acrem Asian Case Reports in Emergency Medicine 2328-0409 2328-0395 beplay体育官网网页版等您来挑战! 10.12677/acrem.2024.123012 acrem-93804 Articles 医药卫生 胆红素水平与冠心病关系的研究进展
Research Progress of Relationship between Bilirubin Level and Coronary Heart Disease
胡松林 华北理工大学附属医院心血管内科一病区,河北 唐山 17 07 2024 12 03 82 87 24 6 :2024 2 6 :2024 2 8 :2024 Copyright © 2024 beplay安卓登录 All rights reserved. 2024 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ 冠状动脉粥样硬化性心脏病(CHD)是一种常见的心血管疾病,随着人们社会生活水平的提高和饮食结构的改变,冠心病的发病率逐年增长,成为心血管系统疾病的最重要疾病之一。上世纪60年代初,美国完成了一项具有划时代意义的大型流行病学研究——Framingham研究,从此人们的认知中多了CHD危险因素这一重要概念,而胆红素(Bilirubin, BIL)属于其中较具代表性的一种,通过检测血清中BIL的浓度,可能对CHD的早期预测以及冠脉病变程度的评判有着极其重要的价值。一些学者认为BIL是冠心病的保护因素,但也有研究表明BIL与CHD的发生不相关甚至呈正相关,本文就BIL与CHD的关系做如下综述。
Coronary artery atherosclerotic heart disease is a common cardiovascular disease. With the improvement of people’s social living standards and changes in dietary structure, the incidence of coronary heart disease has been increasing year by year, becoming one of the most important diseases in the cardiovascular system. In the early 1960s, a groundbreaking large-scale epidemiological study called the Framingham Study was completed in the United States. Since then, people have gained an important concept of CHD risk factors. Bilirubin (BIL) is one representative factor among them. By detecting the concentration of BIL in serum, it may have significant value for early prediction of CHD and evaluation of coronary artery lesions. Some scholars believe that BIL is a protective factor for coronary heart disease, but there are also studies showing that BIL is not related to or even positively correlated with CHD occurrence. This article provides a review on the relationship between BIL and CHD as follows.
冠心病,胆红素
Coronary Heart Disease
Bilirubin
1. 前言

近年来,冠心病的发病率逐渐年轻化 [1] ,在全球范围中,每年至少有大于700万人死于冠心病,占所有疾病死因的12.8% [2] 。冠心病的发病是一个高度复杂的过程,脂质代谢紊乱与其发病密切相关,血液中的脂质大量沉积,使冠状动脉发生动脉粥样硬化,从而引起冠脉管腔狭窄、阻塞,进而导致心肌细胞发生缺血坏死的缺血性心肌病 [3] [4] ,其可以引起胸闷、胸痛、心悸、气短等不适症状,严重时可危及生命。通过不断的研究探索,目前已有超200种危险因素被人们相继发现,其中已被公认的主要危险因素有高龄、男性、吸烟、缺乏运动、高血压、血脂异常、糖尿病、肥胖以及家族史等 [5] ,但是据相关流行病学报道,仍有相当一批CHD患者并不存在以上这些传统致病危险因素,仅凭这些并不能对所有CHD的发生进行准确预判,故此,国内外的学者们目前仍在寻找一些可以对CHD进行准确预测及评估的相关因素。近些年来,人们发现机体内的一些代谢产物可能亦是与CHD发生潜在相关的因素。胆红素异常在冠心病的发生、发展中可能起到一定的作用,它也与不同形式的冠心病,即稳定性冠心病、不稳定性心绞痛、稳定性心绞痛和急性心肌梗死有共同的关联。大量研究表明,血清胆红素在体内主要以人血白蛋白结合型胆红素存在,当人体消耗掉内源性抗氧化剂后(如抗坏血酸和胆红素等),在脂蛋白酶氧化修饰开始时,给予人血白蛋白结合型胆红素,可明显抑制氢过氧化物的形成,而仅补充相同剂量的人血白蛋白却无此效果。较高水平的血清胆红素可有效预防家族性胆固醇升高患者冠心病的发生,这可能是由于胆红素可以抑制LDL转化成ox-LDL,均表明血清胆红素具有抗氧化性,参与人体氧化与抗氧化平衡机制。

<xref></xref>2. BIL的生成与代谢

胆红素代谢过程主要是红细胞破坏,释放出血红蛋白,代谢生成游离的珠蛋白和血红素。血红素经微粒体血红素氧化酶的作用生成胆绿素,进一步在胆绿素还原酶作用下被还原为胆红素。正常人由红细胞破坏形成的胆红素,占总胆红素的80%~85%,其余15%~20%来自含有亚铁血红素的非血红蛋白物质,即骨髓中无效造血的血红蛋白,这种胆红素称为旁路性胆红素,以上形成的胆红素称为游离胆红素。在血液中与清蛋白结合形成的复合体称为非结合胆红素,以清蛋白为载体的非结合胆红素随血流进入肝脏,迅速被肝细胞摄取,肝细胞清除非结合胆红素的效率非常高。游离胆红素在肝细胞内与YZ蛋白结合后,再与谷胱甘肽S-转移酶结合,并被运送到肝细胞的光面内质网,在那里胆红素与配体结合,蛋白分离。与胆红素–尿苷二磷酸葡萄糖醛酸作用,形成单葡萄糖醛酸红素和双葡萄糖醛酸胆红素,即结合胆红素。

3. BIL与冠心病之间的致病机制

BIL与冠心病之间的致病机制目前尚未完全明确,目前多项研究表明主要与以下因素有关。

胆红素作为机体的内源性抗氧化剂之一,其心血管疾病保护机制主要涉及抑制体内低密度脂蛋白氧化修饰 [6] 、清除氧自由基 [7] [8] 、抗增殖 [9] 、抗炎症 [10] 、抗内皮功能障碍等生理作用。当胆红素与白蛋白结合后可自由进入血管壁,其抗氧化性可于血管壁处抑制低密度脂蛋白的氧化和巨噬细胞释放的氧自由基造成的损伤,从而防止动脉粥样硬化的进展 [11] 。另外,胆绿素和胆红素之间通过氧化还原循环清除体内羟基、单态氧等氧化物,亲脂性的活性氧还可直接与胆红素作用,使其氧化成胆绿素,起到抗氧化作用 [12] [13] 。Greabu等 [14] 的一项研究通过校正性别和年龄因素后,指出冠心病患者组的血清胆红素水平明显低于正常对照组,还发现胆红素浓度与白细胞活性具有相关性,从而推断出胆红素的心血管保护机制涉及炎症免疫机制。Hwang等 [15] 于2011年的一项相关性研究发现,随着C反映蛋白水平的升高,总胆红素及直接胆红素水平逐渐减低,提示胆红素的抗动脉粥样硬化作用可能与抗炎作用有关。

4. BIL与冠心病相关性研究 4.1. BIL水平与冠心病发病的相关性

如前所述,近年来冠心病的发病率居高不下,严重危害着人类健康。目前已有研究 [16] 指出的BIL水平与冠心病的发生率呈负相关,根据李鲁 [17] 通过ROC曲线分析,BIL对冠心病有一定的诊断价值,BIL水平与冠心病的发生率呈负相关。Xiao [18] 等研究指出,胆红素可有效保护血管内壁免受损伤,与冠心病的严重程度呈负相关。Villelabeitia-Jaureguizar [19] 等研究发现,冠心病患者的胆红素较低,推测胆红素水平较低可能是冠心病的重要危险因素。Oda [20] 等入选体检男性3375例和女性2069例,调整年龄、肝功、吸烟、体力活动和饮酒因素后,随总胆红素升高,冠心病和中风发病率有降低趋势。然而GuptaN [21] 低血清胆红素水平与冠心病风险增加之间的因果关系目前尚未确定,Stender [21] 团队通过3个孟德尔随机化研究和荟萃分析后指出人血清BIL水平与IHD的发病风险并无因果联系。故此,BIL与CHD之间究竟是什么样的相关关系,仍需大量设计严谨的流行病学研究去进行验证。

4.2. BIL与冠脉病变支数之间的关系

冠状动脉包括左冠状动脉和右冠状动脉,分别开口于升主动脉的左冠状动脉窦和右冠状动脉窦。左冠状动脉又分为左前降支与左回旋支。后两者与右冠脉为冠状血管的三条主要分支。丁宁 [23] 研究结果显示,随着CHD患者冠状动脉病变支数的增加和Gensini积分的增高,TB水平逐渐降低,李姗茜 [24] 按冠脉病变支数分组后,随着冠脉病变支数增多,患者TBIL、LVEF水平降低,NLR呈升高趋势,在不同的冠脉病变支数组间有显著差异(P < 0.05),然而崔妍 [25] 研究中不同冠脉病变组中两两比较大多无统计学意义(P > 0.008),结果与大多数文献报道不一致。故本研究将进一步探讨BIL与冠脉病变支数之间的关系。

4.3. BIL水平与Gensini评分及SYNTAX-II评分关系

冠状动脉造影术(CAG)是诊断冠心病的“金标准”,在临床中应用颇为广泛。Gensini评分是一种基于CAG评价冠状动脉病变严重程度的计分法,根据造影结果,对每支冠脉血管病变狭窄程度进行定量评定,狭窄程度以最严重处为标准,并根据不同冠脉分支将以上得分乘以相应系数,各病变支得分总和即为患者的冠状动脉病变狭窄程度总积分。Syntax-II评分系统也是一项综合评价冠脉病变程度的标准。根据冠状动脉位置、严重程度、分叉等解剖特点对冠状动脉病变进行定量分析,是一项较为全面的评价冠状动脉病变程度的指标,可作为主要不良心脑血管事件的独立预测因子。根据Akboga [26] 等发现稳定性冠心病患者的总胆红素水平与Gensini评分呈负相关。Turfan [27] 等研究证实总胆红素水平与Syntax评分独立负相关(OR = 0.155, 95% CI: 0.039~0.62, P = 0.008),提示稳定性冠心病胆红素升高具有延缓冠脉病变发展的作用。然而Sahin [28] 等将急性ST段抬高心肌梗死患者根据SYNTAX评分是否≥22分分组,发现高总胆红素浓度是SYNTAX评分升高的独立危险因素(OR = 1.86, 95% CI: 1.04~3.35, P = 0.038)。Kaya [29] 等入选急性非ST段抬高心肌梗死患者,发现总胆红素与SYNTAX评分呈正相关(r = 0.495, P = 0.005),多因素分析显示总胆红素是SYNTAX评分的独立危险因素。故BIL水平与冠脉病变程度之间的相关性需要更多的研究去确定。

4.4. SUA与冠脉斑块稳定性的关系

通过上述BIL与冠心病之间的致病机制,我们能了解到胆红素水平可改善动脉粥样硬化的发生进而降低心血管事件的发生。Canpolat [30] 等经冠脉CT评价冠脉斑块性质和严重程度,并将管腔狭窄 > 50%定义为严重狭窄。研究发现斑块组的总胆红素浓度低于无斑块组,严重狭窄组低于非严重狭窄组,非钙化斑块组、混合斑块组低于钙化斑块组和无斑块组,多因素分析提示总胆红素水平与非钙化斑块独立负相关(OR = 0.76, 95% CI: 0.58~0.88, P < 0.001)。Zhu [31] 等使用冠脉内超声评价总胆红素和冠脉斑块的关系,发现总胆红素浓度与脂质斑块独立负相关,提示总胆红素浓度升高可促进斑块稳定,然而Xu [32] 报道了总胆红素浓度水平与冠脉斑块稳定性成负相关,即胆红素水平越高,冠脉斑块越不稳定,通过对上面的多名研究人员临床研究结果分析中,我们不难看出SUA水平与冠脉斑块稳定性关系,仍然值得我们深入进步探讨进一步明确二者之间的关系。

5. 结论

综上所述,我国冠心病居高不下发病率的现状不容乐观,与之相关的预测因子也越来越得到临床工作者及研究者的关注,在临床中BIL的测定简单、费用低,是临床上应用广泛的检验指标。目前部分研究均表明BIL水平与冠心病的发生发展、严重程度有一定相关性,然而,在BIL与冠心病发病率、冠脉病变支数、Gensini评分、斑块稳定性的研究中,这些研究得出的结果有所不同,仍存在一定的争议性。这些都是有待进一步研究去证实的地方。通过进一步明确二者之间的联系,通过提供有效的干预措施,指导冠心病的临床诊断和治疗,改善患者的预后和生活质量。

NOTES

*通讯作者。

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