同胱胺酸與血管病之危險性

Abstract

背景： 同胱胺酸是否是血管病的獨立危險因子，我們提出一些可能的假說:同胱胺酸有可能造成血流動力學的改變而減緩流速，進而造成血管動脈硬化;可能造成腦部大腦白質病變，進而引發中風及失智症;同胱胺酸是血管病的危險因子;高血清同胱胺酸與失智症有關，如果降低血清同胱胺酸，可能可以改善智力，或阻止智力惡化。 研究方法： 針對以上的假設，我們執行以下計劃：1.觀察性研究：觀察不同濃度的同胱胺酸對頸動脈與椎動脈的血流動力影響;2.病例對照研究：有大腦白質病變者其同胱胺酸濃度是否與無病變者不同;3.長期追蹤研究：同胱胺酸的濃度是否為未來發生腦中風及心臟病的預測因子;4.隨機雙盲研究：維他命療法對降同胱胺酸及智力改善或減緩智力退化是否有臨床效用。 結果： 同胱胺酸並不影響大血管之血流動力學。同胱胺酸為大腦白質病變之危險因子，每增加1 μmol/L同胱胺酸，其發生白質病變之相對危險值為1.15 (95% CI, 1.01-1.31)。在長期世代追蹤研究，平均追蹤時間11.95年，同胱胺酸高的族群，其發生腦中風的危險並無顯著增加，但發生心血管疾病之危險性及死亡率有顯著增加。我們定出臨床上最適當的切點，發現同胱胺酸大於9.47 μmol/L者，發生心血管病之危險為小於此值的人的2.3倍 (95% CI,1.24-4.18)，大於11.84 μmol/L者，死亡之危險為2.4倍(95% CI,1.76-3.32)。降同胱胺酸維他命療法之隨機雙盲實驗，治療半年後，維他命組，血清中葉酸及B12濃度明顯高於用安慰劑組，且同胱胺酸濃度在治療組也明顯低於對照組，然而此二組智能之變化並沒有因用維他命治療而有不同。 結論： 同胱胺酸並不影響血管的血流動力，但與微小血管產生的大腦白質病變有關。長期追蹤無症狀之成人，同胱胺酸並不會增加發生腦中風的危險，但卻是心血管病及死亡之危險因子。以降低同胱胺酸之維他命療法，對阿茲海默症患者之智能改善，沒有明顯的幫助。

Background The relationship between elevated plasma homocysteine (Hcy) and vascular disease is stronger in retrospective than in prospective studies. We proposed the following 4 hypotheses: 1. Hcy may influence the hemodynamic flow of cerebral arteries and then may further induce atherosclerotic change; 2. Hcy may induce microangiopathy and lead to cerebral white matter change which may be related to future stroke and dementia; 3. Baseline Hcy may be related to future vascular event; 4. Hcy-lowering therapy with vitamin supplementation might be benefit for persons with dementia. Material and methods We conducted a cross-sectional study to explore the relationship between Hcy and the hemodynamic status of carotid and vertebral artery; a case-control study for Hcy and cerebral white matter lesions; a cohort study for Hcy and long-term vascular events; an experimental randomized control trial study for Hcy-lowering therapy on dementia. Results Hcy was not associated with the hemodynamic change on the extracranial cerebral arteries. However, Hcy is an independent risk factor for cerebral white matter change (multivariate RR 1.15, 95% CI 1.01-1.31). In the prospective cohort study with median 11.95 years of follow-up, participants with Hcy more than 9.47 &micro;mol/L had a 2.3-fold risk for cardiovascular events (95% CI, 1.24-4.18, p=0.008), and participants with Hcy more than 11.84 &micro;mol/L had a 2.4 fold risk for death (95% CI, 1.76-3.32, p<0.0001). Multivitamin supplements significantly elevated the concentration of vitamin B12 (p<0.0001) and folic acid (p<0.0001) and lowered the plasma homocysteine concentration (p=0.004) after 26 weeks’ treatment. However, no significant differences between the vitamin and placebo groups in the scores of cognition and activities of daily living were found. Conclusions Hcy was not associated with the hemodynamic change on the large extracranial cerebral arteries. The effects of Hcy on the brain may be related to cerebral microangiopathy. Homocysteine was significantly related to the cardiovascular events and all-cause death, with optimal cutpoint values as 9.47&micro;mol/L and 11.84&micro;mol/L respectively. Oral supplements by over-the-counter multi-vitamins containing B6, B12, and folic acid decreased Hcy concentration in patients with mild to moderate Alzheimer’s dementia. However, there were no statistically significant beneficial effects on cognition and function for daily living.