胰腺是人体内仅次于肝脏的第二大外分泌器官。胰腺外分泌部由腺泡、导管和间质组成,腺泡合成、贮存和分泌消化酶,导管分泌水和电解质并输送胰液。维持正常的消化功能需要足量的胰液、通畅的胰管引流和食物与胰液充分的混合。胰腺外分泌功能不全(pancreatic exocrine insufficiency, PEI)是指由于各种原因引起人体自身的胰酶分泌不足或胰酶分泌不同步,而导致患者出现消化吸收障碍和营养不良等表现[1]。造成PEI的原因可分为:(1)胰腺实质功能衰退或损伤,胰腺合成能力下降;(2)胰管阻塞,胰液引流不畅;(3)分泌反馈失衡,对胰酶生成的刺激减弱[1]。由于PEI会造成各种严重的症状,检测胰腺外分泌功能(pancreatic exocrine function, PEF)显得十分重要。对于已明确病因的PEI,检测PEF可以帮助制定药物替代治疗的方案及评估其有效性;而对于尚不能确诊的患者,PEF的检测对协助诊断有非常重要的参考价值[1]。PEF的检测主要分为直接检测法和间接检测法,为了解各种方法的特点,本文就PEF检测方法的现状与进展作一综述。
1 直接检测法 1.1 胰泌素试验(secretin test)和胰泌素-雨蛙素试验(secretin-caerulein test)此方法通过静脉注射胰泌素(胰泌素和雨蛙素),放置经口(鼻)十二指肠管收集十二指肠液后测定各物质含量,从而判定PEF[2]。此方法是检测PEF的金标准,其敏感性和特异性均超过90%[2]。胰泌素试验检测胰液含量和碳酸氢盐浓度,胰泌素-雨蛙素试验除了检测以上两者外,还可以检测胰酶含量[3]。此方法可对PEI的严重程度进行分级:(1)轻度功能不全,指胰酶含量和碳酸氢盐浓度大于正常值下限的75%;(2)中度功能不全,指胰酶含量和碳酸氢盐浓度介于正常值下限的30%~75%;(3)重度功能不全,指胰酶含量和碳酸氢盐浓度低于正常值下限的30%[2]。Lankisch等[4]对202例患者行对照研究,发现此方法结果异常而内镜下逆行胰胆管造影(endoscopic retrograde cholangiopancreatography,ERCP)显示正常者最终有90%出现慢性胰腺炎(chronic pancreatitis,CP),此方法结果正常而ERCP显示异常者只有26%发展为CP,故在诊断CP方面,此方法较ERCP更加可靠。但Catalano等[5]对80例复发性胰腺炎患者进行ERCP、超声内镜(endoscopic ultrasonography,EUS)和此方法检测,发现ERCP与EUS对诊断CP的一致性远远高于此方法。此方法有侵入性、操作复杂、费时、价格昂贵等诸多不足,且诊断价值有待进一步证实,因此其在临床中的应用受到很大限制。
1.2 内镜下胰腺功能检测(endoscopic pancreatic function test, ePFT)此方法无需留置十二指肠管,静脉注射胰泌素(胰泌素和雨蛙素)后,直接用十二指肠镜收集注射即刻和注射后15、30、45、60 min的十二指肠液,分析各时间点十二指肠液中胰酶含量和碳酸氢盐浓度并与正常值比较[6]。此方法相对方便、省时,给临床医师提供了一种新的选择。Stevens等[7]比较此方法与留置十二指肠管的传统方法,发现两者对诊断CP并无差异。在收集的液体中提取炎性标志物(如细胞因子)或许可用于早期CP的诊断[2]。但部分学者认为,碳酸氢盐及胰酶的分泌量(并非浓度)才是反映PEF最可靠的指标[2, 8-9]。此方法仅仅通过测定各时间点的物质浓度来评估PEF,其可靠性有待进一步证实。
1.3 胰泌素刺激下的磁共振胰管成像(secretin-stimulated magnetic resonance pancreatography, s-MRP)技术检测开始前30 min口服造影剂以消除胃和十二指肠内高信号密度液体的干扰,之后静脉注射胰泌素,行s-MRP观察胰液在十二指肠中的充盈情况[10]。此方法可对PEF进行分级:胰液局限于十二指肠球部为一级,在降部为二级,达水平部为三级。无胰液分泌或为一级者高度怀疑PEI[11-12]。此方法既可以观察胰管形态又可以半定量评估PEF,从而将形态学和功能学结合,提高了诊断早期胰腺疾病PEF的准确性[13]。另外,此方法侵入性小,不存在置入十二指肠管或内镜造成的不适及不良反应,便于CP患者治疗后的随访,临床应用日趋广泛。Sugiyama等[14]在原先的方法上加以改进,应用胰泌素刺激下的弥散加权磁共振成像(secretin-stimulated diffusion-weighted magnetic resonance imaging)技术,通过弥散系数的变化反映PEF,认为改进后的方法比s-MRP敏感性更高,可用于早期、轻度胰腺疾病PEF的检测。
1.4 Lundh试验(Lundh test)此方法在摄入标准餐后收集十二指肠引流管中的液体,测定胰液排出量。此方法仅仅反映生理状态下的PEF,不能测定胰液分泌的最大量,故不再使用。
2 间接检测法 2.1 常规血清学检测(1) 血清中胰蛋白酶检测:PEI患者往往存在胰蛋白酶分泌不足,Jacobson等[15]研究发现肠源性脂肪泻患者和无脂肪泻的CP患者血清中胰蛋白酶水平与对照组无差异,此物质含量只在胰源性脂肪泻患者中升高,具有高度特异性。(2)血清中营养物质含量检测:PEI患者因消化、吸收不良而造成营养相关并发症,血清中营养物质含量不足与PEI有一定关联。Lindkvist等[16]对114例CP患者行队列研究后发现,血清中营养物质(如血红蛋白、白蛋白、前白蛋白、视黄醇结合蛋白、糖化血红蛋白等)含量可以预测CP患者是否伴发PEI,并指导胰酶替代治疗(pancreatic enzyme replacement therapy, PERT)。
2.2 粪便脂肪检测(1) 72 h粪便脂肪收集试验:受试者连续5 d摄入含有100 g脂肪的食物,收集后3 d的粪便,用Van de Kamer法或红外线光谱测定法测定脂肪含量,若脂肪含量大于7 g/d则认为存在脂肪泻[17]。此方法为粪便脂肪检测的定量方法,是诊断脂肪泻的金标准。虽然它将内源性的脂肪丢失计算在内,夸大了检测结果[18],且不能检测中短链脂肪酸、醇等物质,一定程度上又减少了检测精度[19],但作为最早、最经典的方法,目前仍应用于许多临床研究。(2)脂肪比容试验(steatocrit test):将粪便稀释、匀浆化、离心后,测定上层物质(主要为脂肪)占所有物质的比值,检测脂肪在粪便中的含量[17],脂肪含量大于31%为异常。此方法为粪便脂肪检测的半定量方法。Phuapradit等[20]将此方法用于检测婴幼儿脂肪泻获得满意结果。Sugai等[17]对148例成人的粪便进行此方法与金标准(Van de Kamer法)的一致性研究,发现此方法对于判断是否存在脂肪泻具有方便、快速、廉价、可靠的优点。在原先经典脂肪比容试验(classical steatocrit test)的基础上,Amann等[21]和Tran等[22]增加了酸化步骤,提高了检测的敏感性,故经典脂肪比容试验已被弃用,取而代之的是酸化脂肪比容试验(acid steatocrit test)。虽然此方法可用于筛查胰腺疾病造成的脂肪吸收不良[23-24],但未广泛应用于临床实践。(3)显微镜下脂肪检测:进食至少60 mg/d的脂肪,将粪便样本匀浆化后取直径约5 mm的粪块放置于2个载玻片上,分别检测中性脂肪(neutral fat)和分解脂肪(split fat),滴加苏丹Ⅲ试剂后在放大430倍的显微镜下观察脂肪小球的数量和直径。结果分3个等级:+为正常,++轻度升高,+++明显升高。此方法为粪便脂肪检测的定性方法。Fine等[25]用5个高倍镜视野下各脂肪小球数量的均值反映粪便脂肪含量,并将此方法量化以提高检测的准确性。
Lankisch等[26]指出,不能单凭肉眼观察诊断脂肪泻。粪便脂肪检测提供了诊断脂肪泻的方法,不仅可以协助诊断PEI,还可以监测PERT的疗效。但受试者较差的依从性和检测的复杂性是此方法不可避免的缺点[2]。另外,结果阳性只能说明存在脂肪泻,不能证明脂肪泻由PEI引起。因此,此方法在临床上的应用受到了一定的限制。
2.3 粪便中酶的检测(1) 粪弹力蛋白酶1(elastase 1)检测:弹力蛋白酶1在胃肠道中的含量非常稳定。取受试者的粪便,用单克隆抗体或多克隆抗体特异性地连接弹力蛋白酶1的两端,采用酶联免疫吸附实验(enzyme-linked immunosorbent assay, ELISA)测定其含量,含量小于200 μg/g提示存在PEI[27]。由于采用ELISA方法,检测结果不受PERT影响。此方法可以检测出尚未出现脂肪泻的PEI[28],且操作较为方便,尤适用于CP的筛查和确诊患者的长期随访[2],临床应用广泛。Hardt等[29]对213例患者分别行此方法与ERCP,发现此方法诊断CP的阳性预测值大于90%。Mattar等[30]发现此方法还能用于提示无症状性酗酒患者潜在PEI可能。但此方法仅测定胰酶浓度而非胰液分泌量,故在伴随小肠疾病和腹泻等的患者中会出现假阳性结果。另外,此方法对于诊断轻中度PEI的敏感性较低,在胰腺切除后患者中诊断PEI的准确性会有所下降[31]。(2)粪糜蛋白酶(chymotrypsin)检测:糜蛋白酶在胃肠道中容易灭活,因此不能准确反映PEF,目前只用于评价PERT后的疗效[32]。
2.4 呼气试验(1) 13C呼气试验:口服13C标记的底物,底物被十二指肠内特异性的胰酶水解后,代谢产物进入肝脏进一步分解,最终产生13C标记的CO2并呼出。通过光谱测定法或红外线分析法测定CO2含量,间接反映PEF。PEI患者由于缺乏胰脂肪酶,CO2的回收率较低,若低于29%则认为存在病变[33]。13C标记的底物主要有以下几种:①甘油三油酸酯(triolein)。Goff等[34]指出,将其作为底物可用于区分PEI和其他原因引起的吸收不良,诊断准确性高。②胆固醇辛酸盐(cholesteryl octanoate)。Ventrucci等[35]用此底物进行呼气试验,并与粪糜蛋白酶检测和粪便脂肪检测比较后得出此底物可以诊断脂肪吸收不良和PEI。Mundlos等[36]和Adler等[37]的研究表明此底物还能监测PERT的疗效。③Hiolein。Hiolein是一种特殊的三酰甘油,其3条脂肪链各不相同。将其作为底物同样可以反映脂肪代谢状态和PERT疗效[38]。④结合三酰甘油(mixed triglyceride,MTG)。此底物脂肪链的第1、3位为硬脂酰,第2位为13C标记的辛酰。自从Vantrappen等[39]首次提出可以用其作为呼气试验的底物后,其他学者相继提出MTG具有很高的敏感性和特异性,是最佳底物[32, 40-43],并通过比较不同底物含量、测定时间等寻求最优化的试验方案[43]。此外,Domínguez-Muñoz等[40]通过以MTG作为底物的呼气试验调整PERT方案后患者体质量恢复,血清中视黄醇结合蛋白和前白蛋白含量升高;Löser等[41]将其与粪弹力蛋白酶1的检测方法比较后发现,虽然前者对于诊断重度PEI有很高的敏感性,但对于轻中度PEI的检测仍不及后者。(2)H2呼气试验:口服含H2的糖类底物,若胰酶分泌不足,部分物质被无氧酵解,检测呼出气体中H2的含量即可间接反映PEF。主要有以下几种底物:①米粉。胰腺疾病、小肠疾病、肠道细菌过度生长的患者服用米粉后,呼出的H2含量显著增加。Kerlin等[44]认为,其诊断疾病的敏感性与定量粪便脂肪检测相当。Patel等[45]推荐将其作为筛查PEI的一种方法。与之不同的是,Casellas等[46]将此方法与直接检测法对比后认为,胰腺外因素的干扰及相对较低的敏感性降低了其对PEI的诊断价值。②葡萄糖。对于存在肠道细菌过度生长的PEI患者,摄入葡萄糖后呼出H2含量增加。Casellas等[47]应用此方法后发现PEI伴肠道细菌过度生长在胃十二指肠术后的CP患者中相对常见,抗生素治疗可使部分患者呼出气体中的H2含量恢复正常。
2.5 尿液中特定物质检测口服苯甲酰-酪氨酸-对氨基苯甲酸(苯替酪胺)或二月桂酸,通过测定尿液中特定物质的含量反映受试者的PEF。苯替酪胺试验在美国已不再使用,而二月桂酸荧光素试验也仅在部分欧洲国家使用。
3 小结PEF的检测主要分为直接检测法和间接检测法,直接检测法虽具有较高的准确性,但检测方法有创、相对烦琐,而无创的间接检测法准确性相对较低。各种方法虽已在临床应用多年,但研究进展缓慢,尚无统一的标准。选择最适合于受试者的方法,探索更加优化的检测手段,是未来的发展趋势及研究热点。
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