修回日期: 2018-05-28
接受日期: 2018-06-02
在线出版日期: 2018-09-08
炎症性肠病(inflammatory bowel disease, IBD)是一种由遗传因素和环境因素共同导致的累及消化道的慢性非特异性疾病, 包括溃疡性结肠炎、克罗恩病和未分类炎症性肠病. 目前其诊断主要依靠临床表现、影像学改变、结肠镜检以及病理活检, 但是有一定局限性. 血清学标志物检测法在IBD诊断中优势凸显, 国内外已有大量文献报道. 本文就血清学标志物与炎症性肠病诊治做一述评, 旨在进一步明确其在炎症性肠病诊治中的地位.
核心提要: 血清标志物检测在炎症性肠病(inflammatory bowel disease, IBD)的诊断及鉴别上具有高特异性及敏感性. 同时在IBD分型及手术风险评估也有一定作用. 各项血清学标志物有其特性, 联合多项检测可提高诊断准确性.
引文著录: 蒋科芳, 范一宏. 血清学标志物与炎症性肠病: 血清标志物盛行及对炎症性肠病诊治价值. 世界华人消化杂志 2018; 26(25): 1487-1493
Revised: May 28, 2018
Accepted: June 2, 2018
Published online: September 8, 2018
Inflammatory bowel disease (IBD) is a chronic nonspecific disease of the digestive tract that is caused by genetic and environmental factors, including ulcerative colitis, Crohn's disease, and unclassified IBD. At present, the diagnosis of IBD depends mainly on clinical manifestations, imaging changes, colonoscopy, and pathological biopsy, but there exist some limitations. The advantages of serological markers in IBD diagnosis are prominent, and a large number of relevant studies have been reported. This paper reviews the diagnostic and therapeutic value of serological markers in IBD, with an aim to clarify their role in the diagnosis and treatment of IBD.
- Citation: Jiang KF, Fan YH. Serological markers and inflammatory bowel disease: Prevalence of serum markers and their diagnostic value in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2018; 26(25): 1487-1493
- URL: https://www.wjgnet.com/1009-3079/full/v26/i25/1487.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v26.i25.1487
炎症性肠病(inflammatory bowel disease, IBD)是一种由遗传因素和环境因素共同导致的累及消化道的慢性非特异性疾病, 包括溃疡性结肠炎(ulcerative colitis, UC)、克罗恩病(Crohn's disease, CD)和未分类炎症性肠病(IBD unclassified, IBDU), 其发病率在我国逐年增加. 目前IBD的诊断主要依靠临床表现、影像学改变、结肠镜检以及病理活检, 但是临床发现约10%患者在结肠镜检后仍不能明确诊断[1,2]. 此外, IBD病程常反复, 临床常需借助各类检查以指导用药及治疗. 常规检查如内镜及组织病理学检查有创、耗时、昂贵, 部分患者对其有恐惧心理. 近年研究显示, 血清学标志物检测法相对方便、无创、病人接受度高, 可辅助诊断、进行疾病分层以及手术风险的评估[3], 国内外已有大量文献报道. 因此, 本文就血清学标志物与炎症性肠病做一概述, 旨在进一步明确其在炎症性肠病诊治中的地位.
IBD患者中, 肠屏障功能障碍和肠道通透性增加是一个众所周知的且已被证实的现象[4,5]. 黏膜通透性和炎症相关[6], 肠黏膜的炎症使来自肠道的大量菌群和食物中的抗原释放入血导致血液中抗体的产生. 目前血清抗体按其来源分为以下两类, 即自身抗体和以微生物抗原成分为靶点的抗体.
抗中性粒细胞胞浆抗体(anti-neutrophil cytoplasmic antibodies, ANCA)是一组以单核细胞和中性粒细胞胞浆成分为抗原的自身抗体, 由Davies于1982年首先发现, 大量释放后可导致大面积血管和肠道组织损害[7]. ANCA试验是诊断和监测原发性小血管炎的炎症活动的经典项目. 根据国际共识, ANCA一般采用间接免疫荧光法(indirect immunofluorescence, IIF)检测, 通过该法中荧光集中位置将ANCA分为胞浆型(c-ANCA) 和核周型(p-ANCA). 典型c-ANCA模式表现为颗粒状, 弥漫性胞浆荧光, 常有杂音荧光围绕核裂片; p-ANCA则是在环状反应的核周胞质周围均匀染色[8]. Saxon等[9]研究发现第三种抗中性粒细胞胞浆抗体, 就是所谓的非典型p-ANCA. 由于非典型p-ANCA的靶抗原是核而不是细胞质, 有学者认为将其命名为抗中性粒细胞的核抗原(ANNA)更合适[10]. ANNA是IBD患者中最常见的, 尤其是溃疡性结肠炎. 同时与一些自身免疫性肝脏疾病如自身免疫性肝炎(autoimmune hepatitis, AIH)、原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)也有一定的关联[11]. Prideaux等[12]研究显示, CD患者血清中p-ANCA阳性率在6%-38%, UC为41%-73%, 用p-ANCA鉴别CD和UC的敏感性和特异性分别为52%和91%. 其他国内外的研究均有共同性结论, ANCA对UC有高度特异性[13]. 所以在高度怀疑UC, 特别是初步诊断及鉴别诊断时, ANCA检测值得首先考虑. 但目前的研究发现其检测UC敏感性均小于50%, 不适合IBD的筛查[3]. 研究发现肠壁厚度超过3 mm即可视为IBD的筛查标准[14]. 故笔者认为若能将血清学标志物联合其它无侵入性检测, 如影像学检查(如腹部CT、 MRI检查), 对IBD疑似者, 可提高筛查率及确诊率. 另有报道表明IIF法在检测ANCA时只有90%到95%阳性率[15,16], IIF法联合酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测可靠性更高, 所以合理的检测方式同样值得临床医生重视.
抗胰腺腺泡抗体(antibodies against exocrine pancreas, PAB)是针对胰腺腺泡细胞的颗粒膜糖蛋白的靶抗体, 由Stöcker等[17]于1987年首先在IBD患者的血清中发现. 临床可通过IIF检测, 根据检测结果可将其分为两型: Ⅰ型为胰腺腺泡内呈水滴状荧光, Ⅱ型为胰腺腺泡细胞内均匀斑点样荧光[18]. Prideaux等[19]的研究显示, PAB在CD患者阳性率达29%, UC为10%. Demirsoy等[20]研究提示PAB在诊断IBD的敏感性与特异性分别为: 19%、93%, 阳性及阴性预测值分别为77%、45%, 且PAB对于CD的诊断优于UC. 所以, 与p-ANCA相对应, 当临床高度怀疑CD, 对患者进行PAB检测, 有利于确诊. 若联合检测p-ANCA, 则能提高诊断的明确性.
抗杯状细胞抗体(antibodies to goblet cells, GAB)是小肠上皮特殊的杯状细胞的靶抗原, 在黏液分泌、小肠上皮修复和炎症调节起一定作用, 一般通过ELISA 和IIF法检测. 有研究发现GAB阳性率在UC和CD患者中未见明显差异, 甚至部分UC和CD患者中均未检出GAB[21,22]. Kovacs等研究[18]显示GAB在UC、CD中阳性率分别为12.2%、1.9%. 所以可将GAB视为IBD鉴别诊断指标之一, 但由于其检验效力的限制, 若GAB、PAB、p-ANCA三者联合检测, 则可提高诊断IBD尤其是UC的特异性.
钙网织蛋白(calcium reticulum, CRT)是一种可溶性Ca2+结合蛋白, 最初发现于细胞内质网中. 抗CRT通常用ELISA法测定. Watanabe等[23]研究发现UC患者中的抗CRT滴度显著高于正常人, 且初发病人显著高于长期发病的患者. 值得注意的是, CD患者中抗CRT的阳性率可达30%, 故抗CRT与GAB相似, 应视为诊断UC的辅助指标, 同时面对初发患者、长期患者其诊断效力需要临床医生的及时调整.
粒细胞单核细胞集落刺激因子(granulocyte mono-cyte colony stimulating factor, GM-CSF)是免疫细胞产生的一种细胞因子, 本质是一种糖蛋白. 通过与细胞表面特异性的受体(granulocyte monocyte colony stimulating factor receptor, GM-CSFR)结合发挥作用. GM-CSF与免疫功能有关, 同时参与抗菌作用中及组织损伤时自我修复[24]. 通过ELISA和IIF法可测定抗GM-CSF浓度. 研究发现GM-CSF促进与上皮细胞增殖, 在IBD肠道上皮愈合起重要的作用[25], 且血清抗GM-CSF浓度主要在CD患者中明显升高. 故抗GM-CSF在临床常用于CD和UC鉴别诊断. 同时笔者认为GM-CSF在肠道恢复中起重要作用, 抗GM-CSF对CD患者病情发展、预后评估也有一定意义.
抗酿酒酵母抗体(anti-saccharom-yces cerevisiae antibodies, ASCA)是一种针对酵母菌属的抗体, 是抗多聚糖抗体家族中临床运用最广泛的, 其主要靶点是酵母菌细胞壁上的磷肽甘露多聚糖成分, 可能因炎症使病变肠段渗透性升高, 酵母菌抗原暴露于免疫反应细胞机会增加相关[26]. 临床检测方法主要是IIF和ELISA法. ASCA包括两种亚型. 研究表明IBD患者血清中ASCA阳性率在CD患者中为50%-80%, UC为2%-14%, 正常人为1%-7%[27,28], 这表明ASCA与CD更相关. 其中约66%ASCA-IgG阳性的CD患者ASCA-IgA可同时阳性, 0%-19%的患者只有ASCA-IgA阳性, 可见IgG相较于IgA阳性预测值更高. CD患者中, IgG和IgA同时阳性对CD诊断的特异性高达90%, 尤其是两者呈现高表达时[29]. Vermeire S等研究表明, ASCA检测对IBD的敏感性为41%-76%, 阳性预测值为88%, 阴性预测值为68%[30]. 所以, ACSA检测对CD诊断有极高特异性, 值得首先考虑, 且应对IgG和IgA两种抗体同时检测, 以提高确诊率. 此外, ASCA若能与影像学指标联合, 亦可增加IBD的筛查率及确诊率.
抗乙糖苷壳糖抗体(anti-chitobioside carbohydrate IgA antibodies, ACCA)、抗乙糖苷昆布糖抗体(anti-laminaribioside carbohydrate IgG antibodies, ALCA)、抗乙糖苷甘露二糖抗体(anti-mannanobioside carbohydrate IgG antibodies, AMCA) 是三种不同与ASCA的抗细菌细胞壁多糖的抗体. Lyakhovich等[31]研究发现患者出现上述三者任一阳性, 则诊断CD的特异性可达90.6%, 敏感性77.4%, 联合任两种抗体阳性均可使疾病诊断的特异性提高到99.1%. 所以, 虽然ASCA对于诊断CD的敏感性及特异性相对较高, 若能联合ACCA、ALCA、AMCA检测, 则能大大提高对ASCA阴性的IBD患者的诊断及鉴别诊断效力.
抗大肠埃希菌外膜孔道蛋白C(Anti-Omp C)是一种针对大肠埃希菌细胞外膜的孔道蛋白C的抗体, 分IgA和IgG两个亚型, 可通过ELISA法检测[15,32]. 研究发现抗OmpC阳性率在UC患者可达 5%-11%, CD为55%, 且在CD患者中抗体阳性更易出现肠穿孔[33]. 抗OmpC可视为CD诊断的辅助指标, 特别是对于ASCA阴性CD患者, 若能再联合ACCA、ALCA、AMCA等指标, 则临床确诊率可进一步提升.
抗细菌鞭毛蛋白CBirl抗体(Anti-Cbirl)是消化道细菌常见抗原, 从结肠大鼠模型中发现. Anti-Cbirl通过引起B细胞反应和T细胞反应, 参与黏膜免疫应答[34,35]. 通过ELISA法测定发现, Anti-Cbirl阳性率出现在CD患者可达50%-56%, UC患者中<6%, 正常对照8%和其他胃肠道疾病为14%[36]. 与上述抗OmpC相似, Anti-Cbirl可作为CD诊断的辅助指标, 但需要与其他指标联合检测, 提高诊断效力.
I2抗体(Anti-I2)是一种细菌DNA片段, 最初在假单胞杆菌发现, 是细菌转录因子家族的同源物. 研究表明Anti-I2在CD患者中阳性率可达59.4%[37]. 但Dubinsky等[38]的研究则表明, Anti-I2在UC患者、非IBD患者及健康人群中也有较高的阳性率. 所以, 单个Anti-I2指标由于其特异性不高, 在CD诊断受到限制. 若与其他指标联合检测, 能否提高诊断率, 值得进一步探究(表1).
| 抗体分类 | 血清学标志物 | 临床意义 |
| 自身抗体 | ANCA | ANCA+对UC诊断有高度特异性; 鉴别UC和CD |
| PAB | PAB对诊断IBD低敏感性、高特异性 | |
| GAB | 鉴别UC和CD, 联合ANCA检测利于UC诊断 | |
| 抗CRT | 联合ANCA、GAB检测利于UC诊断 | |
| 抗GM-CSF | 鉴别UC和CD, 抗GM-CSF+利于CD诊断 | |
| 微生物抗原抗体 | ASCA | ACSA+对CD诊断有高度特异性; 鉴别UC和CD |
| ACCA | ACCA、ALCA及AMCA三者联合ACSA检测, 可 | |
| ALCA | 提高CD诊断的敏感性及特异性 | |
| AMCA | 利于CD诊断; CD患者中抗OmpC+更易出现穿孔 | |
| 抗OmpC | 诊断CD的辅助指标, 敏感性及特异性均不高, 联 | |
| Anti-Cbirl | 合ASCA、抗OmpC检测利于CD诊断 | |
| Anti-I2 | 临床应用特异性不高, 值得进一步探究 |
近年研究显示, 血清学标志物检测法相对方便、无创、病人接受度高, 可辅助诊断, 特别是依据临床表现、影像和内镜检查难以明确诊断时. 大部分研究支持上述血清学标志物在IBD患者中阳性率明显高于其他疾病及健康人. 目前常用于临床诊断IBD的指标包括p-ANCA、ASCA、ACCA、ALCA、AMCA. 一项国外的回顾性研究发现, ASCA 诊断IBD的敏感性(31%-45%)和特异性(90%-100%)最高, p-ANCA、ACCA、ALCA、AMCA抗体特异性也较高(98%、94%、86%-97%、94%-99%、92%-97%)[12]. 陶东升[39]、王玉萍等[40]研究也支持ANCA和ASCA在诊断IBD中具有较高的特异性. 但目前上述血清标志物的检测敏感性均小于50%, 不适合IBD的筛查.
关于UC和CD的鉴别诊断, 仅对单个血清学指标而言, p-ANCA诊断UC的敏感度和特异度最高, CD中则是ASCA. 目前国内外不少学者都提出联合多个血清标志物检测用于UC和CD鉴别诊断. 目前ANCA和ASCA的检测已纳入世界胃肠组织制定的IBD诊断, 其中明确提出ANCA+/ASCA-可提示UC, ASCA+/ANCA-可提示CD[41]. 2011年全球指南世界胃肠病学实践指南[42]亦有相同结论. He等[43]研究表明联合ANCA、ASCA、GAB、PAB检测CD敏感性与特异性可达55%和90%; ANCA+联合 ASCA-诊断UC的敏感性和特异性为 55%、90%; GAB+联合ANCA-诊断 CD 的敏感性和特异性则为 45%和95%. 另有回顾性研究发现[44], 在IBDU患者中, 联合p-ANCA+联合ASCA-则可以预测出64% 的UC患者, 联合ASCA+和p-ANCA-可预测出80%的CD患者. 此外, 值得注意的是, 研究发现不同种族的IBD患者, 应用相同的指标检测, 阳性结果可不一致[45,46]. 使用不同的 ELISA 试剂盒, 也会对结果造成影响[47]. 所以, 多个血清学指标联合检测是当下及未来IBD诊断方向, 多个指标互补, 可明显增加鉴别效益. 同时应注意不同种族、检测方法可能带来的问题.
同时, 在很多欧洲国家, 影像学检查显示出较高的IBD诊断准确率[48]. 该检查患者的耐受性较好, 特别是MRI无电离辐射的特性使其更适于患者尤其是年轻患者的长期观察随访. 作为无侵入性、方便的影像学检查和血清学指标, 若两者能有机结合, 则对于IBD的诊治将会有重要作用.
临床多以CDAI评分评估CD的活动性及严重程度[49], 但存在局限性. 近来研究显示, 血清学标志物检测对CD人群疾病表型的分型管理以及手术风险评估具有重要的临床价值. 沈佳佳等[50]研究发现CD患者疾病类型为狭窄型或穿透型, 分别与Anti-I2与ACCA显著相关. 其中联合检测Anti-I2、ACCA和抗OmpC, 任一项阳性诊断穿透型CD的AUC值为0.76; ASCA IgA或AMCA阳性则诊断CD病变累及胃、十二指肠和小肠的AUC值为0.9. 另有研究表明在CD患者中抗OmpC阳性, 更易出现肠穿孔, 手术风险相应上升[33]. Anti-I2阳性与肠道穿孔及是否行小肠手术相关[35]. 血清学检测使CD分层及手术风险评估更便捷, 但进一步明确敏感指标仍需大量循证医学证据, 以提高其临床意义.
伴随着越来越多的证据涌现, 已显示血清标志物在IBD诊断及鉴别诊断中起到积极作用, 在未来需要通过前瞻性对照试验得出更多的数据, 以进一步明确其作用. 目前我国在炎症性肠病诊断和鉴别诊断中的难点以及面临的问题尚多. 对于高度特异性的血清学指标, 如p-ANCA及ASCA, 能否联合其它无侵入性指标如影像学检查(如腹部CT、MRI)等提高诊断效力？当UC合并机会性感染, 如单纯梭菌感染后内镜下可见伪膜形成, 这在IBD中少见, 此时是否可依靠血清学检测改用什么方法诊断？小肠单独受累型CD因常规结肠镜的局限性, 检出率低, 易漏诊, 而胶囊内镜价格昂贵, 双气囊小肠镜有侵入性, 此时是否能够结合血清学指标提高检出率？CD急性期因有血水肿, 可加重原有肠腔狭窄, 肠腔纤维脂肪增生亦可有狭窄, 依靠临床症状和血清学指标往往难以确定, 此时该如何确定此狭窄来源？对于不同种族、性别、年龄疑似IBD患者能否制定合适的血清学检测或联合其它检测来提高诊断效率？另目前蛋白组学、基因组学及代谢物组学的快速发展, 能否联合血清分子标志物和易感基因检测, 以提升诊断及鉴别诊断准确率？
血清标志物检测在IBD诊断中具有高特异度、阳性预测值的特点, 有助于IBD的诊断、鉴别诊断, 同时在疾病分型及手术风险评估有一定作用. 联合多种血清标志物的检测可提高诊断的准确性. 目前由于技术、费用等问题, 血清标志物的检测受到一定限制. 今后可通过对血清学标志物检测技术更多的研究和推广, 提高其在IBD诊疗中的价值.
学科分类: 胃肠病学和肝病学
手稿来源地: 浙江省
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