修回日期: 2026-05-06
接受日期: 2026-05-18
在线出版日期: 2026-05-28
胃肠动力障碍是肝硬化患者中常见的并发症之一. 尽管已有许多研究观察到肝硬化患者合并胃肠动力障碍, 但病理生理机制尚未明确. 在临床实践中, 针对肝硬化患者合并的胃肠动力障碍的早期识别和积极干预仍缺乏足够重视. 本文综述归纳了肝硬化合并胃肠动力障碍的流行病学特征、以"肠-脑-肝轴"紊乱为核心的病理生理机制以及当前的诊断与治疗策略. 本文强调对肝硬化患者合并的胃肠动力障碍应开展积极的监测与筛查, 并采用综合考虑肝硬化患者基础疾病特征的个体化治疗方案, 改善患者的生存质量, 优化疾病预后.
核心提要: 胃肠动力障碍是肝硬化患者中常见的并发症之一. 本文综述归纳了肝硬化合并胃肠动力障碍的流行病学特征、以"肠-脑-肝轴"紊乱为核心的病理生理机制以及当前的诊断与治疗策略.
引文著录: 王天泽, 叶青. 肝硬化与胃肠动力障碍: "从机制到临床". 世界华人消化杂志 2026; 34(5): 368-378
Revised: May 6, 2026
Accepted: May 18, 2026
Published online: May 28, 2026
Gastrointestinal motility disorders are among the most frequently encountered complications in patients with liver cirrhosis. Numerous studies have documented these disorders in cirrhotic patients; however, the underlying pathophysiological mechanisms remain poorly understood. In clinical practice, insufficient attention has been paid to the early identification and active management of gastrointestinal motility disorders in this population. This review comprehensively summarizes the epidemiological characteristics, pathophysiological mechanisms centered on dysregulation of the gut-brain-liver axis, and current diagnostic and therapeutic strategies for gastrointestinal motility disorders in cirrhotic patients. Furthermore, this review emphasizes that proactive surveillance and screening for gastrointestinal motility disorders should be undertaken in cirrhotic patients, and that individualized therapeutic regimens should be adopted to improve patients' quality of life and optimize disease prognosis.
- Citation: Wang TZ, Ye Q. Liver cirrhosis and gastrointestinal motility disorders: From mechanisms to clinical practice. Shijie Huaren Xiaohua Zazhi 2026; 34(5): 368-378
- URL: https://www.wjgnet.com/1009-3079/full/v34/i5/368.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i5.368
核心提要: 胃肠动力障碍是肝硬化患者中常见的并发症之一. 本文综述归纳了肝硬化合并胃肠动力障碍的流行病学特征、以"肠-脑-肝轴"紊乱为核心的病理生理机制以及当前的诊断与治疗策略.
肝硬化是由多种肝损伤机制引发的慢性进展性疾病, 其病理特征为肝组织纤维化、肝细胞变性坏死及再生结节形成. 最终会导致肝功能衰竭, 并引发腹水、食管静脉曲张破裂出血、肝性脑病等多种严重并发症, 严重降低患者生活质量并显著增加死亡风险[1]. 值得注意的是, 胃肠动力障碍也是肝硬化的常见并发症之一, 但与其他并发症相比, 未被充分重视. 胃肠动力障碍是由于胃肠道神经肌肉系统功能异常, 导致胃肠道运动协调性受损、收缩强度改变或运动模式紊乱, 进而引起一系列消化道症状的疾病状态[2]. 已有多项研究证实许多肝硬化患者合并胃肠动力障碍, 但其中的潜在病理生理机制尚不明确. 本综述聚焦肝硬化与胃肠动力障碍的关联和潜在病理生理机制, 以推动肝硬化患者合并胃肠动力障碍的早识别、早干预, 改善患者生存质量及预后, 并为后续的科研方向提供理论参考.
食管动力障碍包括贲门失弛缓症、食管胃结合部流出道梗阻、收缩缺失、远端食管痉挛、高收缩性食管以及无效食管动力等[3]. 观察性研究显示[4], 60%的肝硬化患者存在食管动力异常, 但目前尚无证据表明肝硬化患者食管动力障碍患病率升高. 食管动力障碍的症状主要包括吞咽困难、胸痛、反流、烧心等[5]. 一项对78例无食管静脉曲张的肝硬化患者进行评估的研究显示[6], 与健康对照组相比, 肝硬化患者中反流性食管炎的患病率更高(37%). 研究还表明, 酸与胆汁混合反流是肝硬化患者反流的主要形式, 且随着肝功能损害程度的加重, 混合反流的发生率逐步升高. 然而, 对这些患者症状负担的评估显示, 仅有32%的肝硬化患者出现反流症状, 且主要在夜间出现.
胃动力障碍是一种特征为在没有机械性梗阻的情况下胃排空延迟的胃肠动力紊乱, 主要包括胃轻瘫、功能性消化不良等, 典型症状包括恶心、呕吐、腹胀、早饱、餐后饱胀感、上腹部不适或疼痛等[7]. 目前, 肝硬化患者中胃动力障碍发生率的证据仍非常有限. 一项采用固体食物闪烁扫描术进行胃排空检测的研究显示[8], 64%的肝硬化患者存在胃排空延迟, 显著高于非肝硬化组(28%). 一项纳入了1506名慢性病毒性肝炎患者的研究显示[9], 患者中功能性消化不良的发生率为51.3%, 其餐后窘迫综合征占49.9%, 上腹痛综合征占46.7%. 此外, 一项纳入95名肝硬化患者和40名健康对照的研究显示[10], 肝硬化患者的胃肠道症状评分显著更高. 此外, 肝硬化患者中, Child-Pugh分级与胃肠道症状评分呈高度正相关(P<0.05, r = 0.837), 即Child-Pugh分级越高的肝硬化患者, 胃肠道症状越明显.
肠动力障碍是指肠运动功能异常的状态, 常表现为腹泻、便秘等症状[11]. 其核心特征是肠道推进内容物的能力受损, 出现机械性梗阻症状, 但未发现结构性或器质性病变[12]. 研究显示[13], 肠易激综合征在全球普通人群中的患病率约为11.2%, 而在肝硬化患者中的患病率为35.2%[4]. 一项纳入了75名门诊肝硬化患者的研究显示[14], 80%的肝硬化患者存在肠道相关的症状, 其中腹胀最常见(49.5%), 其次为腹痛(24%)、腹泻(13.3%)和便秘(8%).
总而言之, 胃肠动力障碍及其相关症状在肝硬化患者中很常见, 而这一临床现象与二者之间潜在的病理生理机制密不可分.
"肠-脑-肝轴"是连接胃肠道、肝脏与中枢神经系统的双向通信网络(图1), 通过微生物代谢产物、免疫信号、神经通路和内分泌途径实现三者间的动态交互. 整合了肠道微生物群、屏障功能、肝脏代谢及神经调控机制, 共同维持机体稳态[15].
"肠道部分"主要由肠道屏障、肠道微生物群及其代谢产物组成. 肠道微生物群通过代谢物(如短链脂肪酸)影响肝脏功能, 肠道信号通过循环系统传递到大脑, 影响神经功能[16]. "肝脏部分"主要由肝脏的代谢功能和免疫炎症调节功能组成, 通过胆汁酸循环与肠道部分实现双向通信. 胆汁酸通过独特的合成、循环、受体激活机制紧密连接肠道与肝脏, 调控代谢、免疫、菌群平衡[17], 又通过血液循环影响脑内胆汁酸谱, 调节神经功能[16]. 脑部分通过自主神经系统、神经内分泌通路调节肠道运动和分泌以及肝脏代谢[18]. 肝硬化患者中存在胆汁酸代谢障碍、肠道通透性增加和肠道菌群紊乱、免疫功能障碍、内脏高敏感性、神经内分泌调节紊乱等多个环节异常, 导致"肠-脑-肝轴"稳态失调, 最终引起胃肠动力障碍.
胆汁酸代谢是"肠-肝轴"的关键介导因子, 经典通路由胆固醇7α-羟化酶(cytochrome P450 family 7 subfamily A member 1, CYP7A1)介导, 生成胆酸(cholic acid, CA)与鹅脱氧胆酸(chenodeoxycholic acid, CDCA); 替代通路由胆固醇27-羟化酶介导, 仅生成CDCA. 这些在肝脏合成的胆汁酸称为初级胆汁酸, 可在肝脏与甘氨酸或牛磺酸结合, 形成结合型胆汁酸[19]. 结合型胆汁酸经肝细胞基底侧钠离子-牛磺胆酸共转运多肽(Na+-taurocholate cotransporting polypeptide, NTCP)摄取, 经毛细胆管胆盐输出泵(bile salt export pump, BSEP)分泌入胆汁; 肠道胆汁酸经顶端钠依赖性胆汁酸转运体摄取、有机溶质及类固醇转运体外排, 完成肠肝循环. 游离型胆汁酸经有机阴离子转运多肽被肝脏摄取. 未被回肠重吸收的胆汁酸进入结肠, 经双歧杆菌、乳杆菌、梭菌、肠球菌、瘤胃球菌、黄单胞菌、真杆菌等肠道菌群去结合、去羟化生成次级胆汁酸. 肝脏中, 法尼醇X受体(farnesoid X receptor, FXR)激活小异二聚体伴侣(small heterodimer partner, SHP), 抑制胆汁酸合成关键酶CYP7A1的表达; 肠道中, FXR激活成纤维细胞生长因子15/19, 抑制CYP7A1表达. 基底侧NTCP、多药耐药相关蛋白2(multidrug resistance-associated protein 2, MRP2)即毛细胆管结合型有机阴离子转运蛋白、多药耐药蛋白2/3(multidrug resistance protein 2/3, MDR2/3)即胆管磷脂转运蛋白, 均受胆汁酸-FXR通路调控: FXR通过SHP抑制NTCP, 直接上调毛细胆管转运体(BSEP、MDR2/3、MRP2), 维持胆汁酸稳态、限制胞内胆汁酸浓度[20]. 一项病例对照研究显示, 肝硬化患者中血清胆汁酸浓度显著升高, 且与肝硬化严重程度呈强正相关[21]. 在肝硬化患者中, FXR、SHP及FGF19表达降低, 导致CYP7A1过表达, 胆汁酸生成过多[22]. 此外, 一项研究在小鼠模型中证实[23], FXR表达下调导致胆汁酸转运蛋白BSEP表达减少、NTCP表达增加, 引发胆汁酸蓄积. 胆汁酸蓄积与胃肠动力障碍的症状密切相关. 胆汁酸刺激直肠L细胞释放类胰岛素肽5(insulin-like peptide 5, INSL5), INSL5作为促动力因子, 其升高会缩短结肠内容物停留时间、增强排便意愿, 减少肠道对水分和电解质的吸收; 同时, INSL5水平与大便性状评分(布里斯托大便评分)呈正相关, 即INSL5水平越高, 大便的性状越稀烂, 最终引发腹泻[24]. 更为重要的是, 胆汁酸代谢紊乱会进一步引起肠道通透性增加等"肠-脑-肝轴"其他环节的紊乱.
胆汁酸代谢障碍和肠道菌群紊乱是肝硬化患者肠道通透性增加的两大主要原因. 肠道上皮为单层柱状上皮, 上皮层中的紧密连接与黏着连接是维持肠道机械屏障的关键细胞连接. 部分胆汁酸对肠道屏障起保护作用, CDCA可促进仔猪空肠上皮细胞(intestinal porcine epithelial cell-J2, IPEC-J2)增殖、加速细胞周期、改善线粒体功能、减少活性氧生成, 保护肠道屏障[25]. CDCA可激活肠上皮细胞中的FXR, 通过法尼醇X受体-肌球蛋白轻链激酶通路减少脂多糖诱导的屏障损伤[26]. 牛磺熊去氧胆酸激活武田G蛋白偶联受体5, 可逆转仔猪肠道中紧密连接蛋白(如闭合小环蛋白-1、闭合蛋白、紧密连接蛋白4)的mRNA表达下降, 缓解大肠杆菌诱导的上皮屏障破坏[27]. 部分胆汁酸对肠道屏障起破坏作用, 一项基础研究显示[19], 石胆酸会下调IPEC-J2细胞中紧密连接蛋白及相关基因表达, 还通过激活分化簇95和半胱天冬氨酸蛋白酶8诱导上皮细胞凋亡; 胆酸、脱氧胆酸则通过促进表皮生长因子受体自磷酸化、密封蛋白去磷酸化, 短暂改变人结直肠腺癌细胞系-2细胞紧密连接排列, 增加跨上皮通透性. 肝硬化患者胆汁酸谱失衡, 胆汁酸对肠道屏障的保护和破坏平衡被打破, 肠道屏障被破坏, 肠道通透性增加. 肝硬化患者存在两类典型肠道菌群紊乱: 一是菌群组成改变(肠道菌群失调), 二是小肠内细菌数量异常增多[小肠细菌过生长(small intestinal bacterial overgrowth, SIBO)]. 肠道菌群失调在肝硬化患者中普遍存在[28]. 一项荟萃分析发现[29], 肝硬化患者的肠道菌群丰富度低于健康对照组. 肝硬化患者的肠道菌群变化特点是毛螺菌科、瘤胃球菌科和梭菌减少, 而肠杆菌科、巴斯德氏菌科、链球菌科和杆菌增多. 一项横断面研究显示[30], 门脉高压是肝硬化肠道菌群失调发生的核心驱动因素. 此外, 肝硬化患者治疗中抗生素的应用进一步加重了肠道菌群失调[31]. 菌群失调会引发短链脂肪酸生成减少、肠道动力受损、5羟色胺信号异常, 直接影响肠道蠕动与内脏敏感性; 同时升高肠道通透性、加重炎症、紊乱脑肠轴交互, 进一步加剧腹痛与胃肠功能障碍[32]. 一项纳入47例肝硬化患者的观察性研究显示[33], 51.1%的肝硬化患者存在SIBO. 小肠正常动力是预防SIBO最核心的保护因素. 肠道动力由移行性复合运动(migrating myoelectric complex, MMC)调控, MMC产生的电活动触发蠕动波, 推动肠内容物前移. 肝硬化患者MMC周期显著延长, 小肠传输时间延长, 导致肠内容物淤积, 为细菌定植、过度增殖创造条件[34]. SIBO与胃肠动力障碍相关的临床症状密切相关. 目前已知的SIBO主要有四种类型: 产氢型、产甲烷型、氢-甲烷混合型及产硫化氢型. 产氢型SIBO以腹胀、排气增多、腹痛、腹泻、体重下降为主要表现; 产甲烷型SIBO以腹痛、恶心、排便困难和排便习惯改变为主要表现; 氢-甲烷混合型SIBO的典型表现为腹泻和便秘交替出现; 产硫化氢型SIBO的典型表现包括排出带有硫化氢气味的气体和粪便、口臭、慢性疲劳、头痛和纤维肌痛等[35]. 此外, SIBO会引发吸收不良、营养缺乏、贫血、低蛋白血症[36]. SIBO通过抑制FXR与Takeda G蛋白偶联受体激活, 减少次级胆汁酸合成、降低肠道免疫球蛋白A水平, 进一步损害肠道黏膜免疫; 同时减少抗菌肽合成、激活黏膜免疫, 引发肠道炎症与上皮完整性受损; 下调紧密连接蛋白表达, 进一步增加肠道通透性, 促进致病菌及其代谢产物进入循环系统, 诱发全身炎症[37]. 一项纳入了30例自发性细菌性腹膜炎(spontaneous bacterial peritonitis, SBP)患者、30例未发生自发性细菌性腹膜炎的失代偿期肝硬化患者以及30例健康对照者的研究显示[38], 肠道菌群紊乱与SBP严重程度、炎症指标(白细胞、C反应蛋白、降钙素原)显著相关, 提示肠道菌群紊乱很有可能参与自发性细菌性腹膜炎的病理生理过程. 另有一项荟萃分析[39]证实SIBO与肝性脑病存在显著相关性, 合并肝性脑病的肝硬化患者发生小肠细菌过度生长的风险是无肝性脑病患者的4.43倍. 小肠细菌过度生长可能是肝硬化患者发生肝性脑病的诱因之一. 一项回顾性分析显示[40], 肝性脑病、自发性细菌性腹膜炎是肝硬化患者出院后30 d及90 d再次入院的独立风险因素, 降低肝硬化患者的生存质量.
肝硬化可累及全身多器官系统, 尤其损害免疫系统, 造成免疫功能障碍. 肝硬化相关免疫功能障碍是一种多因素介导的病理状态, 会削弱机体清除循环中细菌、细胞因子与内毒素的能力, 主要包含两大核心要素: 一是对病原体应答异常导致的免疫缺陷; 二是免疫系统持续、过度激活引发的全身炎症[41]. 此外, 肠道通透性增加和肠道菌群失调会造成病理性细菌移位, 即活细菌或细菌产物(如脂多糖)穿过肠黏膜进入体循环的过程, 进一步加重全身炎症[42,43]. 免疫功能障碍和持续低度炎症在胃肠动力障碍的病理生理过程中发挥重要作用[44]. 在黏膜炎症状态下, 肠神经元会上调趋化因子(C-C)配体2的表达, 从而促进单核细胞募集到肠肌层内的肌间神经丛. 单核细胞来源的巨噬细胞浸润肌间神经节, 导致过度的肠神经系统重塑和动力障碍[45].
内脏高敏感性是肠-脑-肝轴多环节异常的结果, 也是胃肠动力障碍的重要机制. 动物实验显示, 胆汁酸代谢障碍导致结肠FXR过表达, 与内脏痛觉敏化密切相关[46]. 菌群代谢产物还会通过影响肠道神经递质合成(如5-羟色胺)、激活Toll样受体等途径, 调节肠道感觉神经功能, 降低疼痛阈值, 间接诱发内脏高敏感性[47]. 慢性低度炎症会敏化肠道内脏神经末梢, 增强其对刺激的反应性[48]. 内脏高敏感性导致机体对胃肠道的生理性蠕动、轻微炎症或压力的疼痛阈值降低, 表现为慢性、反复的腹痛或腹部不适[14].
肝脏是多种激素代谢、灭活及结合蛋白合成的关键器官. 肝硬化时毒素蓄积与蛋白质合成障碍, 直接影响激素稳态. 肝硬化患者存在的内分泌紊乱包括血糖调节异常、低促性腺激素性性腺功能减退症、甲状腺功能障碍、肾上腺功能不全、生长激素功能障碍、继发性醛固酮增多症等[49]. 此外, "肠-脑-肝轴"紊乱也会对部分神经内分泌紊乱起一定作用. 肝硬化进展过程中, 下丘脑-垂体-肾上腺轴呈进行性抑制, 表现为促肾上腺皮质激素分泌不足及肾上腺皮质激素合成减少. 全身炎症和胆汁酸水平升高可抑制HPA轴中枢调控, 同时存在组织糖皮质激素抵抗, 共同导致肾上腺功能不全[50]. HPA轴受抑制, 导致皮质醇水平降低, 进而引发胃肠动力障碍相关症状[51,52]. 此外, 肝硬化还会导致神经系统失衡, 研究显示[53], 肝硬化患者自主神经功能障碍的患病率为30%-67%. 神经内分泌紊乱与胃肠动力障碍密不可分. 标准化心血管自主神经功能检测证实, 自主神经系统失衡是胃排空延迟的核心机制[54,55], 另一机制为调节胃动力的激素异常. 肝硬化患者存在胰岛素抵抗, 导致餐后高血糖、高胰岛素、低生长素水平, 均与胃排空延迟相关[56]. 肝硬化患者中小肠动力障碍的具体机制尚未阐明, 自主神经病变是一个重要的潜在因素. 一项纳入48例肝硬化患者的研究显示[57], 口盲传输时间延长的患者更易合并自主神经病变, 且自主神经病变是口盲传输时间延长的唯一独立预测因素.
食管动力障碍患者可能会出现吞咽困难、胸痛、反流和烧心等症状[5]. 上消化道内镜是疑似食管动力障碍评估的必要检查, 可直接观察黏膜, 排除炎症或恶性病变[58]. 食管钡餐造影可评估食团经食管入胃的转运过程, 是吞咽困难评估的重要补充手段. 可识别狭窄、肿瘤、食管裂孔疝等结构性病变, 也可诊断贲门失弛缓、远端食管痉挛等主要动力障碍. 但钡餐造影对动力障碍的整体灵敏度有限, 仅56%-69%[59,60]. 功能性管腔成像探针(functional lumen imaging probe, FLIP)通过可控容积扩张刺激, 量化食管胃连接部开放能力、食管体部继发性蠕动反应及管腔顺应性, 尤其适用于高分辨率食管测压(high resolution esophageal manometry, HREM)结果不明确、不耐受或不可用的情况[61]. HREM是目前诊断食管动力障碍的金标准方法[62]. HREM的数据分析依赖于芝加哥分类(Chicago Classification), 该分类提供了标准化诊断框架, 但仍在不断演进中[63]. 然而, HREM操作技术复杂, 且会引起患者不适, 患者不耐受或测压导管卷曲, 导管无法通过上食管括约肌、下食管括约肌或食管胃结合部会导致操作失败. 一项回顾性分析显示[64], 152次HREM测试中, 有28次(18%)失败. 在测试期间无法耐受探头的患者更有可能有消化不良史[比值比odds ratio (OR) = 20.3, P<0.001]、恶心/呕吐史(OR = 13.8, P<0.001). 在因测压导管卷曲导致失败的情况中, 有贲门失弛缓症史的患者的比值比为13.2(P = 0.012). 导管无法通过上食管括约肌, 多因鼻腔狭窄/敏感、咽部敏感引发呛咳. 鼻咽通气管辅助法, 可辅助HREM导管经鼻腔通过, 减轻呛咳、恶心, 实现导管正确定位, 作为食管上括约肌插管失败的床旁补救措施[65]. 导管无法通过下食管括约肌或食管胃结合部, 多与食管结构性梗阻相关, 如巨大食管裂孔疝、食管旁憩室、贲门失弛缓等, 此类患者需改用内镜辅助HREM、FLIP或食管钡餐检查[66,67].
胃动力障碍的主要症状包括恶心、呕吐、腹胀、早饱、餐后饱胀感、上腹部不适或疼痛等[7]. 积极监测和早期识别可能的病例在临床上有重要意义. 症状问卷(如胃轻瘫主要症状指数)是一个关键筛查工具可用于量化症状严重度, 结合超声检查, 可帮助识别早期病例[68]. 对于疑似动力障碍的患者, 内镜检查对于排除可能存在的器质性疾病是必要的, 并且能为其诊断提供重要线索[69]. 然而, 内镜检查本身无法直接评估动力功能. 其观察局限于黏膜形态, 对功能性动力异常无诊断价值. 胃排空闪烁扫描(gastric emptying scintigraphy, GES)通过测量餐后胃内放射性残留量评估排空速率, 是目前诊断胃动力障碍的金标准[70]. 在成人指南中, 推荐进行4 h GES以提高准确性[71]. 尽管如此, GES仍存在电离辐射、耗时长、空间分辨率低等问题, 且与症状严重程度的相关性较弱、对神经肌肉病变特异性与敏感性有限[72,73]. 胃内恒压器是目前评估胃容受性的金标准设备, 可直接测量近端胃容积变化, 是研究胃容受性与感觉功能、评估各类治疗干预对胃生理作用的理想手段, 但其为有创操作, 患者耐受性较差, 可能改变胃内容物分布、影响正常胃生理. 因此其很少用于临床, 仅用于部分基础实验. 此外, 饱足饮水试验、胃电图、胃排空呼气试验、无线动力胶囊、胃窦十二指肠测压等检查方法在一定程度上也可以辅助胃动力障碍的诊断, 但其在临床上的应用目前仍存在各种限制因素[74].
小肠动力障碍的主要症状包括腹泻、便秘、腹痛等[11]. 小肠测压是诊断小肠动力障碍的金标准[12]. 一项临床研究发现, 常规测压确立的动力异常标准可直接用于高分辨率记录, 且高分辨率技术能通过收缩传导模式分析提升诊断灵敏度[75]. 一项儿科临床研究显示[76], 小肠闪烁扫描, 用于客观测量小肠转运时间, 对于辅助小肠动力障碍的诊断有一定前景. 此外, 新兴的非侵入性磁共振成像动态成像技术, 结合非刚性配准或光流算法自动计算肠内容物流速、绝对速度及定量动力评分, 可区分小肠蠕动、非蠕动及紊乱运动, 有望实现对小肠运动的无创表征, 辅助诊断小肠动力障碍[77]. 然而, 这些新兴方法在临床中的应用仍较为有限.
食管动力障碍的治疗包括药物治疗、内镜治疗、外科手术治疗等. 药物治疗主要包括质子泵抑制剂如奥美拉唑等, 平滑肌松弛剂如肉毒杆菌毒素、西地那非等[78-80]. 内镜治疗主要包括球囊扩张术、经口内镜下肌切开术(peroral endoscopic myotomy, POEM)等, POEM被广泛视为治疗食管动力障碍的首选微创技术[63,81]. 相较于外科手术(Heller肌切开术), POEM创伤更小, 且可保留正常功能的食管下括约肌[82].
在肝硬化患者中, 肝功能受损可能导致药代动力学改变, 使用质子泵抑制剂存在一定风险. 已有一项大型队列研究(n = 377420)显示, 质子泵抑制剂使用是自发性细菌性腹膜炎的独立危险因素(OR = 2.13, 95%CI: 2.03-2.23)[83]. 一项共纳入260854名肝硬化患者的荟萃分析显示[84], 长期死亡率[危险比hazard ratio (HR) = 1.321, 95%CI: 1.103-1.581, P = 0.002]、失代偿(HR = 1.646, 95%CI: 1.477-1.835, P<0.001)、肝性脑病(HR = 1.968, 95%CI: 1.372-2.822, P<0.001)、自发性细菌性腹膜炎(HR = 1.751, 95%CI: 1.649-1.859, P<0.001)和感染(HR = 1.370, 95%CI: 1.148-1.634, P<0.001)均与使用质子泵抑制剂显著相关. 目前暂无关于质子泵抑制剂在肝硬化患者中使用的权威指南. 一项基于69项研究的专家共识建议[85], 基于现有证据, 对肝硬化患者使用质子泵抑制剂时需注意: Child-Pugh A级或B级患者可使用埃索美拉唑、奥美拉唑或雷贝拉唑(需调整剂量), Child-Pugh C级患者仅推荐埃索美拉唑(每日20 mg); 兰索拉唑与泮托拉唑因暴露量显著增加, 所有Child-Pugh分级肝硬化患者均不建议使用. 关于肝硬化患者食管动力障碍的内镜和手术治疗的证据较为有限. 一项纳入14例肝硬化患者的研究显示[86], 内镜及外科治疗可有效缓解食管动力障碍的症状, 且无并发症. 对于失代偿期肝硬化患者, 门脉高压一度被视作POEM和Heller肌切开术的禁忌证. 不过已有在POEM术围术期通过经颈静脉肝内门体分流术降低门脉压创造内镜手术条件的尝试[87]. 此外, 超声内镜引导下的肉毒杆菌毒素注射能够针对性治疗食管动力障碍, 避开静脉曲张部位, 以降低出血风险. 这使其成为缓解症状的宝贵选择, 但肉毒杆菌毒素的效果是暂时性的, 通常持续6个月至2年[88]. 然而, POEM和超声内镜引导下的肉毒杆菌毒素注射在肝硬化患者中的应用仍以病例报告为主. 总的来说, 对肝硬化患者合并的食管动力障碍, 需积极开展多学科合作, 充分评估治疗的风险和获益, 以安全为首要原则进行个体化决策.
药物治疗是胃肠动力障碍的一线管理策略. 常用的促胃肠动力药主要包括甲氧氯普胺、伊托必利、多潘立酮等[89-91]. 乳果糖和益生菌可用于便秘性的小肠动力障碍[92]. 针对胃动力障碍的内镜治疗包括经口内镜下幽门肌切开术, 外科治疗包括胃电刺激、幽门成形术等[93]. 针对肠动力障碍的内镜治疗包括内镜支架植入术、内镜球囊扩张术等, 外科治疗包括肠切除术[94-96]. 促胃肠动力药在肝硬化患者中安全性和有效性数据不足, 需更多研究补充. 一项比较甲氧氯普胺和多潘立酮在肝硬化患者中应用的研究显示[97], 甲氧氯普胺长期使用可能导致不可逆的迟发性运动障碍等锥体外系并发症, 且与尿量和尿钠显著减少相关, 而多潘立酮的安全性更好. 然而, 使用多潘立酮会使心律失常和心源性猝死的风险显著增加70%, 这很可能是通过延长QT间期导致的[98]. 乳果糖和益生菌在肝硬化患者中安全性良好, 且有改善肝性脑病和肠道菌群失调的作用, 应积极使用[99]. 内镜治疗和外科手术在肝硬化患者中的安全性有待更多研究评估.
肝硬化患者的常用药主要包括肝保护性药物、利尿剂、非选择性β受体阻滞剂(non-selective beta-blockers, NSBBs)、乳果糖、肠道抗菌药如利福昔明等, 目前针对肝保护性药物和利尿剂对胃肠动力障碍的影响的研究较为有限, 本文主要梳理探讨NSBBs、乳果糖和利福昔明对胃肠动力障碍的影响. 食管胃底静脉曲张破裂出血是肝硬化的严重并发症之一, 显著增加患者死亡风险. NSBBs对静脉曲张破裂出血的一级和二级预防均疗效确切, 已成为肝硬化药物治疗的核心药物[100]. 一项纳入35例肝硬化合并门静脉高压患者的临床研究显示[101], 中低剂量普萘洛尔可显著改善肝硬化合并门静脉高压患者的胃肠动力、肠道通透性, 抑制SIBO. 肝性脑病是肝硬化的一种并发症, 以神经精神与运动功能障碍为特征, 会导致患者生活质量下降、死亡率升高. 乳果糖可逆转轻微肝性脑病, 预防显性肝性脑病, 改善生活质量, 提高显性肝性脑病的康复率, 并提升生存率[102]. 乳果糖通过双重机制参与胃肠动力障碍的调节: 直接刺激小肠蠕动、作为益生元重塑菌群-代谢轴. 一项随机对照实验发现[103], 乳果糖可刺激肠道蠕动促进小肠动力. 一项纳入29例慢性功能性便秘患者和20例对照的临床研究显示[92], 乳果糖可提高益生菌丰度、优化肠道微生态环境, 进而缓解便秘症状. 利福昔明是一种非全身性抗生素, 胃肠道吸收极少, 具有广谱抗菌活性, 对革兰氏阳性菌和革兰氏阴性菌均有作用[104]. 利福昔明联合乳果糖可显著降低显性肝性脑病复发风险、减少住院次数, 并改善患者生活质量[105]. 目前暂无研究显示利福昔明对胃肠动力障碍有直接的治疗作用, 但利福昔明可通过调节肠道菌群间接改善胃肠动力障碍. 一项荟萃分析显示[106], 在SIBO合并功能性胃肠病患者中, 利福昔明联合胃肠动力药物显示出较高疗效. 一项前瞻性研究证实[107], 为期四周的利福昔明治疗在缓解腹泻型IBS患者腹痛、腹胀症状及焦虑情绪方面效果良好. 另有一项纳入21例成年功能性消化不良患者的研究发现[108], 利福昔明可有效改善功能性消化不良相关症状. 综上, 肝硬化患者常用药NSBBs、乳果糖和利福昔明能够直接或间接地改善胃肠动力障碍. 因此, 在肝硬化合并胃肠动力障碍患者中积极应用以上药物具有重要意义.
肝硬化合并的胃肠动力障碍, 降低患者生存质量, 显著加重了疾病负担. 现有证据证实以下核心观点: 流行病学研究表明, 肝硬化患者大量合并胃肠动力障碍及相关胃肠道症状; 肠-脑-肝轴功能紊乱是肝硬化合并胃肠动力障碍病理生理机制的核心, 主要涉及胆汁酸代谢障碍、肠道通透性增加和肠道菌群紊乱、免疫功能障碍、内脏高敏感性、神经内分泌调节紊乱等机制. 在肝硬化病人管理中, 早期评估和诊断胃肠动力障碍, 并结合病情, 规避禁忌, 积极进行个体化的治疗, 具有重要意义. 然而, 目前仍存在诸多亟待明确的问题. 其一, 肝硬化合并胃肠动力障碍的病理生理机制尚未完全阐明. 其二, 针对肝硬化合并胃肠动力障碍的最佳诊疗策略和权威诊疗指南仍未建立. 未来研究应聚焦于进一步明确肝硬化合并胃肠动力障碍的具体因果病理生理机制通路, 并探索和验证针对该机制的有效安全的临床干预手段, 形成完整系统的诊疗方案和指南, 有望切实推动肝硬化患者的临床诊疗水平综合提升.
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学科分类: 胃肠病学和肝病学
手稿来源地: 天津市
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科学编辑: 刘继红 制作编辑:张砚梁