慢性阻塞性肺疾病与肌少症的研究进展
Advances in Chronic Obstructive Pulmonary Disease and Sarcopenia
DOI:10.12677/acm.2024.1472100,PDF,HTML,XML,下载: 26浏览: 52科研立项经费支持
作者:陈 璐*,陆孝灵,李 莉,夏应婷:大理大学临床医学院,云南 大理;冷 静#:云南省第三人民医院呼吸与危重症学科,云南 昆明
关键词:慢阻肺肌少症发病机制相关性干预措施Chronic Obstructive Pulmonary DiseaseSarcopeniaPathogenesisCorrelationIntervention
摘要:慢性阻塞性肺疾病,简称:慢阻肺,是一种以气道狭窄和呼吸障碍为特征的慢性炎症性肺疾病。肌少症表现为随年龄增长而出现的肌肉质量和功能减退,肌少症不仅是是慢阻肺发生及发展的独立危险因素,也是导致慢阻肺患者疾病快速进展、住院率及死亡率升高以及不良预后发生的严重并发症之一。因此,对于两种疾病的深入了解,有助于制定有效的管理策略。
Abstract:Chronic Obstructive Pulmonary Disease, or simply: COPD, is a chronic inflammatory lung disease characterized by narrowed airways and impaired breathing. Sarcopenia manifests as a loss of muscle mass and function with age. Sarcopenia is not only an independent risk factor for the development and progression of chronic obstructive pulmonary disease, but also one of the serious complications leading to rapid disease progression, increased hospitalization and mortality rates, and the occurrence of poor prognosis in patients with chronic obstructive pulmonary disease. Therefore, an in-depth understanding of both diseases can help to develop effective management strategies.
文章引用:陈璐, 冷静, 陆孝灵, 李莉, 夏应婷. 慢性阻塞性肺疾病与肌少症的研究进展[J]. 临床医学进展, 2024, 14(7): 951-957. https://doi.org/10.12677/acm.2024.1472100

1. 引言

肌少症与年龄相关,影响肌肉的质量、力量和性能,给患者的生活质量带来重大影响。在呼吸系统疾病患者中,尤其是慢性阻塞性肺疾病患者,肌少症将会导致患者运动耐力降低、生活质量下降和死亡风险增加等事件发生。尽管这种相关性已得到广泛认识,但肌少症在呼吸系统疾病管理中的作用仍然不足。

2. 肌少症的概念

肌肉减少症(Sarcopenia,简称肌少症):这一定义在1989年[1]被首次提出,随后数十年学者们为深入了解该疾病及丰富其定义开展了无数研究。欧洲老年人肌少症工作组[2](EWGSOP)于2010年发布了关于肌少症的共识,2018年又更新了肌少症的概念:肌少症是一种肌肉疾病(肌肉衰竭),是人在一生中发生的肌肉不良变化。随后,亚洲肌少症工作组(AWGS)于2019年也公布了关于肌少症的共识,该指南将肌少症的定义为一组老年综合征,主要特征为与年龄相关的全身骨骼肌肌量减少、肌力下降和躯体功能障碍。其严重危害老年人健康及功能,并且可能会增加临床不良事件发生的概率,如跌倒、骨折、再住院和死亡等[3]。有学者对2771项研究的标题和摘要进行筛选,对标题和摘要是否包含跌倒及骨折的审查产生了241项相关研究,进行全文筛选后有36项研究符合所有纳入标准,对其中的33项进行了Meta分析,最终得出与非肌肉减少症患者相比,肌肉减少症患者跌倒和骨折的风险明显更高[4]。这一定义类似于EWGSOP 2010,但基于亚洲人种的各方面数据调研,它对肌少症每个诊断条目的界值做了调整[5][6],因此目前对肌少症的诊断尚没有统一标准。临床对于诊断肌少症有诸多方法。诊断肌少症的仪器包括核磁、CT、生物电阻抗分析仪(BIA)、双能X线吸收仪(DXA)等。甚至超声对于肌少症的诊断也有一定作用。例如:核磁:是一种无辐射暴露的非侵入性方法,它对于软组织的分辨率非常高,能够清晰区分肌肉与脂肪组织,对人体的测量简单准确且操作重复性好,但是心脏起搏器、金属假体等检查禁忌限制了MRI的应用范围[7]。CT扫描是一种测量肌肉质量的准确方法,在量化脂肪及评估脂肪浸润的肌肉方面是非常有价值的[8],但考虑到该检查具有辐射暴露、设备成本、缺乏便携性等方面,因此也受到一定的限制[9]。双能X线吸收仪(DXA):利用两种不同能量级别的X线束在通过人体时会进行衰减的特性来计算这两种X射线的衰减程度,借此估算全身或特定组织的骨骼矿物质含量、脂肪含量和瘦体质量(皮肤、结缔组织、实质和骨骼肌肉质量)[10]。DXA检测方便且辐射小,是目前最常使用的检查手段之一[11]。然而,DXA技术存在一定的局限性,它无法准确区分肌纤维间的脂肪组织,这可能导致在评估肌肉质量时出现低估的情况。且机体饮食、饮水、身高和肥胖程度等因素影响,因此DXA的准确性略低[12]。生物电阻抗分析(BIA):根据全身电导率估算全身水分,并使用转换方程来估算脂肪量和无脂肪量[13]。由于其具有执行速度快、便于床旁应用的特点,因此它比DXA扫描更具有一些临床相关优势。然而,BIA测量对患者状况高度敏感,例如机体含水量、检查前是否进食、检查过程中电极位置等均会影响最终结果[14]。为了进一步简化诊断标准,有学者还引入了血清肌酐(Cr)/血清胱抑素C (CysC)这一比值,也称为肌肉减少症指数。由于Cr能够反应肌肉质量而CysC不反映,因此Cr/CysC比值被推荐作为肌肉减少症的替代标志物。Cr/CysC比值与肌肉质量与慢阻肺相关不良结局之间的相关性已被证明[15]

3. 肌少症的流行病学

由于世界各地区存在不同人种及族群、有多种研究方法及设备、甚至不同设备的诊断临界值等的不同,因此诸多研究显示肌少症的患病率存在较大差异,一项国外研究中显示在西方国家,一般人群中肌肉减少症的患病率从4.4%到27.5%不等[16][17]。年龄大于65岁的人群中肌少症的患病率为10%~20%,在全球范围内80岁以上的人群中高达50%[18]。按照亚洲肌少症(AWGS)诊断标准,一项纳入了23篇文献的Meta分析,总共涉及21,564名受试者,最后得出的结论为我国老年人患肌少症的总患病率为14%[19],但是,如果按照国际肌少症工作组河欧洲肌少症工作组所发表的诊断标准来看,中国老年肌少症患病率却大不相同,这也进一步印证了即使在同一地区及同一人种运用不同诊断标准进行验证,肌少症患病率也难以统一。

4. 慢阻肺与肌少症的关系

4.1. 慢阻肺与肌少症的相关机制

慢阻肺主要累及肺脏,同时它也能引起全身副作用和其他组织系统的合并症,并与多种疾病共存,如:心血管疾病、胃食管反流、肌肉减少症、骨质疏松症、肺癌、焦虑抑郁等。这些共病对慢阻肺患者疾病的进展、住院率、死亡率以及预后产生了显著影响[20],因此,慢阻肺合并症的管理至关重要。其中,肌肉减少症作为慢阻肺的重要合并症,往往被低估甚至漏诊。它与更频繁的恶化、更严重的呼吸困难、更差的肺功能和更低的运动试验结果相关[21]。因此有诸多实验对两者进行了研究,发现慢阻肺及肌少症在发病机制方面有很多共同之处,例如:1) 炎症反应及氧化应激:慢阻肺病人体内通常会高表达一些炎症因子,如白介素6、C反应蛋白、肿瘤坏死因子等,有研究得出白介素6水平与骨骼肌指数呈负相关,C反应蛋白水平与患者肌肉质量及躯体力量呈正相关[22]。并且氧化应激还会加快肌肉蛋白分解及肌肉萎缩的进程。研究表示炎症因子可通过多种信号通路来增加肌细胞的蛋白质消耗,并抑制蛋白合成。如白介素6通过激活Janus激酶(Janus kinase, JAK)信号传导及转录激活因子信号通路,会使增加肌肉组织中的肌肉生长抑素及某些蛋白水解酶水平升高,加速蛋白质分解代谢,最终导致骨骼肌消耗[23]。2) 线粒体功能障碍:在慢阻肺患者中,骨骼肌细胞中线粒体生物活性及密度均会降低,由于线粒体出现结构及功能紊乱,会导致巨大线粒体的出现[24]。这种形态异常的线粒体生物效能低下而且还会增加活性氧含量,活性氧不仅会损伤周围组织,还能激活某些通路从而促进水解蛋白的表达,最终激活泛素-蛋白酶等系统从而引起肌肉蛋白降解[25]。同时这种异常线粒体会通过自噬导致自身崩解,破碎的线粒体碎片反而会产生更多的活性氧,又通过上述机制加速肌肉蛋白分解。3) 蛋白质合成及代谢紊乱:研究显示人体几乎80%的肌肉干重是由蛋白质组成[26],因此蛋白质合成及分解失衡是导致肌少症发生的关键之一。在慢阻肺病人中,促进骨骼肌生长的信号通路通常会被抑制,而一些负性调控骨骼肌的信号通路常处于激活状态。肌肉生长抑素(MyostSn, MYO)参与骨骼肌蛋白代谢调节。MYO属于转化生长因子-β(TGF-β)家族,负向调控肌细胞的增殖及分化[27],研究表明,慢阻肺患者体内MYO水平明显升高,提示MYO与慢阻肺患者发生肌少症及肌肉功能障碍有一定关系[28]。另外转录调控下核因子κB (NF-κB)、forkheadboxO (FOXO)以及胰岛素样生长因子-1 (IGF-1)等对骨骼肌代谢均有一定影响。4) 失用性萎缩及营养不良:慢阻肺患者因为机体长期慢性缺氧、体力活动减少、缺乏机械刺激将会加重患者呼吸做功和能量消耗,引起骨骼肌分解,同时患者日常通气做功增加,静息能量消耗较正常人明显增多以及能量提供不足,最终导致营养不良,进一步引起骨骼肌分解,使活动受限、日常生活能力丧失,加速残存肺功能恶化。此外吸烟、维生素D缺乏、缺氧、高碳酸血症、类固醇激素的使用等因素在慢阻肺病人并发肌少症中均会产生不同影响。

4.2. 合并肌少症时的临床表现

4.2.1. 运动耐力的减少

肌少症导致肌力下降,进而影响慢阻肺患者的运动耐力和活动能力,使得日常活动更加困难。有学者表示患有慢阻肺合并肌少症的老年人下肢受到的影响通常会比上肢更大[29]。由于慢性缺氧导致患者具有普遍的久坐不动的生活方式以及疾病急性加重期间长时间卧床休息可能会促进肌肉萎缩和骨质流失[30][31]。可能会导致跌倒和骨折的发生率增加,

4.2.2. 呼吸困难增加

肌少症特别是呼吸肌(如膈肌)的减弱,会使得呼吸效率降低,非通气能力增加慢阻肺患者的呼吸困难,同时损害了清理气道能力,增加呼吸道感染及痰栓形成的风险,甚至发生呼吸衰竭、肺性脑病等[32]

4.2.3. 生活质量下降和死亡率增加

肌少症和随之而来的肌肉功能下降,能够显著影响慢阻肺患者的生活质量,并与更高的死亡率相关联。

4.3. 干预措施

4.3.1. 抗阻力运动及有氧训练

体力活动和运动训练是维持肌肉质量和力量的关键[33],例如抗阻力运动和有氧训练,已被证明可以增加肌肉质量、力量和身体机能,同时还可改善患者运动耐量、呼吸困难,并刺激肌肉纤维由II型逐渐转化为更具氧化性的I型纤维,提高线粒体的能力[34][35],因此运动锻炼已可作为治疗肌肉减少症的成功干预措施。

4.3.2. 营养支持治疗

大量证据表明,许多饮食是减轻肌肉减少症负面影响的重要干预措施,在慢阻肺合并肌少症中,例如蛋白质、维生素D、支链氨基酸、多不饱和脂肪酸等已经被证实可以提高骨骼肌蛋白质的合成速率、并对蛋白质合成和运动能力产生积极影响、同时还可以降低慢阻肺病情恶化的速度,这可能会间接减缓患者肌少症的病程[36][37]。因此,患者在加强运动锻炼的同时摄入充足的蛋白质等营养物质也尤为重要。

4.3.3. 药物及激素治疗

虽说运动及饮食干预措施可对肌少症患者可起到一定的作用,但两者并不是最有效的方法,因此引申出了药物治疗。如睾酮、生长激素、生长抑制素抑制剂等,研究表明睾酮可以增加个体的肌肉质量并减少脂肪含量[35],无论睾酮是单独使用或与运动锻炼联合治疗均能增加患者肌肉质量及体内去脂组织含量,同时还能减少患者住院次数及住院时长[38][39]。但其作用机理与剂量密不可分,在给予睾酮时应谨慎,因此共识并没有将睾酮作为肌少症的常规治疗。生长激素可以通过多种途径促进肌肉生长。它可以增加患者的体重、肌肉质量和呼吸肌力量[40]。重要的是,它与睾酮一样,可能会导致患者发生心血管并发症风险增加。

4.3.4. 针对慢阻肺的干预措施

戒烟:是一种可以阻止或延缓慢阻肺进展的最有效手段。因为烟雾及其烟草组成成分不仅能对肺组织和功能产生有害影响,还会损害肌肉线粒体功能和肌肉质量[41][42]。因此戒烟可能会对肌肉功能产生有益影响。支气管扩张剂:可以减轻患者呼吸困难及改善其他呼吸道症状,以间接增加患者运动能力[43]。手术治疗:肺减容手术(LVRS)和支气管镜肺减容术(BLVR)[44]-[46],手术操作不仅改善了呼吸功能和症状,而且还被证明可以提高运动能力和身体成分。

5. 总结与展望

肌肉减少症是可以延缓或者逆转的,尤其是在疾病的早期阶段。因此,早期筛查及诊断肌少症是非常重要,因为早期干预可以预防病理性肌少症的发生或预防肌少症的进展。阻力训练和营养补充等干预措施是解决肌少症的有有效的策略,同时肺系统的有效和新的干预措施(如戒烟、支气管扩张剂和肺减容手术)也可能有助于肌肉维持。未来,我们应该更加深入了解慢阻肺合并肌少症的相关发病机制、治疗策略,充分识别并诊治肌少症,进而提高患者生活质量并改善预后。

基金项目

云南省教育厅科学研究基金项目:慢阻肺患者合并肌少症对肺功能影响的相关性研究,项目编号:2024Y932。

NOTES

*第一作者。

#通讯作者。

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