hyperhomocysteinemia

Elevated levels of homocysteine have been associated with a number of disease states: more than 100 adverse outcomes have been identified.{{Cite journal |last=Smith |first=A. D. |last2=Refsum |first2=H. |date=October 2021 |title=Homocysteine – from disease biomarker to disease prevention |url=https://onlinelibrary.wiley.com/doi/10.1111/joim.13279 |journal=Journal of Internal Medicine |volume=290 |issue=4 |pages=826–854 |doi=10.1111/joim.13279 |issn=0954-6820}}

Elevated homocysteine is a known risk factor for cardiovascular disease as well as thrombosis.{{cite journal |pmid=10063987 |url=http://www.schattauer.de/index.php?id=1268&L=1&pii=th99020165&no_cache=1 |year=1999 |last1=Cattaneo |first1=Marco |title=Hyperhomocysteinemia, atherosclerosis and thrombosis |journal=Thrombosis and Haemostasis |volume=81 |issue=2 |pages=165–76 |doi=10.1055/s-0037-1614438 | s2cid=13228673 |access-date=2016-12-27 |archive-date=2018-07-21 |archive-url=https://web.archive.org/web/20180721145531/https://www.schattauer.de/index.php?id=1690 |url-status=dead }} 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.{{cite journal |doi=10.1161/01.ATV.21.1.74 |pmid=11145936 |title=Serum Homocysteine Levels Are Associated with the Development of (Micro)albuminuria : The Hoorn Study |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=21 |issue=1 |pages=74–81 |year=2001 |last1=Jager |first1=A. |last2=Kostense |first2=P. J. |last3=Nijpels |first3=G. |last4=Dekker |first4=J. M. |last5=Heine |first5=R. J. |last6=Bouter |first6=L. M. |last7=Donker |first7=A. J. M. |last8=Stehouwer |first8=C. D. A. |doi-access=free }} 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,{{cite journal |pmid=16702349 |year=2006 |last1=Jakubowski |first1=H |title=Pathophysiological consequences of homocysteine excess |journal=The Journal of Nutrition |volume=136 |issue=6 Suppl |pages=1741S–1749S |doi=10.1093/jn/136.6.1741S |doi-access=free }} affecting structure and function.

Evidence exists linking elevated homocysteine levels with vascular dementia{{Cite journal|last1=McVeigh|first1=Catherine|last2=Passmore|first2=Peter|date=September 2006|title=Vascular dementia: prevention and treatment|journal=Clinical Interventions in Aging|volume=1|issue=3|pages=229–235|issn=1176-9092|pmc=2695177|pmid=18046875|doi=10.2147/ciia.2006.1.3.229 |doi-access=free }} and Alzheimer's disease.{{cite journal |doi=10.1016/s1474-4422(03)00438-1 |pmid=12849121 |title=Homocysteine and Alzheimer's disease |journal=The Lancet Neurology |volume=2 |issue=7 |pages=425–8 |year=2003 |last1=Morris |first1=Martha Savaria |s2cid=20443022 }}{{cite journal |doi=10.1159/000326301 |pmid=21474939 |title=Folate and Homocysteine in the Cerebrospinal Fluid of Patients with Alzheimer's Disease or Dementia: A Case Control Study |journal=European Neurology |volume=65 |issue=5 |pages=270–8 |year=2011 |last1=Smach |first1=Mohamed Ali |last2=Jacob |first2=Nelly |last3=Golmard |first3=Jean-Louis |last4=Charfeddine |first4=Bassem |last5=Lammouchi |first5=Turkia |last6=Ben Othman |first6=Leila |last7=Dridi |first7=Hedi |last8=Bennamou |first8=Soufien |last9=Limem |first9=Khalifa |s2cid=7689901 }}{{cite journal |doi=10.1371/journal.pone.0012244 |pmid=20838622 |pmc=2935890 |title=Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial |journal=PLOS ONE |volume=5 |issue=9 |pages=e12244 |year=2010 |last1=Smith |first1=A. David |last2=Smith |first2=Stephen M. |last3=De Jager |first3=Celeste A. |last4=Whitbread |first4=Philippa |last5=Johnston |first5=Carole |last6=Agacinski |first6=Grzegorz |last7=Oulhaj |first7=Abderrahim |last8=Bradley |first8=Kevin M. |last9=Jacoby |first9=Robin |last10=Refsum |first10=Helga |bibcode=2010PLoSO...512244S |doi-access=free }} 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.{{cite journal |doi=10.1586/ern.09.75 |pmid=19769453 |title=Homocysteine, folate and vitamin B12in neuropsychiatric diseases: Review and treatment recommendations |journal=Expert Review of Neurotherapeutics |volume=9 |issue=9 |pages=1393–412 |year=2014 |last1=Stanger |first1=Olaf |last2=Fowler |first2=Brian |last3=Piertzik |first3=Klaus |last4=Huemer |first4=Martina |last5=Haschke-Becher |first5=Elisabeth |last6=Semmler |first6=Alexander |last7=Lorenzl |first7=Stefan |last8=Linnebank |first8=Michael |s2cid=13246020 |url=https://www.zora.uzh.ch/id/eprint/21178/1/DACH_Zora.pdf }} Oxidative stress induced by homocysteine may also play a role in schizophrenia.{{cite journal |doi=10.1007/s11064-012-0707-3 |pmid=22270909 |pmc=3321271 |title=The Oxidative Stress May be Induced by the Elevated Homocysteine in Schizophrenic Patients |journal=Neurochemical Research |volume=37 |issue=5 |pages=1057–62 |year=2012 |last1=Dietrich-Muszalska |first1=Anna |last2=Malinowska |first2=Joanna |last3=Olas |first3=Beata |last4=Głowacki |first4=Rafal |last5=Bald |first5=Edward |last6=Wachowicz |first6=Barbara |last7=Rabe-Jabłońska |first7=Jolanta }}

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.{{cite journal |doi=10.1056/NEJMoa032739 |pmid=15141042 |title=Homocysteine as a Predictive Factor for Hip Fracture in Older Persons |journal=New England Journal of Medicine |volume=350 |issue=20 |pages=2042–9 |year=2004 |last1=McLean |first1=Robert R. |last2=Jacques |first2=Paul F. |last3=Selhub |first3=Jacob |last4=Tucker |first4=Katherine L. |last5=Samelson |first5=Elizabeth J. |last6=Broe |first6=Kerry E. |last7=Hannan |first7=Marian T. |last8=Cupples |first8=L. Adrienne |last9=Kiel |first9=Douglas P. |s2cid=22853996 |doi-access=free }}{{cite journal |doi=10.1056/NEJMoa032546 |pmid=15141041 |title=Homocysteine Levels and the Risk of Osteoporotic Fracture |journal=New England Journal of Medicine |volume=350 |issue=20 |pages=2033–41 |year=2004 |last1=Van Meurs |first1=Joyce B.J. |last2=Dhonukshe-Rutten |first2=Rosalie A.M. |last3=Pluijm |first3=Saskia M.F. |last4=Van Der Klift |first4=Marjolein |last5=De Jonge |first5=Robert |last6=Lindemans |first6=Jan |last7=De Groot |first7=Lisette C.P.G.M. |last8=Hofman |first8=Albert |last9=Witteman |first9=Jacqueline C.M. |last10=Van Leeuwen |first10=Johannes P.T.M. |last11=Breteler |first11=Monique M.B. |last12=Lips |first12=Paul |last13=Pols |first13=Huibert A.P. |last14=Uitterlinden |first14=André G. |hdl=1765/8452 |url=http://repub.eur.nl/pub/8452 |hdl-access=free }}

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.{{citation needed|date=June 2022}}

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".{{cite journal |doi=10.1074/jbc.M410818200 |pmid=15496403 |title=A Mathematical Model of the Folate Cycle: new insights into folate homeostasis |journal=Journal of Biological Chemistry |volume=279 |issue=53 |pages=55008–16 |year=2004 |last1=Nijhout |first1=H. Frederik |last2=Reed |first2=Michael C. |last3=Budu |first3=Paula |last4=Ulrich |first4=Cornelia M. |doi-access=free }} 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).{{cn|date=November 2024}}

Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.{{cite journal |doi=10.1093/alcalc/36.3.189 |pmid=11373253 |title=Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: A contradiction to the 'French Paradox'? |journal=Alcohol and Alcoholism |volume=36 |issue=3 |pages=189–92 |year=2001 |last1=Bleich |first1=S. |last2=Bleich |first2=K |last3=Kropp |first3=S |last4=Bittermann |first4=H. J. |last5=Degner |first5=D |last6=Sperling |first6=W |last7=Rüther |first7=E |last8=Kornhuber |first8=J |doi-access=free }}{{cite journal |doi=10.1097/01.alc.0000156083.91214.59 |pmid=15770107 |title=Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS) |journal=Alcoholism: Clinical & Experimental Research |volume=29 |issue=3 |pages=334–6 |year=2005 |last1=Bleich |first1=Stefan |last2=Carl |first2=Marco |last3=Bayerlein |first3=Kristina |last4=Reulbach |first4=Udo |last5=Biermann |first5=Teresa |last6=Hillemacher |first6=Thomas |last7=b??Nsch |first7=Dominikus |last8=Kornhuber |first8=Johannes }}

Smokeless tobacco is implicated as risk factor for hyperhomocysteinemia.{{cite journal |vauthors=Iqbal MP, Yakub M |title=Smokeless tobacco use: a risk factor for hyperhomocysteinemia in a Pakistani population |journal=PLOS ONE |volume=8 |issue=12 |pages=e83826 |date=2013 |pmid=24376761 |pmc=3871626 |doi=10.1371/journal.pone.0083826 |bibcode=2013PLoSO...883826I |url=|doi-access=free }} Smoking also causes hyperhomocysteinemia{{cite journal |vauthors=Haj Mouhamed D, Ezzaher A, Neffati F, Douki W, Najjar MF |title=Effect of cigarette smoking on plasma homocysteine concentrations |journal=Clinical Chemistry and Laboratory Medicine |volume=49 |issue=3 |pages=479–83 |date=March 2011 |pmid=21143017 |doi=10.1515/CCLM.2011.062 |s2cid=34110392 |url=}}

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{{cn|date=November 2024}}.

• About 50% of homocysteine {{Citation needed|date=May 2014}} 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.{{cite journal |doi=10.1186/1475-2891-11-2 |pmid=22230384 |pmc=3274435 |title=MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults |journal=Nutrition Journal |volume=11 |pages=2 |year=2012 |last1=Qin |first1=Xianhui |last2=Li |first2=Jianping |last3=Cui |first3=Yimin |last4=Liu |first4=Zeyuan |last5=Zhao |first5=Zhigang |last6=Ge |first6=Junbo |last7=Guan |first7=Deming |last8=Hu |first8=Jian |last9=Wang |first9=Yanni |last10=Zhang |first10=Fumin |last11=Xu |first11=Xin |last12=Wang |first12=Xiaobin |last13=Xu |first13=Xiping |last14=Huo |first14=Yong |doi-access=free }}{{cite journal |doi=10.1371/journal.pone.0033222 |pmid=22470444 |pmc=3310006 |title=Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population |journal=PLOS ONE |volume=7 |issue=3 |pages=e33222 |year=2012 |last1=Yakub |first1=Mohsin |last2=Moti |first2=Naushad |last3=Parveen |first3=Siddiqa |last4=Chaudhry |first4=Bushra |last5=Azam |first5=Iqbal |last6=Iqbal |first6=Mohammad Perwaiz |bibcode=2012PLoSO...733222Y |doi-access=free }} The homozigote mutation G;G also called C;C (it is equivalent) occurs in about 10% of the population of european ethnicity (white caucasians).https://www.snpedia.com/index.php/rs1801131 consulted 30.10.2023 Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.{{cn|date=November 2024}}

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:{{citation needed|date=June 2022}}

• Moderate: 15–30 nmol/mL (or μmol/L)
• Intermediate: 30–100 nmol/mL
• Severe: > 100 nmol/mL

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.{{Cite journal|last1=Kang|first1=S. S.|last2=Wong|first2=P. W.|date=1996-01-26|title=Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia|journal=Atherosclerosis|volume=119|issue=2|pages=135–138|issn=0021-9150|pmid=8808490|doi=10.1016/0021-9150(95)05648-3}} Fasting for 10 hours is sometimes recommended prior to measurement of homocysteine levels, but this may not be necessary for diagnostic yield.{{Cite journal|last1=Fokkema|first1=M. Rebecca|last2=Gilissen|first2=Marleen F.|last3=Doormaal|first3=Jasper J. van|last4=Volmer|first4=Marcel|last5=Kema|first5=Ido P.|last6=Muskiet|first6=Frits A. J.|date=2003-05-01|title=Fasting vs Nonfasting Plasma Homocysteine Concentrations for Diagnosis of Hyperhomocysteinemia|journal=Clinical Chemistry|volume=49|issue=5|pages=818–821|doi=10.1373/49.5.818|issn=0009-9147|pmid=12709379|doi-access=free}}

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. 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. 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.{{cite journal|last=Watson|first=KE|title=Lowering levels of lipids and homocysteine.|journal=Reviews in Cardiovascular Medicine|date=Fall 2006|volume=7|issue=4|pages=248–50|pmid=17224870}}

• Homocystinuria
• Kilmer S. McCully
• DNA methylation

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{{Medical resources

| DiseasesDB = 29853

| ICD10 =

| ICD9 = {{ICD9|270.4}}

| ICDO =

| OMIM =

| MedlinePlus =

| eMedicineSubj = neuro

| eMedicineTopic = 578

| MeshID =

| SNOMED CT = 419503008

}}

{{Amino acid metabolic pathology}}

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Category:Amino acid metabolism disorders