修回日期: 2017-08-22
接受日期: 2017-08-30
在线出版日期: 2017-11-18
显微镜结肠炎(microscopic colitis, MC)是慢性腹泻的常见原因. 过去20年MC的流行率呈迅速增加趋势, 引起了消化医师们的密切关注. MC的病因不明, 免疫异常是主要的发病机制, 其次是与某些药物密切相关. 临床上以慢性水样、非血性腹泻、痉挛性腹痛、体质量下降与乏力为其特征, 结肠镜检查正常或基本正常, 但结肠活检黏膜呈炎症改变或上皮下出现胶原带增厚, 作为诊断的依据. 目前对MC尚无特效治疗, 主要用类固醇激素布地奈德和免疫抑制剂, 其他药物治疗的疗效尚不完全肯定. 本病预后良好, 属自限性疾病, 研究指出, MC对结肠有保护作用可抵抗结直肠癌变发生, 但最近研究又指出, 先天免疫异常可能有致癌作用, 值得今后重视与研究MC与肿瘤的相关性.
核心提要: 显微镜结肠炎(microscopic colitis, MC)是慢性腹泻的常见原因. MC的病因不明, 免疫异常是主要的发病机制, 其次是与某些药物密切相关. 临床上以慢性水样、非血性腹泻、痉挛性腹痛、体重下降与乏力为其特征, 但无特异性. 结肠镜检查正常或基本正常, 因此诊断有赖于结肠的多处活检. 过去20年MC的流行率呈迅速增加趋势, 引起了消化医师们的密切关注. 目前尚无特效治疗, 主要用类固醇激素布地奈德和免疫抑制剂. 因此, 摸清流行率逐年增加的原因, 深入研究MC的发病机制, 改进诊断方法, 尤其在实验室方面探求简易可靠的诊断方法, 治疗上开展大数据临床对照试验, 进一步研究与肿瘤有无相关性是今后MC研究的重点.
引文著录: 池肇春. 显微镜结肠炎研究进展与现状. 世界华人消化杂志 2017; 25(32): 2858-2865
Revised: August 22, 2017
Accepted: August 30, 2017
Published online: November 18, 2017
Microscopic colitis (MC) is a common cause of chronic diarrhea. Over the past 20 years, the prevalence of MC has been increasing rapidly, which has aroused the close attention of digestive physicians. The etiology of MC is still unknown, and immune abnormalities are the main pathogenesis, followed by some drugs. MC is clinically characterized by chronic non-bloody watery diarrhea, spastic abdominal pain, weight loss, and fatigue, but colonoscopy is often normal or roughly normal. Colonic biopsy often shows mucosal inflammation or subepithelial collagen band thickening, based on which a diagnosis can be made. At present, there has been no special treatment for MC, with steroid budesonide and immunosuppressive agents being the main treatments. As a self-limiting disease, MC has a good prognosis. Studies have found that MC has a protective effect against colorectal cancer. However, it was recently found that innate immune abnormalities may have carcinogenic effects.
- Citation: Chi ZC. Research progress and perspectives of microscopic colitis. Shijie Huaren Xiaohua Zazhi 2017; 25(32): 2858-2865
- URL: https://www.wjgnet.com/1009-3079/full/v25/i32/2858.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v25.i32.2858
显微镜结肠炎(microscopic colitis, MC)首次报告于1976年. MC的真正发病率尚不清楚. 过去20年MC发病率显著增加[1], 在慢性腹泻患者研究MC的发生率为10%-30%. 现在认为MC是一种常见病, 组织与临床上分胶原性结肠炎(collagenous colitis, CC)和淋巴细胞性结肠炎(lymphocytic colitis, LC)两个亚型, 与过去相比CC和LC的发病率和流行率均增加. CC和LC人群流行率为3-5/10000[2-5]. 我国尚无MC流行率和发病率的系统报告. 有研究MC有地域性变化的流行率, Bonderup等[6]以人群为基础研究发现, MC流行率从4.6/100000到2014年增加至24.7/100000. Olmsted人群流行率从1980年的1.1/100000增加至2014年的19.6/100000[7]. 最近10年的流行病学研究[8,9]报告CC平均每年发生率为1.8-5.4/100000/年; LC为1.3-4.5/100000/年. 新近流行病学研究[10]每年发病率稳定在21.0-24.7/100000/年. Kane等[11]从2010-2015年报告MC 540例, 平均发病率为11.3/100000/年, 其中CC 291例(53.9%), 每年发生率为6.1/100000, 203例为LC(37.6%), 每年发生率为4.2/100000. 最近北美研究[12]CC发生率为7.1/100000/年, LC为12.6/100000/年. 从类型比较CC占39.3/100000, LC占63.7/100000. 有关流行率变化的原因一直不明了, 可能与不同的人群背景、环境暴露、保健监护系统、转诊方式、研究计划、诊断标准不同或发病因子的广泛暴露有关[13].
显微镜结肠炎风险因子包括女性、老年、伴有自身免疫性疾病、恶性病、器官移植史、用药史等. 女性是一个重要的风险因子, 根据人群研究[3,4,7,14,15]LC女:男 = 4.4-7.9:1; CC为1.8-5.0:1. MC流行率随年龄增长而增加, 有人提出年龄分布可能有偏见, 因为儿童或年青成人很少做结肠镜也更少做活检, 所以很可能低估了年青人MC的发生率. 有30%-50%的MC患者至少相伴一种自身免疫疾病, 10%-20%伴甲状腺疾病[4,16], 5%-15%乳糜病患者伴MC, 恶性病伴发MC较少见, 但恶性病时发生CC比一般人群高50倍[17,18]. 新近报告少年强直性脊椎炎或SAPHO(滑膜炎-痤疮-脓疱病-骨肥厚-骨髓炎)综合征伴有MC发生[19].
现在的研究提出, MC对疾病易感. MC是一种免疫介导疾病, 是对腔抗原易感个体由免疫失调引起. 现已确定基因多态性可伴有MC发生. 白介素(interleukin, IL)-6-174基因多态性如IL-6GG基因型在LC与CC均较多见[20]. 此基因多态性可能与IL-6产生增加有关, 对MC的发病机制起作用. IL-6是一个潜在炎症前分子, 能促进T和B淋巴细胞变异, 导致巨噬细胞募集到炎症部位, 而且IL-6是前纤维化细胞因子, 促进纤维化发生[21].
以前的研究评估MC与HLA-DQ单倍体型之间相关. Fernández-Bañares等[22]提出, DQ2异源二聚体或DQ2/DQ8等位基因和LC的诊断呈正相关. 在DQ2阳性组比DQ2阴性组LC的流行率几乎高3倍. 根据上述的观察许多作者提出HLA-DQ2基因与MC的发病机制有关. HLA-Ⅱ分子的主要功能是作为T细胞介导免疫反应开始的信号. 所以在MC时有HLA与抗原肽结合异常, 且结肠腔抗原(或是细菌抗原)可触发HLA-免疫调控炎症过程. 研究[22]发现CC和LC伴有HLA-DR3-DQ2单倍体和携带TNF2等位基因.
基质金属蛋白酶(matrix metalloproteinases, MMPs)的不同表达也与MC的发病机制有关. MMPs主要在各种炎症情况表达. Madisch等[23]评估MMPs基因位点-1, -7, -9基因多态性在一个病例对照试验发现对CC易感. 单核苷酸多态性基因型的研究显示, 在MMP-9基因携带GG等位基因时发生CC的风险增加. 有关这个基因多态性的功能作用尚不明了, 可能是MMP-9激活缺陷引起胶原降解异常所致[24].
5-羟色胺(5-hydroxytryptamine, 5-HT)和5-HTT(5-羟色胺再摄取运输)表达可降低实验性结肠炎发生. 5HTTLPR的LL基因型多态性和MC之间有显著相关性. 提出5HTTLPR在MC的发病机制上是一个潜在的侯选基因[25]. 5-HT调节肠蠕动和分泌, 在MC和溃疡性结肠炎患者5-HT水平比健康对照组显著增高.
免疫组织化学分析显示, 固有层CD4+T细胞表达Th2转录因子GATA-3, 而CD8+T细胞表达GATA-3和Th1转录因子T-bet(一种新型T-box基因家族转录因子, 选择性地表达于Th1细胞)[26], 多数CD8+T上皮内淋巴细胞表达T-bet, 仅<20%表达GATA-3. 细胞流测定仪分析和免疫组化研究指出, CC和LC患者的黏膜有严重CD8+T细胞浸润. CD4+和CD8+在固有层和上皮内活性增加也证实白细胞共同抗原和增殖细胞相关核抗原, 其功能与有丝分裂密切的表达也增加[27].
Th1/Tc1(辅助性T细胞1和毒性T细胞)刺激细胞介导免疫. Th17/Tc17产生抗细菌蛋白, 在黏膜屏障抗菌免疫和嗜中性粒细胞的积聚上起重要作用, 且在CC和LC患者中得到证实[28]. 证明提出, 干扰素(interferon, IFN)-γ驱动MC发病机制上发挥关键作用. 它调节上皮内淋巴细胞吸引趋化因子的产生, 且激活巨噬细胞与释放炎症前细胞因子, 如肿瘤坏死因子-α(tumor necrosis factor alpha, TNF-α)、IL-1和IL-6它们将维持和增加局部炎症反应[29].
各种白细胞介素在免疫的发生和发展中在不同阶段发挥作用. 如IL-12是Th1最有力的极化细胞因子[30]. IL-21是被Th17和Tc17细胞分泌的一种细胞因子, IL-21、IL-22和IFN-γ转录水平与MC患者临床活动显著相关[29]. IL-23在CC和LC增加, 在诱导CD4+T细胞与产生IL-17上发挥重要作用. IL-22是另一个Th17细胞因子, 在CC和LC两者均表达, 其作用有两面性, 一方面诱导上皮细胞和结肠成纤维产生细胞IL-8和TNF-α, 诱导增殖和凋亡途径, 以及产生抗菌肽, 防止组织破坏和Ð助组织修复; 另一方面激活结肠肌成纤维产生, 引起过多的胶原产生和储存[31,32].
先天免疫主要是与肠屏障机制的改变有关. 黏膜抗菌蛋白溶酶体表达在CC的结肠隐窝和在LC固有层细胞上调, 再次证明MC的黏膜和肠微生物之间相互作用, 且发现CC和LC仅有轻微的分子不同特征[33,34]. 在CC和LC肠黏膜显示诱导型NO合酶和NO显著增加[35], 另外, 在内皮细胞上NO影响肠上皮细胞的紧密联结引起细胞旁渗透性增加[36], 导致腹泻和电解质失衡发生.
过去10年提出药物引起MC[37]. 药物作为抗原进入肠固有层引起免疫和炎症反应[35]. 非甾体抗炎药(nonsteroidal antiinflammatory drugs, NSAIDs)是引起MC最常见的药物, 据报道[38]长期摄取NSAIDs患者60%-70%存在无症状肠病, 伴有急性腹泻风险增加. 在结肠NSAIDs解耦线粒体氧化磷酸化, 引起细胞内ATPI水平下降, 此反过来引起细胞骨架紧密联结调控丧失, 并增加细胞旁渗透性, 致使肠抗原通过引起免疫反应而导致MC发生.
新近研究强调暴露质子泵抑制剂(proton pump inhibitors, PPIs)和MC发生相关. 在结肠PPIs可影响局部电解质平衡, 损伤液体酸化, 影响结肠黏膜的免疫反应. 长期暴露PPIs降低肠道对镁的吸收引起低镁血症. PPIs也引起肠道pH改变, 从而影响离子通道和紧密联结功能, 最后PPIs抑制H+-K+ATP酶, 肠内pH增高引起宿主防御能力降低, 可直接影响细胞生长, 引起肠道生态失衡或细菌过度生长发生[39-41]. 其他与MC发生相关的药物有抗血小板药[42]、阿卡波糖[43]、β阻滞剂和他汀类药物[44]等.
CC和LC症状非常相似, 也无特异性症状或临床特征. 主要依靠结肠镜组织活检进行确诊. 典型临床表现为慢性复发性水样、非血性腹泻, 一日5-10次不等, 持续5-20年. 腹泻常发生在夜间, 伴有痉挛性腹痛, 易误诊为肠易激综合征. 但少数患者症状从急性开始, 虽腹泻为中-重试, 但发生电解质紊乱或脱水者少见. 其他症状有关节病、大便失禁、乏力、体质量减轻, 部分患者与肠易激综合征(irritable bowel syndrome, IBS)并存. 一般预后良好, 多数患者为自限性[12,47,48].
由于MC常与IBS、炎症性肠病、感染性结肠炎等临床症状相似或并存, 因此首先应与上述疾病鉴别. 放射自显影和实验室检查有助于排除. 单从临床表现难以做出诊断, 对可疑患者应做结肠镜, 并在全结肠多处进行活检, 并推荐有经验的内镜医生和病理学家进行检查, 以免漏诊.
结肠镜检查一般黏膜正常, 新近提出非特异性改变, 包括异常的血管标记、黏膜出现红斑或水肿, 这些改变的意义尚不清楚. Koulaouzidis等[49]报道607例CC, 见黏膜红斑/水肿15%, 黏膜缺陷2%, 黏膜瘢痕0.82%. 超过90%的MC通过直肠和左半结肠活检获得诊断[50]. CC和LC组织病理特征见表1.
| CC | LC |
| ⑴上皮下胶原层增厚>10 µm | ⑴上皮内淋巴细胞≥20/100个上皮细胞 |
| ⑵固有层炎症, 主要是淋巴和浆细胞 | ⑵固有层炎症, 主要是淋巴细胞和浆细胞 |
| ⑶上皮损伤, 如细胞压扁和分离 | ⑶上皮损伤, 如细胞压扁和分离 |
| ⑷上皮内淋巴细胞可存在, 但对诊断CC不需要 | ⑷上皮下胶原层不存在或<10 µm |
近年研究[51]指出, 生化标志在MC的诊断中具有一定价值. 血清标记包括抗核抗体、抗-酿酒酵母免疫球蛋白G(immunoglobulin G, IgG)抗体、抗甲状腺过氧化物、抗核周中性粒细胞浆抗体、抗谷氨酸脱羧酶等, 它们的流行率分别为14%、13%、14%、5%和5%, 而且这些抗体CC患者比LC患者高. 另一个研究来自Holstein等[52]发现15%的CC患者ASCA(一种快速自适应聚光算法)IgA和IgG阳性, 一般来自肠屏障功能破坏. 抗线粒体抗体等自身抗体也常增加, 可作为MC的血清学标记, 然特异性和敏感性低[53], 临床应用价值不大.
MC时粪便蛋白增加, 包括: (1)嗜中性粒细胞来源类蛋白: 嗜中性粒细胞衍生髓过氧化物酶, 为溶酶体过氧化物酶, 有强大的抗菌活性, 在CC活动性患者常增加[54]. 网钙蛋白是一种钙结合有抗菌、抗细胞增殖和免疫调节作用. 它构成2/3细胞浆蛋白储存于嗜中性粒细胞. 活动性MC患者嗜中性粒细胞在黏膜浸润时FC显著增加[55,56]. 乳铁蛋白也是一种肠的炎症标记, MC时常增高[57,58]; (2)嗜酸性细胞类蛋白: 嗜酸性阳离子蛋白、嗜酸性蛋白X在CC患者大便标本中显著增加[54,59], 有一定诊断价值; (3)神经内分泌细胞类蛋白: MC时结肠神经内分泌细胞呈高活性, CC患者嗜铬核蛋白A增高[60]. 上述这些生化标志尚未在临床诊断中广泛应用, 它们的诊断价值也需进一步确定.
治疗前应确定或排除其他疾病, 撤除与MC相关的药物, 如NSAID、PPI等.
饮食中应避免咖啡、乳糖. 对MC目前尚无特效药物治疗, 主要应用类固醇激素和免疫抑制剂, 对症状轻的患者咯哌丁胺(易蒙停)2-16 mg/d, 可作为一线治疗, 但组织学改善不明显[47,61].
随机对照试验指出, 类固醇布地奈德对调整严重的CC和LC是一个有效的标准治疗, 治疗后可使临床症状缓解和维持缓解, 同时组织炎症也显著改善[10,62,63], 常用9 mg, qd或3 mg, 3/d. 因应用2 wk后停用复发率高达61%-80%, 所以提议维持治疗, 即6 mg/d, 用26 wk．目前尚不清楚26 wk后如何持续或撤除治疗.
其他药物治疗大部分是无对照试验或为回顾性分析或个案病例报告. 药物有免疫抑制剂硫唑嘌呤或氨甲喋呤[64]、抗-TNF[65]、乳香浸膏、益生菌、已酮可可碱、维拉帕米、奥曲肽、抗菌治疗等[66,67]. 一个安慰对照随机临床试验[68]用水杨酸铋治疗MC, 结果100%组织学和临床缓解. 另一个回顾性分析提出用5-ASA(美沙拉嗪)800 mg, 3/d, 50%患者症状改善. 有报告美沙拉嗪与消胆胺4 g/d联用, 2 wk后腹泻消失率84%, 维持治疗超过6 mo LC 患者临床和组织学缓解率85%, LC 91%[62,69], 值得进一步研究. 最近报告[65,70]对布地奈德难治患者用抗TNF治疗, 但治疗复发率高达66%-100%[71]. 最近报道CC患者用粪细菌移植(FMT)治疗有效, 用流式细胞仪评价FMT的免疫调节治疗作用, 并可调节肠道菌群[72]. 有待进一步临床研究.
外科手术干预是最后治疗手段, 适用于患者有严重症状, 对药物治疗无反应的患者, 包括次切结肠切除、乙状结肠切除、分流回肠切开术[73,74].
MC是一个涵盖性术语, 是一种免疫介导性疾病, 由基因易感性引起, 其中适应免疫反应失调起关键作用. 多发生在成人, 尤其是老年人, 女性多于男性, 流行率有地域和种族差异．尽管CC和LC临床表现极相似, 但应该说还是两种不同的实体. 鉴于MC流行率不断上升, 今后应当有计划开展流行病学调查, 加强发病机制的研究, 前瞻性临床安慰对照试验, 结合我国中医特色, 总结出一条有效的治疗途径, 以填补国内空白.
显微镜结肠炎(microscopic colitis, MC)于1976年被Lindstrom与Freean首次提出. 近20年来发病率逐渐上升, 认为是以免疫异常为中心引起的以非血性腹泻为特征的一种常见慢性腹泻疾病, 并引起了广大医学界的重视, 并对其病因学、发病机制、诊断与治疗全方位多层次进行研究. 临床资料证明, MC在我国也并不少见, 但尚未引起足够重视和开展这一方面的研究.
在发病机制方面主要在免疫异常、药物作用、肠菌失调等几个方面进行了研究, 且取得了不少的进展, 但精准机制尚不明确. 由于临床表现无特异性, 肠镜检查又多无异常发现, 因此, 近年在免疫和生化指标上寻找诊断线索, 取得了可喜的成绩. 布地奈德和免疫抑制剂仍是当前的主要治疗, 美沙拉嗪和粪便细菌移植是有希望的两个治疗方法, 应当深入研究和扩大临床试验. 中医中药治疗MC也值得探索和研究.
在共识基础上建立诊治指南, 确立常规的检查和治疗策略.创建MC工作计划, 开发我国MC的流行病学调查, 同时开展相关临床研究, 建立我国自己的诊治指南.
CD45: 是细胞膜上信号传导的关键分子, 在淋巴细胞的发育成熟、功能调节及信号传导中具有重要意义. 已发现CD45至少有9个亚型, 如CD45RA、CD45RB、CD45RC、CD45RO等, 由3个外显子(A, B和C)选择性地连接而成. 其中缺乏3个外显子的亚型称为CD45RO, 仅表达外显子A的亚型称为CD45RA.
雷招宝, 主任药师, 江西省丰城市人民医院药剂科; 刘杰民, 副主任医师, 贵州省人民医院消化内镜科; 孙金山, 副教授, 副主任医师, 新疆军区总医院消化内科
本文对显微镜结肠炎致病机制的讨论比较深入, 是一篇有参考价值的述评.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 山东省
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