非酒精性脂肪性肝病(NAFLD)是除酒精和其他明确损肝因素所致的,以肝细胞脂肪变性和脂质沉积增多为主要特征的临床综合征,是全球最常见的慢性肝病之一[1]。2024年5月,中华医学会肝病学分会将NAFLD更名为代谢相关(非酒精性)脂肪性肝病(MAFLD)[2]。流行病学调查[3]显示,NAFLD的患病率在世界范围内呈上升趋势,同时肥胖和代谢性合并症(胰岛素抵抗、血脂异常、向心性肥胖和高血压)的患病率也在上升。NAFLD是我国最常见的慢性进展性肝病,其患病率高达25%以上,且发病年龄呈年轻化、低龄化趋势[4]。目前,临床上缺乏非酒精性单纯性脂肪性肝病的有效治疗药物,而针刺、穴位埋线、刮痧、推拿等中医外治疗法在降脂、减重、缓解临床症状等方面有着独特的优势[5]。本文通过总结近年来国内外中医外治法治疗NAFLD的相关临床研究进展,并分析其可能的分子作用机制,从而为今后基础实验和临床研究提供一定的科学理论依据。
历代中医典籍中并无NAFLD相关的病名,根据其临床表现和体征,可将其归属于“肝癖、胁痛、积聚”等范畴,其病位在肝,与脾、肾关系密切[6]。《灵枢·百病始生》曰:“肝之积,曰肥气”。肥气即膏脂积蓄,若脾失健运则散精之职无能,水谷精微不归正化,膏脂转运输布不利,滞留营中。王士雄《温热经纬》云:“盖太饱则脾困,过逸则脾滞,脾气滞而少健运,则饮停湿聚矣。”故本病证属本虚标实,病理因素可概括为痰、湿、浊、瘀、热。病因病机主要为饮食不节,嗜食肥甘厚味,或感受湿热疫毒,劳逸失调等,导致湿热内生,痰湿阻络,气血运行不畅,久而成瘀,湿热痰瘀互结于肝而形成本病。治疗原则以疏肝健脾补肾治本,清利湿热、化痰祛瘀治标。
中医认为针刺有行气活血、健脾疏肝、调整经络、扶正祛邪等作用,可作为中医特色疗法之一用于NAFLD[5]。笔者前期研究[7]发现,电针和普通针刺中脘、天枢、大横、带脉、章门、丰隆等穴位,均可降低肥胖型非酒精性单纯性脂肪肝(NAFL)患者的体质量、BMI、腰围、臀围,并且电针效果明显优于普通针刺。有研究[8]显示,针灸治疗MAFLD的选穴遵循疏肝、补脾、益肾、化痰、祛湿的治疗原则,核心穴组为“足三里-丰隆-太冲”,并辨证配穴,可为临床提供参考依据。电针中脘、曲池、水分、滑肉门、大横、关元、气海等穴位结合生活方式控制,可以有效治疗肥胖型NAFLD,在改善肝脂肪含量、糖脂代谢、胰岛素抵抗、腰围和腰臀比等方面优于单纯生活方式控制[9]。临床研究[10]发现针刺内关、肾俞、太冲、太溪、天枢及足三里、关元、丰隆、三阴交、曲池、阴陵泉、合谷等穴位,治疗NAFLD的疗效较好,能明显降低血脂水平,改善肝功能,且留针30 min治疗效果明显。
穴位埋线疗法属于针灸疗法的一种,通过可吸收缝合线在体内液化、分解、吸收,从而对穴位产生一种柔和而持久的刺激以达疗效,是治疗NAFLD的一种有效手段和方法[11]。由笔者团队制定、中华中医药学会肝胆病分会发布的《穴位埋线治疗非酒精性脂肪性肝病中医实践指南》[12],指出了穴位埋线疗法治疗NAFLD的治疗方案、操作方法和要求,以及临床观察指标等内容。穴位埋线选用中脘、天枢、带脉、滑肉门、关元、气海等穴位,能够有效降低患者血清肝功能、血脂水平,提高血浆脂联素、过氧化物酶体增殖激活α受体(PPAR-α)水平,改善肝脂肪沉积,且疗效优于普通针刺[13]。穴位埋线肝俞、脾俞、中脘、天枢、足三里等穴位,能够持续刺激穴位,长效的机械刺激和溶解过程中的理化刺激可以增强治疗NAFLD患者的效果,能够明显降低患者脂肪肝程度及血脂水平,恢复肝功能[14-15]。穴位埋线梁门、大横、天枢、滑肉门、带脉、水分等穴位,治疗痰湿体质单纯性肥胖合并NAFLD患者效果更为明确[16]。
刮痧疗法属于砭石疗法的范畴,是NAFL患者的有效干预方式之一,包括刮拭手厥阴心包经、手少阳三焦经,刮拭背部、带脉和任脉,以及胃经胆经为主的四井排毒,具有疏通经络、调气排毒、驱邪外出等功效[5]。张峰等[17-18]报道虎符铜砭刮痧单独或联合温阳健脾汤药治疗NAFLD的疗效确切,可有效改善患者的血脂、血糖水平和肝功能,缓解患者相关临床症状。该团队前期研究[19]发现虎符铜砭刮痧联合化痰祛湿活血方,能明显改善NAFLD患者的中医证候,降低体质量、腰围、臀围、腰臀比、TG、HDL-C、FibroScan检测的受控衰减参数,对减重、降脂效果显著;并发现虎符铜砭刮痧配合无饥饿禁食疗法能够改善NAFLD患者的临床症状,减轻体质量,改善肝脂肪变性程度,降低患者血清ALT、AST、TC、TG水平[20]。
早在古代殷墟甲骨文中便有文字记载古代人利用手法治疗腹部疾患的证据。以中医脏腑学说和经络学说为基础的腹部推拿作为一种非药物、易被接受且有效的绿色自然疗法,在治疗NAFLD时推拿手法以健脾为主,并疏肝理气、平补平泻,达到“疏其血气,令其条达,以平为期”的目的[21]。腹部推拿治疗NAFLD选取肝脾经脉循行路线,会直接影响冲、任、督、带、肾、胃六脉,进而对十二经脉气血及五脏六腑产生作用,达到疏通经络、行气活血、调整脏腑的功效。腹部推拿治疗可能通过降低血清瘦素水平及血清肿瘤坏死因子α(TNF-α)含量,降低NAFLD患者的BMI、腰臀比、腰围[22]。有学者以“肠-肝轴”为切入点, 提出利用腹部推拿调“肠”以达到“治肝”的研究思路,有助于更全面、更深入地揭示揉腹法治疗NAFLD的关键作用点和途径,为整体提升腹部推拿的应用水平提供科学依据[23]。
笔者前期研究[24]发现,根据“肝与大肠相通”理论,通过合募配穴法针刺配合药物,可以起到协同增效的作用,能够降低NAFLD的体质量、腰围、BMI、ALT、AST、TG、TC及瘦素指标水平。王新陆教授[25]从血浊论治脂肪肝经验的基础上,采用针药结合,与刺络放血、俞募拔罐等方法协同治疗脂肪肝。针对气滞血瘀型脂肪肝,以行气化浊汤为主以化浊行气,配以支沟-阳陵泉以疏通经络,太冲-合谷以调理脏腑,天枢-膈俞以通调气血[26]。针灸名方“手足十二针”联合中药治疗NAFLD中度NAFL和轻中度非酒精性脂肪性肝炎较单纯中药治疗效果更好,可激发经络之气,增强机体的抗病和应变能力[27]。加味茵陈蒿汤联合针刺合谷、三阴交、足三里、内关、太冲、太溪等穴位治疗,可以明显调节NAFLD患者的肠道菌群含量,抑制氧化应激指标谷胱甘肽过氧化物酶、超氧化物歧化酶、丙二醛的表达及细胞炎性因子指标转化生长因子β、TNF-α、白细胞介素8(IL-8)水平,且不良反应少[28]。中药降脂理肝汤内服与针刺三阴交、肝俞、丰隆、足三里、太冲穴位联用治疗NAFLD,能够进一步提高患者临床疗效,促使其肝功能改善、血脂水平降低[29]。
脐针疗法、刺络泻血疗法、腹部拔罐以及八段锦功法等中医特色疗法,在治疗NAFLD中各具优势。在神阙穴选取坤位、兑位、坎位、震位(参照脐八卦全息图定位)的脐针疗法可能通过调节血脂代谢、改善肝功能、调节氧化应激平衡等途径,发挥治疗NAFLD的作用[30]。刺络泻血疗法可改善肝郁脾虚痰瘀互结型NAFLD(单纯性脂肪肝)患者B超影像学表现,降低TG、TC水平,改善中医证候疗效[31]。腹部拔罐辅助治疗NAFLD患者,以脾胃相关的神阙、天枢、大横、中脘、气海、关元穴为主,能够改善NAFLD患者临床观察指标,尤其是腹型肥胖者效果最佳[32]。中国传统健身气功·八段锦功法是一套独立而完整的健身功法,是一种借助形体活动、呼吸吐纳、心理调节相结合的中小强度有氧运动,研究[33]发现,该方法24周运动处方干预可有效改善轻、中、重NAFLD患者的脂代谢水平,改善肝脏功能状态,降低血糖,达到疏通气血经脉、疏肝利胆、调理脏腑、增强体质的功效。
穴位埋线中脘、曲池、带脉、天枢、大横、水分、关元等穴位,同时联合耳穴贴压胃、脾、大肠、三焦、皮质下、内分泌穴位,对减轻患者的体质量,改善腰围、臀围、BMI,抑制食欲,以及改善中医症候有明显的效果[34]。穴位注射足三里穴联合中药调脂方穴位外敷章门、期门穴,能够通过经络腧穴的传导调节作用,达到健脾祛湿逐瘀的效果,从而缓解NAFL的症状[35]。温针灸联合八段锦训练治疗NAFLD有较好的临床疗效,二者联合有可能成为医院规范化开展NAFLD防治理想的运动方式和手段[36]。推拿拍打操包括直推肋缘法、左右拍打法、揉腹法、按摩神阙穴、拍打胫前等方法,联合耳穴贴压肝、肾、三焦、内分泌、交感穴位,通过疏通肝经,按压神阙穴、拍打足三里、丰隆穴位以达到疏肝理气、健脾和胃、燥化脾湿等功效,对轻度NAFLD湿浊内停证患者的疗效显著[37]。
目前普遍认为胰岛素抵抗是2型糖尿病和NAFLD共同发病的基础,针灸具有改善胰岛素敏感性的潜力。电针刺激中脘、曲池、水分、滑肉门、大横、关元等穴位,可能通过下调自噬相关因子Atg1、Atg13、Beclin-1表达,抑制下丘脑细胞过度自噬以及降低糖原合成酶激酶-3β的表达,进而改善高脂高糖诱导的大鼠胰岛素抵抗[38]。低频电针可能通过调节肝组织腺苷酸激活蛋白激酶/哺乳动物雷帕霉素靶蛋白复合物1/核糖体蛋白S6激酶和相关分子的表达,改善Zucker糖尿病肥胖大鼠的胰岛素抵抗,调节肝脏能量代谢[39]。电针丰隆穴可显著降低高脂血症模型大鼠血脂水平,改善肝脂肪堆积,提高胰岛素敏感性,其机制可能与抑制相关肝脂质合成分子表达、降低血清炎症因子、升高胰岛素底物受体磷酸化水平有关[40]。
针刺在调节脂质代谢方面具有积极作用,而脂质代谢与NAFLD的进展密切相关。电针可能通过调控腺苷酸激活蛋白激酶/乙酰辅酶A羧化酶信号通路,改善db/db小鼠糖脂代谢紊乱[41]。王喜臣等[42]研究发现“疏肝降脂”针法刺激中脘、足三里、丰隆、三阴交、期门、太冲穴,可能通过调节肝组织中脂质相关代谢基因UCP2、PPAR-α、PGC-1α、AMPKα的表达,改善NAFLD大鼠模型的形态学特征和血清血脂水平,促进急性损伤引起的肝细胞凋亡,进而对NAFLD起到治疗作用。针刺足三里、关元、涌泉穴可能通过下调小肠载脂蛋白微粒体甘油三酯转运蛋白、载脂蛋白B和载脂蛋白C2的表达,抑制脂质吸收,改善脂质代谢,进而改善NAFLD代谢综合征小鼠模型的状况[43]。
氧化应激是指活性氧簇及其代谢产物的产生过多,超过机体对其防御能力,出现促氧化物和抗氧化物之间的失平衡状态,是介导NAFLD肝细胞进一步发生炎症的重要机制[44]。NAFLD通常伴有氧化应激,而氧化应激反之促进肝脏中的脂质积累。王海英等[45]研究报道电针刺激双侧带脉穴,可以减轻腹型肥胖型NAFLD大鼠体质量、腹围,减少腹部内脏脂肪堆积,改善肝脂质代谢,其机制可能与抑制氧化应激有关。核转录E2相关因子2(Nrf2)/Kelch样环氧氯丙烷相关蛋白1(Keap1)/血红素氧合酶(HO-1)信号通路在调节氧化应激反应中发挥着极为重要的作用,研究[46]发现针刺疗法可以通过激活Nrf2/Keap1/HO-1信号通路,改善高脂血症大鼠氧化应激与脂质水平,增加机体抗氧化能力,从而达到治疗高脂血症的目的。
炎性因子参与NAFLD的发生与发展,伴随着患者病情的加重,其炎症因子IL-6、IL-8、TNF-α、超敏C反应蛋白等炎性指标在脂肪肝中往往高表达,可诱发脂肪性肝炎及促使其进展,促使肝细胞外基质增生和刺激炎症细胞加速生长[47]。针刺双侧带脉穴位可减轻高脂饮食诱导的NAFLD模型大鼠血清炎症因子IL-6、IL-10和TNF-α水平,改善血脂异常,改善肝功能指标[48]。电针刺激丰隆、三阴交、阴陵泉穴,可能通过增强Sirt1表达,抑制NLRP3/NF-κB信号通路,减轻非酒精性脂肪肝肝脏炎症反应[49]。丰隆穴、太冲穴刺络泻血疗法可显著降低高脂血症大鼠血清中NAFLD相关炎性因子IL-6、IL-18和TNF-α水平[50]。
内质网应激在肝脏细胞脂肪变性的过程中起调控作用,主要激活3条信号通路:未折叠蛋白反应、超负荷反应及固醇调节级联反应,其中固醇调节级联反应与脂质合成关系密切,在NAFLD形成过程中起重要的作用[51]。罗翱等[52]研究报道电针刺激丰隆、足三里穴可能通过抑制肝脏蛋白激酶R样内质网激酶表达进而靶向调控下游活化转录因子4/转录因子C/EBP同源蛋白信号通路,抑制内质网应激,显著改善NAFLD大鼠肝功能,发挥肝脏保护效应。电针丰隆、足三里穴对NAFLD大鼠有良性调节作用,其作用机制可能为下调肝组织固醇调节元件结合蛋白-1c基因与蛋白表达,改善内质网应激,调节脂质代谢紊乱,从而减轻肝组织炎性损伤,且电针丰隆穴效果更优[53]。
肠道菌群是肠道微生态系统中最重要的活性成分,人体的健康与肠道内的菌群结构息息相关,菌群与宿主形成了一种动态的平衡关系,肠道菌群可通过调节免疫力、补充营养和体内肠道稳态等影响宿主健康,肠道菌群失调与NAFLD的发生发展密切相关[54]。有研究[48]表明针刺可降低厚壁菌与拟杆菌的比例,增加拟杆菌门S24-7菌科、普雷沃菌科、拟杆菌科、布劳特菌属、未分类拟杆菌、拟杆菌属和普雷沃菌属的丰度,降低瘤胃球菌科的丰度,提示针刺可以通过调节肠道菌群组成显著改善高脂饮食诱导的NAFLD大鼠的脂质代谢、肝功能指标和全身炎症反应。电针刺激中脘、天枢、关元、丰隆四穴具有较好的治疗营养型肥胖症的作用,其机理可能是通过平衡肠道菌群的结构,良性调节肠黏膜上Toll样受体5蛋白的分布与表达,降低肠黏膜慢性炎症反应,进而促进机体脂质代谢[55]。
埋线丰隆穴及丰隆加三阴交穴均可改善NAFLD大鼠血脂水平,但丰隆加足三里未能显著改善NAFLD大鼠血脂水平,表明丰隆配伍三阴交对NAFLD大鼠具有协同作用,但丰隆配伍足三里可能具有一定的拮抗作用,而代谢组学提示胆碱代谢通路可能是其协同和拮抗作用的内在机制[56]。电针刺激NAFLD大鼠的双侧丰隆、肝俞穴可能通过降低大鼠血清脂多糖含量,下调细胞焦亡非经典途径相关因子肝组织消皮素D(GSDMD)、GSDMD末端氨基结构域(GSDMD-N)、半胱氨酸天冬氨酸蛋白酶-11、IL-1β、IL-18以及TNF-α表达,进而抑制NAFLD大鼠肝细胞焦亡[57]。
综上所述,包括针刺、穴位埋线、刮痧、推拿等在内的中医外治疗法,在NAFLD的治疗中展现了独特的优势和广阔的应用前景。但既往相关临床研究的样本量较少,缺乏多中心、随机、对照、双盲的循证研究,无长期随访追踪研究,临床研究课题设计存在重复性,尚缺乏创新性,具体作用机制方面尚需进一步深入研究和验证。针对不同中医外治疗法的治疗种类、作用时间、不同腧穴的选择是否会对NAFLD动物模型产生不同效应,以及从分子水平、转录组学和代谢组学等方面也是需要在未来研究的重点。
基于以上问题,在以后的研究中还应进一步开展深入的实验研究和多中心大样本随机对照试验,同时利用现代化的研究手段,从机制与疗效上对中医外治疗法治疗NAFLD进行科学的阐释与评估,以期形成一整套具有中医特色的标准化临床诊疗方案体系,为中医外治疗法治疗NAFLD提供强有力的证据支撑。
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