreviated to TMG) as a methyl donor.
- The remaining homocysteine is transsulfurated to cysteine, with vitamin B6 as the co-factor.
Genetic defects in 5-MTHF reductase can consequently lead to hyperhomocysteinemia. The most common polymorphisms are known as MTHFR C677T and MTR A2756G. These polymorphisms occur in about 10% of the world's population.
The best way to prevent hyperhomocysteinemia is to eat foods which contain B6, B9, B12 and taurine, such as potatos, greens, beans, and fish. The only natural sources of B12 are from animal products. It is also found in fortified breakfast cereals and enriched soy or rice milk. Supplementation with pyridoxine, folic acid, B12, or trimethylglycine (TMG or betaine) reduces the concentration of homocysteine in the bloodstream, as does taurine supplementation.
Individuals with hyperhomocysteinemia may benefit from dietary supplementation with vitamin B6, B12, and other nutrients. Individuals with the MTHFR C677T gene polymorphism' may not respond to supplementation with folic acid because their ability to convert folic acid into its active form is impaired, and so supplementation is recommended to occur with 5-methyltetrahydrofolate instead.
N-acetyl-cysteine (NAC) has shown the ability to significantly reduce homocysteine levels. It is believed that NAC displaces homocysteine from its protein carrier in the blood, promoting the formation of cysteine.
Vitamin supplements counter the deleterious effects of homocysteine on collagen. As they inefficiently absorb B12 from food, elderly persons may benefit from taking higher doses orally such as 100 µg/day (found in some multivitamins) or by intramuscular injection.
Effectiveness of treatment
In patients who already have major disease, reducing homocysteine levels may in fact have no effect on stroke risk, the risk of a heart attack, or thromboembolic events. One study found that in patients with diabetic nephropathy, lowering homocysteine with vitamin B was in fact associated with a doubling of cardiovascular complications (heart attack, stroke, death) and a deterioration in kidney function.
Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular events. When folic acid is given as a supplement, it may increase the build-up of arterial plaque. A second hypothesis involves the methylation of genes in vascular cells by folic acid and vitamin B12, which may also accelerate plaque growth. Finally, altered methylation may catalyse l-arginine to asymmetric dimethylarginine, which is known to increase the risk of vascular disease.
Effectiveness of lowering homocysteine
Despite evidence suggesting links between elevated homocysteine and a range of conditions, several studies have found equivocal benefits in maintaining low homocystein levels. There is tentative but inconclusive evidence for congestive heart failure and bone health. However, the HOPE-2 study found a statistically significant 25% reduction in the risk of stroke.
- Guo, H; Chi, J; Xing, Y; Wang, P (March 2009). "Influence of folic acid on plasma homocysteine levels & arterial endothelial function in patients with unstable angina.". The Indian journal of medical research 129 (3): 279–84. PMID 19491420.
- Miller, JW; Nadeau, MR; Smith, D; Selhub, J (May 1994). "Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats.". The American journal of clinical nutrition 59 (5): 1033–9. PMID 8172087.
- van Guldener C, Stehouwer CD (2001). "Homocysteine-lowering treatment: an overview". Expert Opinion on Pharmacotherapy 2 (9): 1449–1460. doi:10.1517/146565184.108.40.2069. PMID 11585023.
- Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis.". Thrombosis and haemostasis 81 (2): 165–76. PMID 10063987.
- Jager, A; Kostense, PJ; Nijpels, G; Dekker, JM; Heine, RJ; Bouter, LM; Donker, AJ; Stehouwer, CD (Jan 2001). "Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study.". Arteriosclerosis, thrombosis, and vascular biology 21 (1): 74–81. doi:10.1161/01.ATV.21.1.74. PMID 11145936.
- Morris, MS (July 2003). "Homocysteine and Alzheimer's disease.". Lancet neurology 2 (7): 425–8. doi:10.1016/s1474-4422(03)00438-1. PMID 12849121.
- Smach, MA; Jacob, N; Golmard, JL; Charfeddine, B; Lammouchi, T; Ben Othman, L; Dridi, H; Bennamou, S; Limem, K (2011). "Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer's disease or dementia: a case control study.". European neurology 65 (5): 270–8. doi:10.1159/000326301. PMID 21474939.
- Smith, AD; Smith, SM; de Jager, CA; Whitbread, P; Johnston, C; Agacinski, G; Oulhaj, A; Bradley, KM; Jacoby, R; Refsum, H (Sep 8, 2010). "Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.". PLoS ONE 5 (9): e12244. doi:10.1371/journal.pone.0012244. PMC 2935890. PMID 20838622.
- Dietrich-Muszalska, A; Malinowska, J; Olas, B; Głowacki, R; Bald, E; Wachowicz, B; Rabe-Jabłońska, J (May 2012). "The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients.". Neurochemical research 37 (5): 1057–62. doi:10.1007/s11064-012-0707-3. PMC 3321271. PMID 22270909.
- McLean, RR; Jacques, PF; Selhub, J; Tucker, KL; Samelson, EJ; Broe, KE; Hannan, MT; Cupples, LA; Kiel, DP (May 13, 2004). "Homocysteine as a predictive factor for hip fracture in older persons.". The New England Journal of Medicine 350 (20): 2042–9. doi:10.1056/NEJMoa032739. PMID 15141042.
- van Meurs, JB; Dhonukshe-Rutten, RA; Pluijm, SM; van der Klift, M; de Jonge, R; Lindemans, J; de Groot, LC; Hofman, A; Witteman, JC; van Leeuwen, JP; Breteler, MM; Lips, P; Pols, HA; Uitterlinden, AG (May 13, 2004). "Homocysteine levels and the risk of osteoporotic fracture.". The New England Journal of Medicine 350 (20): 2033–41. doi:10.1056/NEJMoa032546. PMID 15141041.
- Sato, Y; Honda, Y; Iwamoto, J; Kanoko, T; Satoh, K (Mar 2, 2005). "Effect of folate and methylcobalamin on hip fractures in patients with stroke: a randomized controlled trial.". JAMA: the Journal of the American Medical Association 293 (9): 1082–8. doi:10.1001/jama.293.9.1082. PMID 15741530.
- Bleich, S; Bleich, K; Kropp, S; Bittermann, HJ; Degner, D; Sperling, W; Rüther, E; Kornhuber, J (May–Jun 2001). "Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the 'French Paradox'?". Alcohol and alcoholism (Oxford, Oxfordshire) 36 (3): 189–92. doi:10.1093/alcalc/36.3.189. PMID 11373253.
- Bleich, S; Carl, M; Bayerlein, K; Reulbach, U; Biermann, T; Hillemacher, T; Bönsch, D; Kornhuber, J (March 2005). "Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS).". Alcoholism, clinical and experimental research 29 (3): 334–6. doi:10.1097/01.alc.0000156083.91214.59. PMID 15770107.
- Qin, X; Li, J; Cui, Y; Liu, Z; Zhao, Z; Ge, J; Guan, D; Hu, J; Wang, Y; Zhang, F; Xu, X; Wang, X; Xu, X; Huo, Y (Jan 10, 2012). "MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults.". Nutrition journal 11: 2. doi:10.1186/1475-2891-11-2. PMC 3274435. PMID 22230384.
- Yakub, M; Moti, N; Parveen, S; Chaudhry, B; Azam, I; Iqbal, MP (2012). "Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population.". PLoS ONE 7 (3): e33222. doi:10.1371/journal.pone.0033222. PMC 3310006. PMID 22470444.
- "Three of the B Vitamins: Folate, Vitamin B6, and Vitamin B12". The Nutrition Source. Harvard School of Public Health.
- Botto, LD; Yang, Q (May 1, 2000). "5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.". American Journal of Epidemiology 151 (9): 862–77. doi:10.1093/oxfordjournals.aje.a010290. PMID 10791559.
- Zoccali, C; Mallamaci, F; Tripepi, G (Nov–Dec 2007). "It is important to lower homocysteine in dialysis patients.". Seminars in dialysis 20 (6): 530–3. doi:10.1111/j.1525-139X.2007.00345.x. PMID 17991199.
- Nolin, TD; Ouseph, R; Himmelfarb, J; McMenamin, ME; Ward, RA (September 2010). "Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.". Clinical journal of the American Society of Nephrology : CJASN 5 (9): 1588–94. doi:10.2215/CJN.00210110. PMC 2974398. PMID 20538838.
- "B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial". The Lancet Neurology 9 (9): 855–865. 1 September 2010. doi:10.1016/S1474-4422(10)70187-3.
- House, AA; Eliasziw, M; Cattran, DC; Churchill, DN; Oliver, MJ; Fine, A; Dresser, GK; Spence, JD (Apr 28, 2010). "Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.". JAMA: the Journal of the American Medical Association 303 (16): 1603–9. doi:10.1001/jama.2010.490. PMID 20424250.
- Watson, KE (Fall 2006). "Lowering levels of lipids and homocysteine.". Reviews in cardiovascular medicine 7 (4): 248–50. PMID 17224870.
- Zoungas, S; McGrath, BP; Branley, P; Kerr, PG; Muske, C; Wolfe, R; Atkins, RC; Nicholls, K; Fraenkel, M; Hutchison, BG; Walker, R; McNeil, JJ (Mar 21, 2006). "Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial.". Journal of the American College of Cardiology 47 (6): 1108–16. doi:10.1016/j.jacc.2005.10.064. PMID 16545638.
- Bønaa, KH; Njølstad, I; Ueland, PM; Schirmer, H; Tverdal, A; Steigen, T; Wang, H; Nordrehaug, JE; Arnesen, E; Rasmussen, K; NORVIT Trial, Investigators (Apr 13, 2006). "Homocysteine lowering and cardiovascular events after acute myocardial infarction.". The New England Journal of Medicine 354 (15): 1578–88. doi:10.1056/NEJMoa055227. PMID 16531614.
- Martí-Carvajal, AJ; Solà, I; Lathyris, D; Salanti, G (2009-10-07). "Homocysteine lowering interventions for preventing cardiovascular events.". Cochrane database of systematic reviews (Online) (4): CD006612. doi:10.1002/14651858.CD006612.pub2. PMID 19821378.
- Jardine, MJ; Kang, A; Zoungas, S; Navaneethan, SD; Ninomiya, T; Nigwekar, SU; Gallagher, MP; Cass, A; Strippoli, G; Perkovic, V (2012-06-13). "The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis.". BMJ (Clinical research ed.) 344: e3533. doi:10.1136/bmj.e3533. PMC 3374481. PMID 22695899.
- Vizzardi, E; Bonadei, I; Zanini, G; Frattini, S; Fiorina, C; Raddino, R; Dei Cas, L (January 2009). "Homocysteine and heart failure: an overview.". Recent patents on cardiovascular drug discovery 4 (1): 15–21. doi:10.2174/157489009787259991. PMID 19149701.
- Ahmadieh, H; Arabi, A (October 2011). "Vitamins and bone health: beyond calcium and vitamin D.". Nutrition Reviews 69 (10): 584–98. doi:10.1111/j.1753-4887.2011.00372.x. PMID 21967159.
- Lonn, E; Yusuf, S; Arnold, MJ; Sheridan, P; Pogue, J; Micks, M; McQueen, MJ; Probstfield, J; Fodor, G; Held, C; Genest J, Jr; Heart Outcomes Prevention Evaluation (HOPE) 2, Investigators (Apr 13, 2006). "Homocysteine lowering with folic acid and B vitamins in vascular disease.". The New England Journal of Medicine 354 (15): 1567–77. doi:10.1056/NEJMoa060900. PMID 16531613.