Research progress in effects of proton pump inhibitors on Coronavirus Disease 2019
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摘要: 新型冠状病毒感染宿主细胞是利用刺突糖蛋白先与细胞表面受体结合，然后被细胞蛋白酶裂解以促进膜融合。质子泵抑制剂（PPIs）能从多方面抑制病毒传播，既可以抑制空泡型质子泵，提高内吞途径中细胞器的腔内pH值，靶向内吞体分选转运复合体，抑制病毒的膜融合和复制，防止病毒从感染细胞传播至未感染细胞，也可以发挥抗炎和抗纤维化作用而减轻肺炎的临床症状，还可以通过联合用药增强其他药物的抗病毒特性。但现有的临床证据尚未明确PPIs的有益作用，甚至发现PPIs可能会增加新型冠状病毒肺炎（COVID-19）的感染风险或严重程度。本文基于现有证据综述PPIs对COVID-19的潜在治疗作用和临床风险，旨在使COVID-19与PPIs相关的风险和收益平衡受到关注。Abstract: The infection mechanism of novel coronavirus infection involves a two-step process where the spike glycoprotein first binds to a cell surface receptor and is subsequently cleaved by a cellular protease to facilitate membrane fusion.Proton pump inhibitors (PPIs) can inhibit the spread of novel coronarirus in many ways.It inhibits cavitation proton pump to lead to raised organelle pH sorts and transports complex by targeting endosome inhibits membrane fusion and replication of novel coronavirus infection,and prevents viral transmission from infected to uninfected cells.They also can act against novel coronavirus infection by exerting anti-inflammatory and antifibrotic effects so as to reduce the clinical symptoms of pneumonia.Combined drug therapy can also be used to enhance the antiviral properties of other drugs.But the current clinical evidences do not point towards a beneficial effect clearly yet.This paper reviewed the potential therapeutic effects and clinical risks of PPIs on Coronavirus Disease 2019(COVID-19) based on the existing evidences,aiming to make clinical attention to the balance between the risks and benefiting associated with COVID-19 and PPIs.
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Keywords:
- proton pump inhibitors /
- Coronavirus Disease 2019 /
- therapy /
- risk of infection /
- severity
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随着经济和社会的发展，心血管疾病和各种代谢性疾病逐渐成为医疗卫生系统沉重的负担。据《中国心血管健康与疾病报告2020》[1]推算，中国心血管病患人数3.3亿，心血管病死亡是城乡居民总死亡原因的首位[2]，中国糖尿病的患病率逐年攀升[3]。研究[4-6]表明，胰岛素抵抗(IR)是心血管疾病和各种代谢性疾病发生发展的重要影响因素，因此在疾病发生之前及早识别IR至关重要。传统用于评估IR的方法主要有高胰岛素-正葡萄糖钳夹法(HIEC)、稳态模型评估(HOMA-IR)等，但复杂且耗时，对研究环境的适用性有限。近年来，甘油三酯葡萄糖(TyG)指数以及甘油三脂葡萄糖体质量(TyG-BMI)指数成了新的评估IR的替代标志物，可由空腹甘油三酯、空腹血糖、体质量指数计算得出，其诊断的准确性已在相关研究中得到验证，应用前景广阔。研究[7]表明, TyG-BMI指数相对于TyG指数的诊断意义更显著。现就TyG-BMI指数的研究进展及其与常见病的相关性作综述。
1. TyG-BMI指数
IR反映的是细胞对胰岛素的反应能力受到损害的病理现象[8], 其发病机理主要包括体内胰岛素受体、传导通路和β3-肾上腺素能受体发生变化，或者体内对抗正常调节通路的作用增强[9]。传统评估IR的方式均有一定的局限性, HIEC于1979年首次提出，至今仍是评估IR的“黄金标准”[10], HIEC的主要局限性在于费时、费力及昂贵，需要经验丰富的操作员来解决技术难题，且钳夹利用的稳态胰岛素水平可能超生理学。HOMA-IR局限性在于接受胰岛素治疗的受试者对胰岛素的敏感性需要进一步验证; 对于严重受损或缺乏β细胞功能的患者, HOMA-IR可能无法提供适当的结果。
TyG-BMI指数最早于2016年提出，通过比较脂质、脂肪因子及脂质和脂肪因子的比率，以及内脏脂肪指标、TyG和TyG相关参数对早期识别IR的价值，得出了TyG-BMI指数与HOMA-IR的关联性最强，提示TyG-BMI指数可用于IR早期鉴定，简单、功能强大且临床效果较好[7]。另有研究[11-12]表明，当TyG指数结合一些肥胖指标如BMI、腰围(WC)及腰围身高比(WTHR)时, 可提高其评价IR的效率。一项研究[13]通过比较TyG指数、TyG-BMI指数、TyG-WC和TyG-WHtR与IR的关联，得出TyG-BMI指数在预测IR方面高于其他参数，进一步证明可以使用TyG-BMI指数作为临床环境中评估IR的替代指标。TyG指数结合TyG-BMI指数评估IR, 其预测价值可能会进一步提升，为临床常见心血管相关慢性病的早期预防提供更积极的指导。
2. TyG-BMI指数与常见心血管相关慢性病的关系
2.1 TyG-BMI指数与动脉粥样硬化
IR对动脉粥样硬化影响的主要机制是IR可以触发内皮功能障碍，增加在内皮细胞、血管平滑肌细胞增殖和迁移中起重要作用的血管细胞黏附分子-1(VCAM-1)的表达，触发白细胞黏附，加速动脉粥样硬化的发展。同时, IR可以潜移默化地长时间诱导巨噬细胞的内质网应激，并且促进巨噬细胞凋亡，最终在动脉粥样硬化进展中导致斑块坏死[14]。
既往研究[15]发现, IR是冠心病患者动脉粥样硬化斑块进展的独立预测因子。一项关于评估成年人动脉粥样硬化性心血管疾病(ASCVD)风险的研究[16]也发现, TyG-BMI指数与女性的ASCVD风险升高显著相关。一项关于缺血性脑卒中研究[17]发现，一般人群中TyG-BMI指数与缺血性脑卒中之间存在独立联系，并且该关系为线性，没有阈值或饱和作用, TyG-BMI指数每增加1个标准差，缺血性脑卒中的发生风险就增加20%。同时, TyG-BMI指数对改善缺血性中风的危险分层具有潜在的实用性，以上研究说明TyG-BMI指数与动脉粥样硬化具有一定的相关性，但目前关于其他动脉粥样硬化性疾病如血栓形成、动脉闭塞等的研究较少，还需进一步探索。
2.2 TyG-BMI指数与高血压前期
高血压前期是指收缩压120~139 mmHg和/或舒张压80~89 mmHg。全世界44周岁以下的成年人高血压前期的发生率为37.5%~77.1%[18-20]。IR对血压的影响是一个复杂的多因素关系，包括遗传因素和环境因素[21]。早年研究[22]发现，在血管系统，胰岛素可以通过刺激一氧化氮(NO)的产生诱导血管舒张。因此, IR状态会抑制NO的产生，继而影响血管舒张。目前, IR引起血压升高的机制主要包括组织中血管紧张素Ⅱ和醛固酮的活性升高[23-24]、交感神经的活性升高[25]、氧化应激[26]以及“内皮性胰岛素抵抗现象”，该现象指出内皮细胞受损可能是外周血胰岛素敏感性降低的原因[27]。
一项研究[28]通过调查105 070名无高血压的非肥胖者，按相应的公式计算BMI、WC、WtHR和TyG指数、TyG-BMI指数、TyG-WC、TyG-WHtR, 得出TyG指数、TyG-BMI指数、TyG-WC和TyG-WHtR均与收缩压、舒张压呈正相关，完全调整混杂因素后，发现只有TyG-BMI、TyG-WC与高血压前期显著相关。该研究表明, TyG-BMI指数作为一种简单的IR替代指标，相对于TyG指数，是非肥胖患者高血压前期的可靠补充监测指标。但该研究调查者类别较单一, TyG-BMI指数的适用条件具有一定的限制，需要进一步研究。
2.3 TyG-BMI指数与糖尿病前期
糖尿病前期是介于糖尿病患者和健康者之间的中间状态。其存在使2型糖尿病的发病风险高了3~10倍[29]。目前糖尿病前期尚无准确的定义或者诊断标准，常用空腹血糖受损(IFG, 指空腹血糖波动在100~125 mg/dL)或葡萄糖耐量受损(IGT，指口服75 g葡萄糖耐量试验2 h, 血浆葡萄糖水平波动在140~200 mg/dL)来表示[30]。目前，评估糖尿病前期的主要方式仍是实验室检查，包括血糖、糖化血红蛋白、血浆胰岛素水平等，指标较单一，诊断效能有限。
最新的研究通过评估11个与肥胖和脂质相关的参数在识别老年哥伦比亚人群中糖尿病前期风险方面的预测能力，得出糖尿病前期参与者的肥胖指标包括BMI、WC、WHtR、TyG指数、TyG-BMI指数、TyG-WC和TyG-WHtRs等与健康组相比显著升高。TyG指数与肥胖指标的结合可用于预测空腹血糖高的风险[13]。此外，进一步的研究[8]发现, TyG-BMI指数是预测成年人中糖尿病前期的最佳指标。
2.4 TyG-BMI指数与高尿酸血症(HUA)
HUA的诊断标准是男性或绝经后妇女的血清尿酸≥420 μmol/L, 绝经前妇女血清尿酸≥360 μmol/L。除引起痛风、慢性肾脏疾病外, HUA也在高血压、糖尿病、心血管疾病的发生发展过程中发挥重要作用[31]。因此，早期识别并及早干预HUA具有重要意义。IR引起HUA的机制主要是通过尿酸转运蛋白完成的。肾脏作为代谢尿酸的重要器官，其主要作用机制是依靠肾小管中的各种尿酸转运蛋白[32], 这些转运蛋白由基因编码，受遗传、环境等多因素影响[33-34]。胰岛素可作为一种内源性调节因子，通过影响肾脏中的尿酸转运蛋白的作用来影响尿酸的代谢[35]。因此，存在IR时，代偿性的高胰岛素血症可影响尿酸转运蛋白的表达，进而减少尿酸的代谢，在HUA的发生发展中起重要作用[36]。
一项关于中国东北地区6 466名受试者的研究[37]发现，TyG指数与HUA之间存在线性而牢固的联系，TyG指数每增加一个标准差，血清尿酸浓度升高12.528 μmol/L, 并增加54.10% 的HUA风险，当将TyG分成四分位数时，最高四分位数的HUA风险是最低四分位数的2.73倍，说明同时控制血糖和脂质对预防HUA具有重要意义。一项关于42 387名接受常规健康检查且无HUA的成年人的研究[38]发现，TyG整合肥胖指标时，相对于TyG指数，可以增强其与女性患者HUA的关联性，具体而言，患病组与正常组相比，TyG-BMI指数在女性中的平均差异为51.90, 在男性中为36.90, 而TyG指数在女性中的平均差异为0.18, 在男性中为0.13。
2.5 TyG-BMI指数与非酒精性脂肪性肝病(NAFLD)
NAFLD是一种常见的肝脏代谢性疾病，实质是肝细胞脂质异常沉积，可发展为非酒精性脂肪性肝炎(NASH)，最终导致肝硬化甚至肝癌。研究[39]表明, IR与NAFLD密切相关, IR通过激活肝星状细胞促进肝脏炎症与纤维化进展。NAFLD常见于与肥胖相关的代谢异常的个体，在非肥胖的中国人群中，也有超过1/5的人患有NAFLD[40]。既往研究[41-42]通过招募50名无症状女性，得出TyG筛查单纯性脂肪变性的敏感性为0.94, 特异性为0.69, 最佳截止点为4.58, 表明TyG指数作为IR的替代标志物，与SteatoTest、NashTest、脂肪肝指数和算法相比，是最佳的筛查指标，可以有效识别有NAFLD危险的个体。
研究发现, TyG-BMI指数与NAFLD风险之间存在更加牢固且积极的联系，优于TyG指数、BMI、甘油三酯和空腹血糖，并且进一步证明，与肥胖者相比，非肥胖个体中的TyG-BMI指数与NAFLD风险更紧密。研究[40]表明, TyG-BMI指数每增加1个标准差, NAFLD的优势比为3.4(95%CI∶3.0~3.9), TyG指数每增加1个标准差, NAFLD的优势比为2.1(95%CI∶1.9~2.2)。分析原因可能是TyG指数联合BMI考虑了体质量带来的影响, BMI作为评估肥胖的指标之一，将其纳入复合指标可能提升了诊断效能。
3. 展望
综上所述, TyG-BMI指数作为一种由TyG指数延伸而来新的评估IR的有效且简单经济的指标，在动脉粥样硬化、高血压前期、糖尿病前期、HUA以及NAFLD中均有确切的意义，且相对于TyG指数，预测上述常见心血管相关慢性病的能力更好。但目前国内外对于TyG-BMI指数的研究仍然较少，缺乏大样本数据和实验研究数据支持，也缺乏更多相关心血管相关慢性病的关联性分析，仍需进一步深入研究。
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