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1 PDF hosted at the Radboud Repostory of the Radboud Unversty Njmegen The followng full text s a publsher's verson. For addtonal nformaton about ths publcaton clck ths lnk. Please be advsed that ths nformaton was generated on and may be subject to change.
2 Postgrad Med J 996; 72: lp The Fellowshp of Postgraduate Medcne, 996 Classc dseases revsted Homocystnura: what about mld hyperhomocystenaema M van den Berg, GHJ Boers Summary Hyperhomocystenaema s assocated wth an ncreased rsk of atherosclerotc vascular dsease and thromboembolsm, n both men and women. A varety of condtons can lead to elevated homocystene levels, but the relaton between hgh levels and vascular dsease s present regardless of the underlyng cause. Pooled data from a large number of studes demonstrate that m ld hyperhomocystenaema after a standard methonne load s present n 2 of young patents wth coronary artery dsease, n 24 of patents wth cerebrovascular dsease, and n 32 of patents wth perpheral vascular dsease. From such data an odds rato of 30 (95 confdence nterval 5.9 to 28.), as an estmate of the relatve rsk of vascular dsease at a young age, can be calculated n subjects wth an abnormal response to methonne loadng. Furthermore, mld hyperhom o-cystenaema can lead to a two- or three-fold ncrease n the rsk of recurrent venous thromboss. Elevated homocystene levels can be reduced to normal n vrtually all cases by smple and safe treatment wth vtamn B6, folc acd, and betane, each of whch s nvolved n methonne metabolsm. A clncally benefcal effect of such an nterventon, currently under nvestgaton, would make largescale screenng for ths rsk factor mandatory. Keywords: hyperhomocystenaema, atheroscleross, pathogeness, homocystnura nsttute for C ardovascular Research, D epartm ent of Vascular Surgery, Free Unversty H osptal, P O Box 7057, 007 M B Am sterdam, The Netherlands M van den Berg D epartm ent o f nternal M edcne, Unversty Hosptal N jm egen, 6500 H B Njm egen, The Netherlands GHJ Boers Accepted 22 November 995 Atherosclerotc dsease, notably coronary artery dsease, remans the major cause of death n the western world. Ths ncreased rsk of mortalty from cardovascular dsease cannot be fully explaned by tradtonal rsk factors such as hyperlpoprotenaema, smokng, hypertenson and male sex. Snce the last decade, mldly elevated homocystene levels have also been recognsed as a serous rsk factor n the development of atherosclerotc dsease and thromboembolsm. Severe hyperhomocystenaema, such as n homocystnura due to cystathonne synthase defcency, s nherted as an autosomal recessve trat and may lead to occlusve arteral dsease and thromboembolsm even n early nfancy. From a collaboratve study on more than 600 homozygous patents, Mudd et al observed that there was a 50 chance for untreated patents to suffer from a vascular event before the age of 30 years.2 n lne wth ths observaton, the hypothess has been put forward that even mld hyperhomocystenaema may predspose for arteral occlusve dsease, even at a young age. ndeed, case- controlled, cross-sectonal, and prospectve epdemologcal studes have shown that mldly elevated homocystene levels are assocated wth an ncreased rsk of arteral occlusve dsease.3" Ths relatonshp has been reported for both fastng homocystene levels and for hyperhomocystenaema unmasked by means of a methonne loadng test n whch homocystene metabolsm s stressed wth an oral dose of L-methonne (0. g/kg body weght). Whether fastng or postmethonne plasma homocystene level s the better predctor of vascular dsease has not been clarfed. t has been shown that safe doses of vtamns can nduce normalsaton of such ncreased homocystene blood levels4,5 and may amelorate endothelal functon n mldly hyperhomocystenaernc vascular patents.8 n concluson, mld hyperhomocystenaema has been recognsed as an mportant rsk factor for atherosclerotc dsease, thus provdng the ratonale for large-scale screenng and nterventon wth nnocuous vtamns n patents wth elevated homocystene levels. Relevant aspects of ths unconventonal rsk factor are brefly dscussed n ths paper. 4 Metabolsm and aetology of hyperhomocystenaema The essental amno acd methonne, whch s present n proten of anmal orgn, s the only source of homocystene n man,normally, homocystene s rapdly catabolsed by transsulphuraton nto cystene or s remethylated to methonne (fgure ). Cystathonne synthase catalyses the frst step n transsulphuraton wth vtamn B6 n ts actve form, pyrdoxal phosphate, as cofactor. n many body tssues remethylaton by the folate- and vtamn B2- C dependent enzyme N -methyltetrahydrofolate-homocystene methyltransferase s operatonal and n the lver homocystene s also remethylated by betane (trmethylglycne), formed from cholne. Plasma homocystene s the sum of homocystene, whether free or bound to protens, and the homocystenyl moetes of the dsulphdes homo cystne and cystene-homocystene. Hyperhomocystenaema refers to levels of such 'total5 homocystene level n the blood, plasma or serum. Epdemologcal studes strongly suggest a graded response rather than a threshold effect of homocystene levels, but for practcal reasons the followng classfcaton has been made: moderate, ntermedate and severe fastng hyperhomocystenaema, wth levels between 6 and 30> 3 and 00, and more than 00 fmol/, respectvely.9n dagnosng hyperhomocystenaema n the ndvdual patent t s preferable to perform a methonne loadng test0, as stated later. The generally used cut-off ponts for post-load hyperhomocystenaema are sex specfc, e, n men 54, n premenopausal women 5, and n postmenopausal women 69 /mol/, respectvely.0, Severe hyperhomocystenaema, also' known as homocystnura, s an
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4 Mld hyperhomocystenaema and vascular dsease 55 contrbute to the accelerated development of macroangopathy n dabetcs. These fndngs should therefore be consdered n the context of a postve relaton between homocystene and creatnne. The ntra-ndvdual day-to-day varaton n fastng homocystene levels s rather wde, up to 25. One of the causes of ths varaton could be detary changes durng the day precedng de fastng samplngs because t has been shown that a proten-rch meal may affect plasma homocystene levels for at least eght hours.23 A post-methonne-load homocystene determnaton, four to sx hours after the methonne ntake, wll have a dstance n tme from the last proten-contanng meal of at least 6 hours and durng the test tself the protocol nhbts proten ntake. Therefore., less ntra-ndvdual varaton n post-methonne plasma homocystene levels mght be expected (box ). The antfolate drug methotrexate, folate-defcency-nducng ant-epleptcs, and ntrous oxde, whch nactvates vtamn B 2y wll ncrease plasma homocystene (box ). Recently, the modulaton of plasma homocystene by these and varous other pharmacologcal agents, such as pencllamne and oestrogens, has been extensvely revewed.20,24 Mld hyperhomocystenaema and vascular dsease Prevalence of mld (post-load) hyperhomocystenaema -2 n the general populaton3 Among 730 screened vascular patents: of those wth perpheral arteral dsease4, of those wth cerebrovascular dsease4,5 5 of those wth coronary artery dsease4 Box 2 Dagnoss elevated homocystene levels n the fastng state^ and/or after methonne loadng (0. g/kg orally) Box 3 n 976, Wlcken and Wlcken were the frst to publsh results suggestng that even mld hyperhomocystenaema could have a possble role n the pathogeness of coronary artery dsease.25 They showed that about 30 of young patents wth angographcally proven coronary artery dsease demonstrated mld hyperhomocystenaema, four hours after a methonne load. Ths unque fndng suggested an mportant role for even mld hyperhomocystenaema n the pathogeness of vascular dsease at a young age. Snce then, numerous studes have shown that mld hyperhomocystenaema s a frequent fndng amongst vascular patents. n 992 pooled data revealed a prevalence of 32 n patents wth perpheral vascular dsease, 24 n patents wth cerebrovascular dsease, and 2 n patents wth coronary artery dsease,3,26 From pooled data an odds rato of 3.0 (95 Cl ) could be calculated as an estmate of the relatve cardovascular rsk n subjects wth an abnormal response to methonne loadng compared to normal responders.3 The recently publshed data by van den Berg et a t and Franken et ap are n lne wth the fndng of hgh prevalences of mld post-load hyperhomocystenaema amongst vascular patents (box 2). Recently, prospectve studes have ndeed confrmed that mld hyperhomocystenaema n men s assocated wth an ncreased ncdence of myocardal nfarcton6,7 and, possbly, of stroke.27 n addton, a dose-response relatonshp s supported by the fact that hyperhomocystenaema s reported to be assocated wth the severty of perpheral arteral dsease28 and wth the number of stenosed coronary vessels29 n arterosclerotc patents. Malnow et a/30 observed a graded ncrease n the prevalence of carotd artery ntmal-medal thckenng wth ncreasng random homocystene levels n asymptomatc subjects, whch was more pronounced n women. Selhub et a t reported a relatonshp between random homocystene levels and the prevalence of carotd artery stenoss. Taken together, the epdemologc evdence may ndcate a graded effect of plasma homocystene levels, as n hypercholesterolaema, rather than a threshold effect. t has recently been shown that mld hyperhomocystenaema s a strong rsk factor for recurrent venous thromboss and can lead to a two-fold or three-fold ncrease n rsk.32 Possble relatonshps between plasma homocystene and convental rsk factors for vascular dsease have been studed but no such relaton was establshed for tobacco smokng, hypertenson, serum lpds, or dabetes melltus. Therefore, so far, hyperhomocystenaema seems to be an ndependent rsk factor for cardovascular dsease.2,33 At ths stage, t s unresolved whch s the most senstve ndcator of excess cardovascular rsk, ether the fastng, the post-load homocystene level, or both (box 3). dentfcaton of patents at rsk smply on the bass of ther fastng homocystene level mght be nsuffcent because, dependng on the cut-off pont, about of patents wth hgh post-methonne homocystene have a normal fastng level.4,0 The latter fndng, moreover, suggests the exstence of multple underlyng metabolc defcts, because fastng and post-methonne homocystene levels are thought to be determned by dfferent pathways, e, remethylaton and transsulphuraton of homocystene, respectvely. A serous argument aganst the use of the post-methonne homocystene level as the crteron of hyperhomocystenaema s the fact that the methonne loadng test s too laborous and expensve to nclude n the desgn of epdemologcal studes wth large numbers of partcpants. Even n dagnostc procedures n ndvdual vascular patents, the practcal concerns and hgh costs of establsh-
5 56 van den Berg3 Boers ng post-methonne homocystene levels suggest that ths test s not feasble as a routne screenng procedure. f t s to become so, more effort s needed to standardse the samplng of fastng homocystene levels and more attenton should be pad to de food ntake on the day precedng the blood samplng, to mnmse the wde ntra-ndvdual daly varaton of these levels, as mentoned before. Pathogeness of vascular dsease n mld hyperhom ocystenaem a Atherogenetc mechansms of homocystene damagng endothelal cells by generaton of hydrogen peroxde, oxdaton of low-densty lpoproten, and depleton of ntrc oxde o prolferaton of smooth muscle cells coagulaton/fbrnolyss nteracton: nhbtng expresson of thrombomoduln Box 4 Homocystene, an amno acd wth a free sulphhydryl group, s generally held to be atherogenc and thrombogenc, although de exact pathophysologcal sequence has not been clarfed. Homocystene s thought to damage endothelal cells by several mechansms, eg, generaton of hydrogen peroxde34 oxdaton of low-densty lpoprotens, and depleton of ntrc oxde-medated detoxfcaton of homocystene.35 n studes n anmals, hgh homocystene levels have been shown to nduce endothelal cell njury.36,3 n vtro studes ndcate that cultured endothelal cells from oblgate heterozygotes for homocystnura are more susceptble to homocystene-medated njury than normal cells.38 Another potental mechansm, recently descrbed by Tsa et a/39 s that homocystene nduces the prolferaton of smooth muscle cells, a key feature of atherogeness. t has also been reported that homocystene nhbts the expresson of thrombomoduln on the surface of the endothelal cell, leadng to decreased proten C actvaton and thus, possbly, contrbutng to the development of thromboss n hyperhomocystenaemc patents.40 Although data n humans are scarce, van den Berg et a t showed n hyperhomocystenaemc patents wth lower extremty occlusve atherosclerotc dsease that endothelal dysfuncton, as estmated by ncreased plasma von Wllebrand factor concentratons, was amelorated by treatment of hyperhomocystenaema wth folc acd and vtamn B<,. n concluson, abnormaltes of endothelal cells, platelets, clottng factors, serum lpds or dsorders n the complex nteracton of these factors have been held responsble for the vascular damage and thrombogeness. A survey of all proposed hypotheses has been presented elsewhere (box 4)., The cause of mld hyperhomocystenaema n vascular patents Analogous to the frst observaton by Sardharwalla et al of mldly elevated homocystene levels n oblgate heterozygotes for cystathonne synthase defcency,4 t has been proposed that such hyperha mocystenema detected n vascular patents also orgnates from heterozygosty for ths specfc enzyme defect. n the two reports presentng determnatons of cystathonne synthase actvty n cultured fbroblasts from hyperhomocystenaemc vascular patents, an ntermedate enzyme defcency was ndeed found. n recent years, however, t has become ncreasngly clear that the dentfcaton of patents wth vascular dsease as heterozygotes for cystathonne synthase defcency s not convncng.42,43 More recent determnatons of enzyme assays n hyperhomo- cystenaemc vascular patents show that cystathonne synthase actvty s defcent only n sporadc cases and wde varablty n actvty n cultured fbroblasts may occur, even n healthy persons2 and recently t has been shown that heterozygous carrers and homocystnurc patents were free from nactvatng mutatons.44 The role of the cystathonne synthase gene may have been overestmated n the past and, therefore, the re-methylaton pathway has ganed more nterest n recent years. Recently, Rozen s group cloned the gene responsble for the enzyme methylenetetrahydrofolate reductase, whch has permtted mutatonal analyss n ths gene, facltatng the evaluaton of the re-methylaton pathway n the aetology of hyperhomocystenaema.46 Thermolablty of 5,0 methylenetetrahydrofolate reductase proves to be a far more common genetc defect among these patents.4,42 Homozygotes for ths mutaton have been detected n 5 of the general populaton and n up to 7 of 22 coronary patents,5 Recently, a common mutaton n 5,0-methylenctetrahydrofolate reductase has been dentfed, whch n the heterozygous or homozygous state correlates wth reduced enzyme actvty and decreased thermostablty n lymphocyte extracts.46 n addton, ndvduals homozygous for the mutaton have sgnfcantly elevated plasma homocystene levels, bot n the fastng state and after methonne loadng.46 Notwthstandng the occurrence of thermo- lable enzyme n 28 of some groups of hyperhomocystenaemc vascular patents,4~ ths prevalence stll does not seem hgh enough to predct a predomnant role of ths defect among possble causes of mld hyperhomocystenaema n vascular patents.
6 Mld hyperhomocystenaema and vascular dsease 57 T reatment n fastng homocystene folc acd: 0.65 mg daly: 40 reducton 2.5 mg daly: 37 reducton 5 mg daly: 50 reducton 0 mg daly: 50 reducton vtamn B6: vtamn B]2: no effect only modest effect (-5), but should be added to avod folc acd refractorness and deteroraton of neuropathy n vtamn B 2- defcent cases. A suffcent dose s 0.4 mg daly n post-methonne hyperhomocystenaema vtamn B6j 00 mg + folc acd, 5 mg daly: 50 reducton vtamn B6, 00 to 250 mg daly: 40 reducton folc acd (n = 6 patents only): 45 reducton (lower doses of vtamn B6 and/or folc acd have not been studed) To lower fastng homocystene levels 0.65 mg folc acd plus 0.4 mg cyanocobalamn To lower post-methonne homocystene levels 00 mg vtamn B6 plus 5 mg folc acd Box 5 Homo cystene-lowerng nterventons FASTNG HOMOCYSTENE LEVELS From pooled datat can be estmated that t s possble to nduce a reducton of about 40 of mldly elevated fastng plasma homocystene levels by the use of doses of folc acd as low as 0.65 mg daly. A lower dose has not been studed. A dose of 2.5 mg daly had the same effect as 0.65 mg35 mg daly resulted n a slghtly larger decrease of about 503and ncreasng the dose up to 0 mg daly had no extra effect. Supplementaton of vtamn B6 dd not affect fastng homocystene levels sgnfcantly. Vtamn B2 n an oral dose of 0.4 mg cyanocobalamn daly has only a modest effect but s added to folc acd therapy manly to avod folc-acd refractorness n the case of vtamn B2 defcency and to prevent the development of neuropathy due to unrecognsed perncous anaema (box 5). n summary, the prescrpton of 0.65 mg folc acd plus 0.4 mg cyanocobalamn daly s suffcent to lower a mld fastng hyperhomocystenaema by about 50. POST-METHONNE HOMOCYSTENE LEVELS Avalable data on the effect of varous homocystene-lowerng regmens upon mldly elevated post-methonne homocystene levels 5show that the use of 00 mg vtamn B6 plus 5 mg folc acd decreases homocystene levels by about 50. Vtamn B6 as a sngle agent n doses from 00 to 250 mg daly resulted n a slghtly lower reducton of about 40. Folc acd as the sole therapy has been studed n only sx patents so far and showed a 45 decrease n these patents. The effcacy of lower doses of vtamn B6 and/or folc acd as a sngle or combned therapy has not been explored. Remarkably^ only the combnaton of vtamn B6 plus folc acd resulted n normalsaton of post-methonne homocystene levels n 90 or more of the treated patents^ whereas the respectve sngle treatments dd much less3e3about 50 (box 5). n summary3 00 mg vtamn B6 and 5 mg folc acd daly should be prescbed for the treatment of post-methonne hyperhomocystenaema. Conclusons The prevalence of mld hyperhomocystenema n young patents wth arteral occlusve dsease s hgh and hyperhomocystenaema has to be accepted as a serous rsk factor for vascular dsease. Future studes wll hopefully elucdate n whch way atheroscleross and thromboembolc events are nduced n patents wth hyperhomocystenaema. Furthermore^ smple and nexpensve therapy wth nnocuous vtamns can normalse homocystene metabolsm, as assessed by the homocystene plasma level before and after methonne loadngs n vrtually all these patents. nterventon studes are needed to clarfy f such treatment wll also reduce morbdty and mortalty. The demonstraton of a clncal beneft of homocystene-lowerng nterventons would be requred to
7 58 van den Berg, Boers Learnng ponts mld hyperhomocystenaema s a rsk factor for atherosclerotc dsease and venous thromboss «a methonne loadng test s recommended for the dagnoss of hyperhomocystenaema n the ndvdual patent n the case of an abnormal test result, treatment wth vtamns nvolved n homocystene metabolsm should be consdered Box 6 justfy routne screenng for ths rsk factor on a large scale. Meanwhle, to clarfy the ndvdual patent s rsk of developng areroscleross or thromboembolc events^ t s advsable to perform a methonne loadng test for the screenng of hyperhomocystenaema5 at least n those cases n whch conventonal rsk factors are absent (box 6). r > <>». V "» M udd SH, Levy HL, Skovby F. Dsorders of transsulfuraton. n; Scrver CR, Beaudet AL, Sly W Sj Valle D, cds, The metabolc and molecular bass of nherted dsease. New York: McGraw- Hll, 995; pp M udd SH, Skovby F, Levy HL, et al. The natural hstory of homocystnura due to cystathonne-synthase defcency. Am J Hum Genet : Ueland PM, Refsum H, Brattstrom L. Plasma homocystene and cardovascular dsease. n: Francs RB Jr, ed. Atherosclerotc cardovascular dsease~} hemostass, and endothelal functon. New York; Marcel Dekker, 992; pp van den Berg M, Franken D G, Boers GHJ, et al, Combned vtamn B6 plus folc acd therapy n young patents wth arteroscleross and hyperhomocystenema. J Vase Surg 994; 20: Franken D G, Boers GHJ, Blom HJ, et al. Treatment of mld hyperhomocystenaema n vascular patents. Artenoscler Thromb 994; 4: Stampfer MJ, Malnow M R, Wllett W C, et a l A prospectve study of plasma homocyst(e)nc and rsk of myocardal nfarcton n US physcans. JAM A 992; 268: Arnesen E, Refsum H, Bonaa K-, et al. The Tromso study: serum total homocystene and myocardal nfarcton, a prospectve study. n; Abstracts, 3rd nternatonal Conference on Preventve Cardology. Oslo 993; p78, 8 van den Berg M, Boers GHJ, Franken D G, et al. Hyperhomocystenaema and endothelal dysfuncton n young patents wth perpheral occlusve dsease. Bur J Cln nvest 995: 25: Malnow MR. Homocystene and arteral occlusve dseases. J ntern Med 994; 236: Bostom A G, Jacques PF, Nadeau M R, et al. Post-methonne load hyperhomocystenaema n persons wth normal fastng total plasma homocystene: ntal results from the N H LB famly heart study. Atheroscleross 995; 6: Boers G H J, van den Berg M, Franken D G. Treatment of mld hyperhomocystenaema. n; H Rosenberg, Graham, P Uelandj H Refsum, eds. Homocystene metabolsm, from basc scence to clncal medcne. Norwell, USA: Kluwer Academc Publshers, 996; (n press). 2 Clarke R, Day L, Robnson K, et al. Hyperhomocystenema: an ndependent rsk factor for vascular dsease. N Engl J Med 99; 324: 49-55, 3 Boers GHJ, Fowler B, Smals AGH, et al. mproved dentfcaton of heterozygotes for homocystnura due to cystathonne synthase defcency by the combnaton of methonne loadng and enzyme determnaton n cultured fbroblasts. Hum Genet 985; 69: Kang SS3 Wong PWK, Bock H G, et a l ntermedate hyperhomocystenema resultng from compound heterozygosty of methy enetetrahydrofolate reductase mutatons. Am J Hum Genet 99; 48: Kang SS, Wong PWK, Susmano A, et al Thermolable methylenetetrahydrofolate reductase: an nherted rsk factor for coronary artery dsease. Am J Hum Genet 99; 48: Selhub J, Jacques PF, Wlson PWF, Rush D, Rosenberg H, Vtamn status and ntake as prmary determnants of homocystene n elderly patents, JAM A 993; 270: Shn HC, Lnkswler HM, Tryptophan and methonne metabolsm of adult females as affected by vtamn B-6 defcency. J Nutr 974; 04: Mller JW, Rbaya-Mercado JD, Russell RM, et a l Effect of vtamn B-6 defcency on fastng plasma homocystene concent ratons Am J Cln Nutr 992; 55: Brattstrftm L, sraelsson B, Norrvng B, et a. mpared homocystene metabolsm n earlyonset cerebral and perpheral occlusve arteral dsease, Effects of pyndaxne and folc acd treatment. Atheroscleross 990; 8: Ueland PM, Refsum H. Plasma homocystene, a rsk factor for vascular dsease plasma levels n health, dsease, and drug therapy. 7 Lob Cln Med t9&9;ll4: , 2 Hultberg B, Agardh E, Andersson A, f al. ncreased levels of plasma homocystene are assocated wth nephropathy, but not severe retnopathy n type dabetes melltus. Scand J Cln Lab nvest 99; 5: Agardh C D, Agardh E, Andersson A, ct a l Lack of assocaton between plasma homocystene levels and mcroangopathy n type dabetes melltus. Scand J Cln Lab nvest 994; 54: 637-" 4, 23 Guttormsen AB, Schneede J, Fskerstrand T, et a l Plasma concentratons of homocystene and other amno compounds are related to food ntake n healthy human subjects. J Nutr 994; 24: Refsum H, Ueland PM. Clncal sgnfcance of pharmacologcal modulaton of homocystene metabolsm. Trends Pharmacol Sc 990; : Wlcken DEL, Wlcken B. The pathogeness of coronary artery dsease. A possble role for methonne metabolsm. J Cln nvest 976; 57: Boers GHJ. Hyperhomocystenaema: a newly recognzed rsk factor for vascular dsease. N ethj Med 994; 45: Verhoef P, Hennekens CH, Malnow R, et al. A prospectve study of plasma homocyst(e)ne and rsk of schemc stroke. Stroke 994; 25: 924r Taylor LM, DeFrang RD, Harrs EJ, et a l The assocaton of elevated plasma homocyst(e)ne wth progresson of symptomatc perpheral arteral dsease. J Vase Surg 99; 3: von Eckardsten A, Malnow M R, Upson B, et a l Effects of age, lpoprotens, and hemostatc parameters on de role of homocyst(e)nema as a cardovascular rsk factor n men. Artenoscler Thromb 994; 4: Malnow M R, Neto FJ, Szklo M, et a l Carotd artery ntmal-medal wall dckenng and plasma homo cyst (e) n e n asymptomatc adults; the Atheroscleross Rsk n Communtes Study. Crculaton 993; 87: Selhub J, Jacques PF, Bostom AG, et a l Assocaton between plasma homocystene concentratons and extracranal carotd-artery stenoss. N Engl J Med 995; 332: den Hejer M, Blom HJ, Gerrts WBJ, et a l s hyperhomocystenaema a rsk factor for recurrent venous thromboss lancet 995; 345: Molgaard J, Malnow M R, Lassvk C, ct a l Hyperhomocyst(e)naema: an ndependent rsk factor for ntermttent claudcaton. J ntern Aled Res 992; 23: Starkebaum G, Harlan JM. Endothelal cel! njury due to copper-catalyzed hydrogen peroxde generaton from homocystene. J Cln nvest 986; 77: Stamler JS, Osborne JA, Jarak A. Adverse vascular effects of homocystene are modulated by endothelum-derved relaxng factor and related oxdes of ntrogen. J Cln nvest 993; 9: Harker LA, Slcluer SJ, Scott CR, et a l Homocystnema. Vascular njury and arteral thromboss. N Eng! J Med 974; 29: Harker LA, Ross R, Slchter SJ, Scott CR. Homocystene-nduced atheroscleross. The role of endothelal cell njury and platelet response n ts geness. J Cln nvest 976; 58: dc Groot PG, Wllems C, Hocrs GHJ, ct a l Endothelal cell dysfuncton n homocystnura. Eur J Cln nvest 3: Tsa J-C, P err ell a M A, Yoshzum M, ct a l Promoton of vascular smooth muscle cell growth by homocystene: a lnk to atheroscleross. hvc Natl Acad Sc USA 994; 9: Letuz SR, Sadler JE, nhbton of thrombomoduln surfase expresson and proten C actvaton by the thrombogenetc agent homocvstene. J Cln nvest 993; 9: Sardhanvalla B, Fowler B, Robns AJ, et a l Detecton of heterozygotes for homocystnura. Arch Ds Chld 974; 49: Engbersen AMT, Blum HJ, Franken D G, ef a l 'Fhermolable 5,O-methylenetetrahydrofolate reductase as the cause of mld hyperhomocystenema. Ant J Hum Genet 995; 56: Whtehead AS, Ward l 'lan S, et a l The molecular genetcs of homocystnura, hyperhomocystenaema, and premature vascular dsease n reland. n; Mato JM, Caballero A, eds. Methonne metabolsm; molecular mechansms and clncal mplcatons. Aladnd; CSCt 994; pp Kozch V, Kraus H, de Franchs R., ct a l Hyperhomocysteneama n premature arteral dsease: examnaton of cystathonne B-synthase alleles at the molecular level. Hum Atolec Genet 995; 4: Goyette, Sumner JS, Mlos R, et a l Human methylenetetrahydrofolate reductase: solaton of cdna, mappng and mutaton dentfcaton. Nat Genet 994; 7: Frosst P, Blom HJ, Mlos R, ct al, A canddate genetc rsk factor for vascular dsease: a common mutaton n rnethylenetctrahydrofolate reductase. Nat Genet 995; 0: -3.
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