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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
世界华人消化杂志. 2016-10-08; 24(28): 3940-3945
在线出版日期: 2016-10-08. doi: 10.11569/wcjd.v24.i28.3940
肝特异性对比剂Gd-EOB-DTPA增强磁共振成像评价肝功能的研究进展
饶圣祥, 曾蒙苏
饶圣祥, 曾蒙苏, 复旦大学附属中山医院放射科 上海市影像医学研究所 上海市 200032
饶圣祥, 副主任医师, 主要从事腹部影像的研究.
作者贡献分布: 饶圣祥与曾蒙苏负责选题, 查找文献; 饶圣祥负责论文撰写.
通讯作者: 饶圣祥, 副主任医师, 200032, 上海市枫林路180号, 复旦大学附属中山医院放射科, 上海市影像医学研究所. raoxray@163.com
电话: 021-64041990
收稿日期: 2016-04-25
修回日期: 2016-05-25
接受日期: 2016-05-31
在线出版日期: 2016-10-08

肝特异性对比剂Gd-EOB-DTPA的肝功能评价越来越受到重视, 其吸收和排泄的路径与吲哚青绿15 min滞留实验及核素肝胆显像剂甲溴苯宁的吸收排泄路径相似即通过肝细胞膜表面的有机阴离子转运系统有机阴离子转运系统1(organic anion transporter 1, OATP1)B1和OATP1B3吸收进入肝细胞内, 再通过多耐药蛋白载体排泄入胆道系统. Gd-EOB-DTPA增强磁共振(magnetic resonance, MR)优势在于常规的MR增强检查可同时获得肝功能信息, 可以评价节段性肝功能且没有电离辐射损伤. 其评价方法主要通过胆道内对比剂排泄的量、肝实质的强化率、MR弛豫时间的测定和灌注扫描参数的测定等, 在评价肝功能储备、肝纤维化分级、非酒精性脂肪肝程度等有广泛的应用前景.

关键词: 肝功能; Gd-EOB-DTPA; 磁共振成像

核心提要: Gd-EOB-DTPA增强磁共振成像可以"一站式"的获得临床所需的解剖和肝功能的信息, 同时可以评价肝节段性功能储备, 为慢性肝病或手术患者的治疗和预后提供有用的依据.
引文著录: 饶圣祥, 曾蒙苏. 肝特异性对比剂Gd-EOB-DTPA增强磁共振成像评价肝功能的研究进展. 世界华人消化杂志 2016; 24(28): 3940-3945
Assessment of liver function by Gd-EOB-DTPA enhanced magnetic resonance imaging
Sheng-Xiang Rao, Meng-Su Zeng
Sheng-Xiang Rao, Meng-Su Zeng, Department of Radiology, Zhongshan Hospital, Fudan University; Shanghai Medical Imaging Institute, Shanghai 200032, China
Correspondence to: Sheng-Xiang Rao, Associate Chief Physician, Department of Radiology, Zhongshan Hospital, Fudan University; Shanghai Medical Imaging Institute, 180 Fenglin Road, Shanghai 200032, China. raoxray@163.com
Received: April 25, 2016
Revised: May 25, 2016
Accepted: May 31, 2016
Published online: October 8, 2016

Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), a liver-specific magnetic resonance imaging (MRI) contrast agent, is increasingly used for imaging-based liver function tests. Like indocyanine green and mebrofenin, Gd-EOB-DTPA is taken up by hepatocytes through organic anion-transporting polypeptides 1 (OATP1) B1 and B3 and is then excreted into the bile by multi-drug resistance protein (MRP2). The advantages of Gd-EOB-DTPA-based liver function tests include function measurement integrated in an existing MRI protocol, ability of evaluating segmental liver function, and no ionizing radiation. The approaches based on Gd-EOB-DTPA for function measurement are as follows: measurement of biliary elimination, hepatic parenchymal enhancement, MR relaxometry, and MR perfusion. These approaches have potential value for assessing liver reserve, hepatic fibrosis, non-alcoholic fatty liver disease and so on.

Key Words: Liver function; Gd-EOB-DTPA; Magnetic resonance imaging
0 引言

肝功能的评价, 一直是临床医生关注的一个焦点, 无论是肝外科手术前的准确预测、术后的有效随访还是对于内科患者对于肝脏弥漫性病变(如肝纤维化/肝硬化、脂肪肝等)的随访监测, 对于提高手术的成功率及延长患者的生存期, 都有十分密切的联系, 而就迄今运用于临床的各种肝功能评价方法, 都有其一定的局限性. 目前临床上最常用的肝功能评价方法包括Child-Pugh评分、终末期肝病模型(model for end-stage liver disease, MELD)评分、吲哚青绿15 min滞留实验(indocyanine green 15 retention, ICG R15)、LiMAX test等[1-3], 都只能评估整体肝功能的变化, 对于不同肝段之间的肝功能的区别, 难以有效评价.

近年来以影像为基础的肝功能储备的评价应运而生, 开始受到临床的关注和重视[4-7], 尤其是肝脏特异性对比剂Gd-EOB-DTPA(gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid)(商品名普美显, Primovist)不仅对于肝局灶性病变的检出、定性具有优势[8-11], 而且对于肝功能评价有潜在的应用价值[12-16]. 本文就Gd-EOB-DTPA增强磁共振(magnetic resonance, MR)成像对肝功能的评价的方法和价值的相关研究进行综述, 旨在提高读者在相关领域的研究的认识和兴趣.

1 Gd-EOB-DTPA增强MR评价肝功能的机制和优势

静脉团注Gd-EOB-DTPA可通过肝窦面的肝细胞膜表面的有机阴离子转运系统1(organic anion transporter 1, OATP1)B1和OATP1B3吸收进入肝细胞内, 滞留数小时至24 h之久, 再通过主要位于胆道面的肝细胞膜上多耐药蛋白载体(multi-drug resistance protein, MRP)MRP2排泄入胆道系统, 其通过肝脏吸收比例约为注射剂量的50%, 且其化学结构不会改变[17-19]. Gd-EOB-DTPA的吸收和排泄的路径与ICG R15及核素肝胆显像剂甲溴苯宁的吸收排泄路径相似, 因此Gd-EOB-DTPA增强MR可用于肝功能的评价. 当肝脏发生不同的病变时, 部分肝细胞遭破坏、肝细胞的正常功能受损, 肝实质吸收和排泄入胆总管对比剂Gd-EOB-DTPA的量会发生变化, 从而引起MR信号强度的改变, 以此来反映肝功能的改变.

Gd-EOB-DTPA增强MR的优势在于在常规的MR增强检查方案中的基础上同时获得肝功能信息. Gd-EOB-DTPA增强MR在术前可以"一站式"的获得外科手术前所需的信息, 包括肝肿瘤的体积及分布、肝脏的解剖、血供和其他肝外的信息如有无淋巴结转移等, 这是其他肝功能检查所不具备的; 而且其克服了整体评价的肝功能的缺点, 可以显示肝实质的损害分布的不均匀性, 实现节段性肝功能的评价[20,21]. 研究发现Gd-EOB-DTPA增强MR与99m锝-甲溴苯宁、ICG R15对肝功能储备的准确性相似[12,13], 而Gd-EOB-DTPA增强MR较核素检查具有更高的空间和时间分辨率, 同时MR没有辐射的损害, 因此更具有临床的应用价值.

2 Gd-EOB-DTPA增强MR评价肝功能的方法

Gd-EOB-DTPA增强MR检查评价肝功能的主要通过测量胆道内对比剂的排泄和肝实质的强化程度的变化来反映肝细胞的功能状态. 具体方法主要有以下几点: 胆道内对比剂排泄的量、肝实质的强化率、MR弛豫时间的测定和灌注扫描参数的测定等.

2.1 胆道内对比剂排泄的量的评价

Gd-EOB-DTPA增强MR后20 min在所有正常健康人群中均看到肝内外胆道内很好的显示[22], 在慢性肝病伴肝功能损害的患者中胆道的显影会相应延迟. 常采用的评价方法主要包括: 特异期主观评价胆道结构显影的清晰度、胆总管显影的时间和信号值(signal intensity, SI)测定、胆总管与肌肉相对值、胆囊充盈时间和程度等.

研究显示[23-27]慢性肝病/肝硬化患者Gd-EOB-DTPA增强MR主要表现: (1)肝功能损害时(MELD≥11和总胆红素≥30 μmol/L)肝内外胆道结构的显示不清, 严重时甚至不显影[23]; (2)胆道充盈时间明显延迟, 而且强化程度(直接强化或相对强化)明显减弱; (3)胆囊管开放充盈时间延长(>30 min); (4)胆管强化的程度与ICG R15显著相关, 因此可以潜在反映肝功能的程度.

胆道强化的评价方法比较简单、直观, 只需应用常规序列就可以做出判断, 不需要额外的序列和复杂技术, 但是胆道的强化程度和时间不仅仅与肝功能有关, 而且与胆道的压力和胆汁流量有关, 如果胆汁动力学发生改变如胆道结石、胆道炎症等, 其评价肝功能准确性受到限制[27,28].

2.2 肝实质的MR SI的改变

这是目前临床和研究最常用的一种方法, 采用的评价方法: 特异期主观观察或MR SI测量肝实质的强化改变、肝实质的信噪比、利用肌肉或脾脏作为内在参照物校正等.

"延迟期高信号门静脉"征即静脉注射Gd-EOB-DTPA延迟30 min后门静脉与周围肝实质相比呈相对高信号, 此征出现的概率约13%, 并与血直接胆红素相关, 判断胆红素高于2.18 mg/dL的敏感性为89%, 特异性为96%[29]. 肝实质强化程度的测量可以反映肝细胞的功能状态, 在患者中的慢性肝功能损害的特异期肝实质的信噪比或相对强化率明显低于正常功能的患者, 而且与ICG R15显著相关[30,31]. 目前大部分文献利用内参物(肌肉或脾脏)计算校正肝脏强化率[32]、肝实质强化指数[33]和肝细胞吸收指数(hepatocellular uptake index, HUI)[34]等. Watanabe等[33]报道肝实质强化指数对肝纤维化分级的准确性明显优于扩散加权成像、血液检查和临床指标.

肝脏SI的直接测量比较简单, 与测量CT值相似, 直接利用感兴趣区的测量就可以得到相应的值, 这也是目前临床上应用最广的原因. 但是其存在一定缺陷: MR的SI的影响因素比较多如MR的扫描参数不同SI亦不同, 而且MR SI与钆的浓度成正相关而不是线性相关[35]. 虽然采用内参校正, 可减少误差, 但是计算相对比较麻烦不适合临床常规使用, 尤其HUI测量和计算均比较复杂, 限制其广泛应用.

2.3 MR弛豫时间的测定

Gd-EOB-DTPA不仅可以缩短T1弛豫时间, 亦可缩短T2*弛豫时间. 因此可以通过T1mapping参数图和T2*加权成像参数图测量相应的T1值和T2*值来评价肝功能[15,36-42]. 我们研究[15]发现肝硬化患者MELD分数越高肝胆特异期的T1弛豫时间明显延长, 而且增强前后T1弛豫时间的降低率明显下降. 同时发现Gd-EOB-DTPA肝胆特异期T1弛豫时间的测量有利于早期发现梗阻性黄疸的肝损伤[36]、肝纤维化的分级[37]以及有助于非酒精性脂肪肝的分级[38]. 理论上, Gd-EOB-DTPA缩短T1弛豫时间较T2*弛豫时间更明显, 有报道显示慢性肝损伤患者肝胆特异期的T2*弛豫时间与肝功能正常的患者无明显区别, 但是T2*弛豫时间的降低率明显下降[42].

弛豫时间的测量比较客观的反映肝细胞内Gd-EOB-DTPA的浓度, 因此对于肝功能的评价优于SI的直接测量[43]. 全肝测量T1弛豫时间测量有助于提高肝功能评价的准确性[44], 但是T1和T2*弛豫时间的测量尤其全肝测量需要有特殊序列和软件的支持, 而且肝细胞吸收Gd-EOB-DTPA的量除了受肝细胞功能影响外, 还受到肝脏血流灌注的影响.

2.4 MR灌注扫描技术

MR肝脏灌注是利用灌注参数来定量肝脏肿瘤或肝实质的微循环状态[45,46]. Saito等[13]运用Gd-EOB-DTPA动态增强扫描运用示踪动态计算模型, 与ICG15及99mTc-乙二烯三胺戊乙酸半乳糖基人血清白蛋白(99mTc-labeled diethylenetriaminepentaacetic acid galactosyl human serum albumin, 99mTc-GSA)的单光子发射型计算机断层显像(single photon emission computed tomography, SPECT)图像相关性很好, 适合评价肝功能储备. 另外有研究发现Gd-EOB-DTPA动态灌注扫描有望用于原发性硬化性胆管炎的节段及亚段性肝功能的评价[47,48]、肝纤维化分级[49]和炎症活动度[50]的评价.

MR灌注扫描不仅考虑了肝细胞功能不同导致吸收Gd-EOB-DTPA的浓度不同, 还考虑肝脏血流状态的不同, 从这一点上其优于其他的方法, 但是由于Gd-EOB-DTPA被肝细胞吸收与常规MR对比剂不一样, 因此其灌注分析需要特殊软件和复杂的数学模型的计算. 另外MR灌注分析的困难还在于肝脏双血供、采集图像的呼吸伪影、缺乏统一的标准等. 因此还需要进一步研究和标准化.

3 结论

Gd-EOB-DTPA增强MR成像作为一种无创伤性检查手段, 能同时评价肝脏的解剖和功能储备具有独特的优势, 尤其是定量评价肝段、肝叶的肝脏储备能力, 从而进一步完善肝脏功能检测的方法, 对肝肿瘤手术的术前判断和弥漫性肝病监测有广泛的应用前景, 但其测量方法和评价指标的需要进一步临床验证和标准化.

评论
背景资料

临床上常用的肝功能评价方法包括Child-Pugh评分、自终末期肝病模型(model for end-stage liver disease, MELD)评分、吲哚青绿15 min滞留实验(indocyanine green 15 retention, ICG R15)、LiMAX test等仅能评价整体肝功能, 存在一定的限制, 而以影像为基础肝功能评价可以同时提供空间分布信息.

同行评议者

吕维富, 教授, 主任医师, 安徽省立医院影像科

研发前沿

本文研究着重于Gd-EOB-DTPA增强磁共振(magnetic resonance, MR)成像在评价节段性肝功能的应用, 目前需要确定最优的测量方法和评价指标的标准化.

相关报道

目前此方面研究都处于动物实验或单中心的临床研究阶段, 常用的测量方法各异, 但是在肝功能评价方面已初步显示其优越性.

创新盘点

本文介绍了Gd-EOB-DTPA增强MR成像评价肝功能的机制、优势, 并比较目前不同测量方法的优缺点及应用的注意点.

应用要点

Gd-EOB-DTPA增强MR成像作为一种无创伤性检查手段, 无射线危害, 具备定量评价肝脏功能储备的能力, 对肝肿瘤手术的术前判断和弥漫性肝病监测有广泛的应用前景.

名词解释

T1弛豫时间: 90度射频脉冲质子由纵向磁化转到横向磁化之后再恢复到纵向磁化激发前状态所需时间. 不同的组织的T1是相对固定的, 且存在差别. 肝细胞吸收Gd-EOB-DTPA的量的不同, 其T1弛豫时间亦不同.

同行评价

本文综述了肝特异性对比剂Gd-EOB-DTPA增强MR成像评价肝功能的研究进展. 选题有一定的新颖性, 对于指导临床工作有一定的帮助.

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: 上海市

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