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{{Infobox medical condition (new)
| name = Hyperhomocysteinemia
| synonyms = '''Hyperhomocysteinaemia'''
| image = Plasma tHcy.svg
| caption = [[Homocysteine|Total plasma homocysteine]]
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'''Hyperhomocysteinemia''' is a medical condition characterized by an abnormally high level of [[homocysteine|total homocysteine]] (that is, including [[homocystine]] and homocysteine-cysteine disulfide) in the [[blood]], conventionally described as above 15
As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of
[[vitamin B6|vitamin B<sub>6</sub>]], [[folic acid]] (vitamin B<sub>9</sub>), and [[Cobalamin|vitamin B<sub>12</sub>]] can lead to high homocysteine levels.<ref name="Miller-p1033-9">{{cite journal |pmid=8172087 |year=1994 |last1=Miller |first1=J. W. |title=Vitamin B-6 deficiency vs folate deficiency: Comparison of responses to methionine loading in rats |journal=The American Journal of Clinical Nutrition |volume=59 |issue=5 |pages=1033–9 |last2=Nadeau |first2=M. R. |last3=Smith |first3=D |last4=Selhub |first4=J |doi=10.1093/ajcn/59.5.1033}}</ref> Other possible causes of hyperhomocysteinemia include genetics, excessive [[methionine]] intake, and other diseases.<ref>{{Cite journal |last=Kim |first=Jihyun |last2=Kim |first2=Hyunhee |last3=Roh |first3=Heewon |last4=Kwon |first4=Youngjoo |date=2018-04-01 |title=Causes of hyperhomocysteinemia and its pathological significance |url=http://link.springer.com/10.1007/s12272-018-1016-4 |journal=Archives of Pharmacal Research |language=en |volume=41 |issue=4 |pages=372–383 |doi=10.1007/s12272-018-1016-4 |issn=0253-6269}}</ref>
Hyperhomocysteinemia is typically managed with vitamin B<sub>6</sub>, vitamin B<sub>9</sub> and vitamin B<sub>12</sub> supplementation.<ref name="ExpertOpPharm2001-Coen">{{cite journal |doi=10.1517/14656566.2.9.1449 |pmid=11585023 |title=Homocysteine-lowering treatment: An overview |journal=Expert Opinion on Pharmacotherapy |volume=2 |issue=9 |pages=1449–60 |year=2005 |last1=Stehouwer |first1=Coen DA |last2=Guldener |first2=Coen van |s2cid=45945199 }}</ref> Hyperhomocysteinemia is a risk factor for cardiovascular disease;
== Signs and symptoms ==
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=== Cardiovascular risks ===
Elevated homocysteine is a known risk factor for cardiovascular disease as well as [[thrombosis]].<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> Homocysteine degrades and inhibits the formation of the three main structural components of [[arteries]]: [[collagen]], [[elastin]] and [[proteoglycans]]. In [[protein]]s, homocysteine permanently degrades cysteine [[disulfide bridges]] and lysine amino acid residues,<ref>{{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 }}</ref> affecting structure and function.
=== Neuropsychiatric illness ===
Evidence exists linking elevated homocysteine levels with [[
=== Bone health ===
Elevated levels of homocysteine have also been linked to increased [[Fracture (bone)|fractures]] in elderly persons. Homocysteine auto-oxidizes and reacts with reactive oxygen intermediates, damaging endothelial cells and increasing the risk of [[thrombus]] formation.<ref>{{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. |
=== 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.{{citation needed|date=June 2022}}
== Causes ==
=== Vitamin deficiency ===
Deficiencies of vitamins B<sub>6</sub>, B<sub>9</sub> and B<sub>12</sub> can lead to high homocysteine levels.<ref name="Miller-p1033-9" />
=== Alcohol ===
Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.<ref>{{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 }}</ref><ref>{{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 }}</ref>
=== Tobacco ===
Smokeless tobacco is implicated as risk factor for hyperhomocysteinemia.<ref name="pmid24376761">{{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 }}</ref> Smoking also causes hyperhomocysteinemia<ref name="pmid21143017">{{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=}}</ref>
=== 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.
* About 50% of homocysteine {{Citation needed|date=May 2014}} is converted back to methionine by [[remethylation]] via the [[methionine synthase]] major pathway. This requires [[5-methyltetrahydrofolate|active folate]] and vitamin B<sub>12</sub>, in order to donate a methyl group. Active folate is known as 5-methyltetrahydrofolate (5-MTHF).▼
▲* About 50% of homocysteine {{Citation needed|date=May 2014}} is converted back to methionine by remethylation via the [[methionine synthase]] major pathway. This requires [[5-methyltetrahydrofolate|active folate]] and vitamin B<sub>12</sub>, 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 [[MTHFR|5-MTHF reductase]] can consequently lead to hyperhomocysteinemia. The most common [[polymorphism (biology)|polymorphisms]] are known as MTHFR C677T and MTR A2756G.<ref>{{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 }}</ref><ref>{{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 }}</ref>
== 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:{{citation needed|date=June 2022}}
* Moderate: 15–30 nmol/mL (or
* 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.<ref>{{Cite journal|
Fasting for 10 hours is sometimes recommended prior to measurement of homocysteine levels, but this may not be necessary for diagnostic yield.<ref>{{Cite journal|
== Treatment ==
Vitamins B<sub>6</sub>, B<sub>9</sub>, or B<sub>12</sub> supplements (alone or combined
== See also ==
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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}}
{{Authority control}}
[[Category:Amino acid metabolism disorders]]
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