同型半胱氨酸临床诊疗指南(JANA)

TheJournaloftheAmericanNutraceuticalAssociationVol.7,No.1,Winter2004–ARiskFactorforVascularDiseases:GuidelinesfortheClinicalPracticeThomasG.Guilliams,PhDDirector,ScienceandRegulatoryAffairs,OrthoMolecularProductsInc.,StevensPoint,WisconsinClinicalInstructor,UniversityofWisconsin-MadisonSchoolofPharmacyReprintedwithpermissionfromtheJournaloftheAmericanNutraceuticalAssociation.Duplicationinwholeorpartisnotpermittedwithoutpermission.REVIEWARTICLEWinter2004Vol.7,No.1JANA11ABSTRACTAsanemergingindependentriskfactorforcardiovas-culardiseaseandotheragingdiseasessuchasAlzheimer’s,homocysteine-relatedresearchhasgeneratedavastamountofliteratureandsparkedavigorousdebateoverthepastdecade.Infact,acomprehensivetextbookisnowavailabledescribingtheroleofhomocysteineinhealthanddisease.3Thisreviewwillsurveythehistoryofhomocysteineresearch,therationaleforconsideringhomocysteineasacausativeagentratherthanjustamarkerforvasculardis-eases,andreviewtheinterventiontrialsforloweringhomo-cysteineinpatients.INTRODUCTIONHomocysteineisasulfuraminoacidandanormalintermediateinmethioninemetabolism.Whenexcesshomocysteineisproducedinthebodyandnotreadilycon-vertedintomethionineorcysteine,itisexcretedoutofthetightlyregulatedcellenvironmentintotheblood.Itistheroleoftheliverandkidneytoremoveexcesshomocysteinefromtheblood.Inmanyindividualswithinbornerrorsofhomocysteinemetabolism,kidneyorliverdisease,nutrientdeficiencies,orconcomitantingestionofcertainpharma-ceuticals,homocysteinelevelscanrisebeyondnormallev-elsandleadtoadversehealthoutcomes.Theroleofelevatedbloodhomocysteinelevelsinclin-icalpracticeisstillbeingdebated.Thecentralquestionis,whetheritisclinicallybeneficialtomeasureforandtreatele-vatedlevelsofhomocysteine?1,2Whilesomemayconsiderhomocysteinesimplyasamarkerbutnotatreatablecausativeagent,orperhapsignorehomocysteineasaninnocuousmetabolitecoincidentaltoothertreatableriskfac-tors,theweightofthescientificevidencesuggestsotherwise.HISTORICALPERSPECTIVEIntheearly1960s,researchersdescribedseveralinbornerrorsofhomocysteinemetabolisminyoungchil-drenthatledtoextremelyhighlevelsofhomocysteinethatinturnresultedinmentalretardationandearlydeath,oftencausedbysomecardiovascularevent.Afterpostmortemexaminationsofmanysimilarcases,KilmerMcCully,MD,notedanemergingpatternofarteriosclerosisduetoforma-tionoffibrousplaquesandlossofelasticity.McCully’suniquetraininginbiochemistryandpathology,alongwithhisinclinationtobecurious,placedhiminauniqueposi-tiontopioneeranewtheoryincardiovascularresearch.Heconcluded,asdidothers,thatseverelyelevatedlevelsofhomocysteineweredirectlyresponsibleforthevariousvas-cularlesionsinindividualswithgeneticdefectsinhomo-cysteinemetabolism.Hefurtherpostulatedthatmoderatelyelevatedhomocysteineduetoheterozygousmutationsinhomocysteine-relatedgenesorpoorvitaminstatuswouldREVIEWARTICLEHomocysteine–ARiskFactorforVascularDiseases:GuidelinesfortheClinicalPracticeThomasG.Guilliams,PhD*Director,ScienceandRegulatoryAffairs,OrthoMolecularProductsInc.,StevensPoint,WisconsinClinicalInstructor,UniversityofWisconsin-MadisonSchoolofPharmacy*Correspondence:ThomasG.Guilliams,PhD3017BusinessParkDriveStevensPoint,WI54481Phone:[phone]Fax:[phone]E-mail:[e-mail]12JANAVol.7,No.1Winter2004alsoleadtoincreasedriskofcardiovasculardiseaseinthegeneralpopulation.4Sincehisnewtheoryquestionedtheroleofcholesterolandotherlipidsinthegenesisofarte-riosclerosis,findingacceptancewithinthemainstreammedicalcommunitywasdifficult;eventually,his28-yearaffiliationwithHarvardMedicalSchool(undergraduatethroughassistantprofessor)cametoanendwhenhewasunableto“prove”thetheorytothesatisfactionofsomeofhiscolleagues.WhileemployedasapathologistattheVeteransAffairsMedicalCenterinProvidence,RhodeIsland,hecontinuedhisworkthroughthepastseveraldecades.AcolorfuldescriptionofboththehomocysteinetheoryofcardiovasculardiseaseandthehistorybehinditsdiscoverycanbefoundinMcCully’sbookTheHomocysteineRevolution(KeatsPublishing).Bytheearly1990s,elevatedhomocysteinewasbeingconsideredanindependentriskfactorforcardiovasculardisease(alongwithcholesterolandotherlipidmarkers,age,gender,smokingstatus,obesity,hypertension,anddia-betes).Aprospectivestudyofmalephysiciansin1992foundthatacutemyocardialinfarction(MI)ordeathduetocoronarydiseasewasstatisticallyrelatedtoincreasedhomocysteinelevels,afteradjustingforotherriskfactors.5In1995,akeymeta-analysiswaspublishedbyJAMAinwhich27studiesinvolvingover4,000subjectsconcludedthathomocysteinewasanindependentriskfactorforcar-diovasculardisease(CVD)andestimatedthat10%ofthepopulation’sCVDriskisattributabletoelevatedhomocys-teine.6Intotal,nearly100retrospectiveandprospectiveclinicalstudieslinkhomocysteinelevelswithincreasedriskofcardiovascularoutcomes,andnumerousreviewsoftheliteratureareavailable.7-11Accordingtoarecentmeta-analysisofthedata,acausalrelationshipbetweenhomocysteineandcardiovascu-lardiseaseishighlylikely.12Theauthorsconclu