Hyperhomocysteinemia

Hyperhomocysteinemia
Total plasma homocysteine
Classification and external resources
ICD-9-CM 270.4
DiseasesDB 29853
eMedicine neuro/578

Hyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 µmol/L.[1]

As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of vitamin B6, folic acid (vitamin B9), and vitamin B12 can lead to high homocysteine levels.[2]

Hyperhomocysteinemia is typically managed with vitamin B6, vitamin B9 and vitamin B12 supplementation.[3] Supplements of these vitamins; however, do not change outcomes.[4]

Health effects

Elevated levels of homocysteine have been associated with a number of disease states.

Cardiovascular risks

Elevated homocysteine is a known risk factor for cardiovascular disease and thrombosis.[5] 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.[6] 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.

Neuropsychiatric illness

Evidence exists linking elevated homocysteine levels and Alzheimer's disease.[7][8][9] There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia.[10] Oxidative stress induced by homocysteine may also play a role in schizophrenia.[11]

Bone health

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.[12][13]

A study on elderly Japanese individuals who had experienced a stroke found that folate and B12 reduce the incidence of osteoporotic hip fractures.[14]

Causes

Deficiencies of the vitamins B6, B9 and B12 can lead to high homocysteine levels.[2] Vitamin B12, or cobalamin, acts as a cofactor for the enzyme Methionine synthase (which forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle). Vitamin B12 deficiency prevents the 5-methyl tetrahydrofolate (5-MTHF) from being converted into THF. As a result, this disrupts the folate pathway and leads to an increase in homocysteine which damages cells (for example, damage to endothelial cells can result in increased risk of thrombosis).

Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.[15][16]

Genetic

Homocysteine is a non-protein amino acid, synthesized from methionine and either recycled back into methionine or converted into cysteine with the aid of the B-group vitamins.

Genetic defects in 5-MTHF reductase can consequently lead to hyperhomocysteinemia. The most common polymorphisms are known as MTHFR C677T and MTR A2756G.[17][18] These polymorphisms occur in about 10% of the world's population.

Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.

Treatment

Vitamins B6, B9, or B12 supplements, while they lower homocysteine level do not change the risk of heart disease, stroke, or death.[4] This also applies to people with kidney disease on dialysis.[19]

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.[20]

See also

References

  1. ↑ 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.
  2. 1 2 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.
  3. ↑ van Guldener C, Stehouwer CD (2001). "Homocysteine-lowering treatment: an overview". Expert Opinion on Pharmacotherapy. 2 (9): 1449–1460. doi:10.1517/14656566.2.9.1449. PMID 11585023.
  4. 1 2 Martí-Carvajal, Arturo J.; Solà, Ivan; Lathyris, Dimitrios (15 January 2015). "Homocysteine-lowering interventions for preventing cardiovascular events". The Cochrane Database of Systematic Reviews. 1: CD006612. doi:10.1002/14651858.CD006612.pub4. ISSN 1469-493X. PMID 25590290.
  5. ↑ Cattaneo, M (February 1999). "Hyperhomocysteinemia, atherosclerosis and thrombosis.". Thrombosis and haemostasis. 81 (2): 165–76. PMID 10063987.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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 2935890Freely accessible. PMID 20838622.
  10. ↑ Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M (2009). "Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations". Expert Review of Neurotherapeutics (Review). 9 (9): 1393–412. doi:10.1586/ern.09.75. PMID 19769453.
  11. ↑ 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 3321271Freely accessible. PMID 22270909.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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 (1): 2. doi:10.1186/1475-2891-11-2. PMC 3274435Freely accessible. PMID 22230384.
  18. ↑ 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 3310006Freely accessible. PMID 22470444.
  19. ↑ Nigwekar, Sagar U.; Kang, Amy; Zoungas, Sophia; Cass, Alan; Gallagher, Martin P.; Kulshrestha, Satyarth; Navaneethan, Sankar D.; Perkovic, Vlado; Strippoli, Giovanni F. M.; Jardine, Meg J. (31 May 2016). "Interventions for lowering plasma homocysteine levels in dialysis patients". The Cochrane Database of Systematic Reviews (5): CD004683. doi:10.1002/14651858.CD004683.pub4. ISSN 1469-493X. PMID 27243372.
  20. ↑ Watson, KE (Fall 2006). "Lowering levels of lipids and homocysteine.". Reviews in cardiovascular medicine. 7 (4): 248–50. PMID 17224870.
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