Hyperhomocysteinemia Explained

Hyperhomocysteinemia
Synonyms:Hyperhomocysteinaemia

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine (that is, including homocystine and homocysteine-cysteine disulfide) in the blood, conventionally described as above 15 μmol/L.[1]

As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies ofvitamin B6, folic acid (vitamin B9), and vitamin B12 can lead to high homocysteine levels.[2] Other possible causes of hyperhomocysteinemia include genetics, excessive methionine intake, and other diseases.[3]

Hyperhomocysteinemia is typically managed with vitamin B6, vitamin B9 and vitamin B12 supplementation.[4] Hyperhomocysteinemia is a risk factor for cardiovascular disease; supplements of these vitamins may slightly reduce stroke outcome but not myocardial infarction, death from any cause or adverse events.[5]

Signs and symptoms

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 as well as thrombosis.[6] 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.[7] 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,[8] affecting structure and function.

Neuropsychiatric illness

Evidence exists linking elevated homocysteine levels with vascular dementia[9] and Alzheimer's disease.[10] [11] [12] 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.[13] Oxidative stress induced by homocysteine may also play a role in schizophrenia.[14]

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.[15] [16]

Ectopia lentis

Homocystinuria is the second most common cause of heritable ectopia lentis. Homocystinuria is an autosomal recessive metabolic disorder most often caused by a near absence of cystathionine b-synthetase. It is associated with intellectual disability, osteoporosis, chest deformities, and increased risk of thrombotic episodes. Lens dislocation occurs in 90% of patients, and is thought to be due to decreased zonular integrity due to the enzymatic defect. Lens dislocation in homocystinuria is usually bilateral and in 60% of cases occurs in the inferior or nasal direction.

Causes

Vitamin deficiency

Deficiencies of vitamins B6, B9 and B12 can lead to high homocysteine levels. Vitamin B12 acts as a cofactor for the enzyme methionine synthase (which forms part of the S-adenosylmethionine (SAM) biosynthesis and regeneration cycle). Vitamin B12 deficiency prevents the 5-methyltetrahydrofolate (5-MTHF) form of folate from being converted into THF due to the "methyl trap".[17] 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).

Alcohol

Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.[18] [19]

Tobacco

Smokeless tobacco is implicated as risk factor for hyperhomocysteinemia.[20] Smoking also causes hyperhomocysteinemia[21]

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.[22] [23] The homozigote mutation G;G also called C;C (it is equivalent) occurs in about 10% of the population of european ethnicity (white caucasians).[24] Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.

Diagnosis

A blood test can be performed to quantify total homocysteine concentration in the plasma, of which approximately 80% is generally protein-bound. Classification of hyperhomocysteinemia is defined with respect to serum concentration as follows:

If total homocysteine concentration is not found to be elevated, but clinical suspicion is still high, an oral methionine loading challenge several hours prior to quantification of homocysteine concentration may be used to increased sensitivity for marginal abnormalities of homocysteine metabolism.[25]

Fasting for 10 hours is sometimes recommended prior to measurement of homocysteine levels, but this may not be necessary for diagnostic yield.[26]

Treatment

Vitamins B6, B9, or B12 supplements (alone or combined) lower homocysteine level and might slightly reduce the risk of stroke but not of myocardial infarction compared to standard care or placebo in clinical trials.[5] When combined with medicine to reduce blood pressure (antihypertensive drugs), it is not clear if treatments that lower homocysteine can help prevent a stroke in some people.[5] 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.[27]

See also

Notes and References

  1. 19491420 . 2009 . Guo . H . 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 . Chi . J . Xing . Y . Wang . P .
  2. 8172087 . 1994 . Miller . J. W. . 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 . Nadeau . M. R. . Smith . D . Selhub . J . 10.1093/ajcn/59.5.1033.
  3. Kim . Jihyun . Kim . Hyunhee . Roh . Heewon . Kwon . Youngjoo . 2018-04-01 . Causes of hyperhomocysteinemia and its pathological significance . Archives of Pharmacal Research . en . 41 . 4 . 372–383 . 10.1007/s12272-018-1016-4 . 0253-6269.
  4. 10.1517/14656566.2.9.1449 . 11585023 . Homocysteine-lowering treatment: An overview . Expert Opinion on Pharmacotherapy . 2 . 9 . 1449–60 . 2005 . Stehouwer . Coen DA . Guldener . Coen van . 45945199 .
  5. Martí-Carvajal . Arturo J . Solà . Ivan . Lathyris . Dimitrios . Dayer . Mark . 2017-08-17 . Cochrane Heart Group . Homocysteine-lowering interventions for preventing cardiovascular events . Cochrane Database of Systematic Reviews . en . 2021 . 9 . 10.1002/14651858.CD006612.pub5 . 6483699 . 28816346.
  6. 10063987 . Hyperhomocysteinemia, atherosclerosis and thrombosis . 1999 . Cattaneo . Marco . Thrombosis and Haemostasis . 81 . 2 . 165–76 . 10.1055/s-0037-1614438 . 13228673 . 2016-12-27 . 2018-07-21 . https://web.archive.org/web/20180721145531/https://www.schattauer.de/index.php?id=1690 . dead .
  7. 10.1161/01.ATV.21.1.74 . 11145936 . Serum Homocysteine Levels Are Associated with the Development of (Micro)albuminuria : The Hoorn Study . Arteriosclerosis, Thrombosis, and Vascular Biology . 21 . 1 . 74–81 . 2001 . Jager . A. . Kostense . P. J. . Nijpels . G. . Dekker . J. M. . Heine . R. J. . Bouter . L. M. . Donker . A. J. M. . Stehouwer . C. D. A. . free .
  8. 16702349 . 2006 . Jakubowski . H . Pathophysiological consequences of homocysteine excess . The Journal of Nutrition . 136 . 6 Suppl . 1741S–1749S . 10.1093/jn/136.6.1741S . free .
  9. McVeigh. Catherine. Passmore. Peter. September 2006. Vascular dementia: prevention and treatment. Clinical Interventions in Aging. 1. 3. 229–235. 1176-9092. 2695177. 18046875. 10.2147/ciia.2006.1.3.229 . free .
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  11. 10.1159/000326301 . 21474939 . 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 . 2011 . Smach . Mohamed Ali . Jacob . Nelly . Golmard . Jean-Louis . Charfeddine . Bassem . Lammouchi . Turkia . Ben Othman . Leila . Dridi . Hedi . Bennamou . Soufien . Limem . Khalifa . 7689901 .
  12. 10.1371/journal.pone.0012244 . 20838622 . 2935890 . 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 . 2010 . Smith . A. David . Smith . Stephen M. . De Jager . Celeste A. . Whitbread . Philippa . Johnston . Carole . Agacinski . Grzegorz . Oulhaj . Abderrahim . Bradley . Kevin M. . Jacoby . Robin . Refsum . Helga . 2010PLoSO...512244S . free .
  13. 10.1586/ern.09.75 . 19769453 . Homocysteine, folate and vitamin B12in neuropsychiatric diseases: Review and treatment recommendations . Expert Review of Neurotherapeutics . 9 . 9 . 1393–412 . 2014 . Stanger . Olaf . Fowler . Brian . Piertzik . Klaus . Huemer . Martina . Haschke-Becher . Elisabeth . Semmler . Alexander . Lorenzl . Stefan . Linnebank . Michael . 13246020 .
  14. 10.1007/s11064-012-0707-3 . 22270909 . 3321271 . The Oxidative Stress May be Induced by the Elevated Homocysteine in Schizophrenic Patients . Neurochemical Research . 37 . 5 . 1057–62 . 2012 . Dietrich-Muszalska . Anna . Malinowska . Joanna . Olas . Beata . Głowacki . Rafal . Bald . Edward . Wachowicz . Barbara . Rabe-Jabłońska . Jolanta .
  15. 10.1056/NEJMoa032739 . 15141042 . Homocysteine as a Predictive Factor for Hip Fracture in Older Persons . New England Journal of Medicine . 350 . 20 . 2042–9 . 2004 . McLean . Robert R. . Jacques . Paul F. . Selhub . Jacob . Tucker . Katherine L. . Samelson . Elizabeth J. . Broe . Kerry E. . Hannan . Marian T. . Cupples . L. Adrienne . Kiel . Douglas P. . 22853996 . free .
  16. 10.1056/NEJMoa032546 . 15141041 . Homocysteine Levels and the Risk of Osteoporotic Fracture . New England Journal of Medicine . 350 . 20 . 2033–41 . 2004 . Van Meurs . Joyce B.J. . Dhonukshe-Rutten . Rosalie A.M. . Pluijm . Saskia M.F. . Van Der Klift . Marjolein . De Jonge . Robert . Lindemans . Jan . De Groot . Lisette C.P.G.M. . Hofman . Albert . Witteman . Jacqueline C.M. . Van Leeuwen . Johannes P.T.M. . Breteler . Monique M.B. . Lips . Paul . Pols . Huibert A.P. . Uitterlinden . André G. . 1765/8452 . free .
  17. 10.1074/jbc.M410818200 . 15496403 . A Mathematical Model of the Folate Cycle: new insights into folate homeostasis . Journal of Biological Chemistry . 279 . 53 . 55008–16 . 2004 . Nijhout . H. Frederik . Reed . Michael C. . Budu . Paula . Ulrich . Cornelia M. . free .
  18. 10.1093/alcalc/36.3.189 . 11373253 . Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: A contradiction to the 'French Paradox'? . Alcohol and Alcoholism . 36 . 3 . 189–92 . 2001 . Bleich . S. . Bleich . K . Kropp . S . Bittermann . H. J. . Degner . D . Sperling . W . Rüther . E . Kornhuber . J . free .
  19. 10.1097/01.alc.0000156083.91214.59 . 15770107 . Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS) . Alcoholism: Clinical & Experimental Research . 29 . 3 . 334–6 . 2005 . Bleich . Stefan . Carl . Marco . Bayerlein . Kristina . Reulbach . Udo . Biermann . Teresa . Hillemacher . Thomas . b??Nsch . Dominikus . Kornhuber . Johannes .
  20. Iqbal MP, Yakub M . Smokeless tobacco use: a risk factor for hyperhomocysteinemia in a Pakistani population . . 8 . 12 . e83826 . 2013 . 24376761 . 3871626 . 10.1371/journal.pone.0083826 . 2013PLoSO...883826I . free .
  21. Haj Mouhamed D, Ezzaher A, Neffati F, Douki W, Najjar MF . Effect of cigarette smoking on plasma homocysteine concentrations . . 49 . 3 . 479–83 . March 2011 . 21143017 . 10.1515/CCLM.2011.062 . 34110392 .
  22. 10.1186/1475-2891-11-2 . 22230384 . 3274435 . 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 . 2012 . Qin . Xianhui . Li . Jianping . Cui . Yimin . Liu . Zeyuan . Zhao . Zhigang . Ge . Junbo . Guan . Deming . Hu . Jian . Wang . Yanni . Zhang . Fumin . Xu . Xin . Wang . Xiaobin . Xu . Xiping . Huo . Yong . free .
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  24. https://www.snpedia.com/index.php/rs1801131 consulted 30.10.2023
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  26. Fokkema. M. Rebecca. Gilissen. Marleen F.. Doormaal. Jasper J. van. Volmer. Marcel. Kema. Ido P.. Muskiet. Frits A. J.. 2003-05-01. Fasting vs Nonfasting Plasma Homocysteine Concentrations for Diagnosis of Hyperhomocysteinemia. Clinical Chemistry. en. 49. 5. 818–821. 10.1373/49.5.818. 0009-9147. 12709379. free.
  27. Watson. KE. Lowering levels of lipids and homocysteine.. Reviews in Cardiovascular Medicine. Fall 2006. 7. 4. 248–50. 17224870.

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