慢性乙型肝炎肝纤维化无创诊断的进展

徐　瑞　常　江　黄　华　计洋洋　邓振华

昆明医科大学第二附属医院消化内科一病区(650101)



慢性乙型肝炎肝纤维化无创诊断的进展

徐瑞常江*黄华计洋洋邓振华

昆明医科大学第二附属医院消化内科一病区(650101)

摘要慢性乙型肝炎(CHB)为肝纤维化的常见原因之一，肝纤维化的正确评估对治疗决策和预后判断十分重要。肝活检是诊断肝纤维化的金标准，但其为侵入性检查，费用高，重复性差，患者不易接受，故迫切需要探索肝纤维化的无创诊断方法。近年发现弹性成像技术、血清学指标以及多个血清学指标构成的诊断模型对肝纤维化具有诊断价值。本文就CHB肝纤维化的无创诊断进展作一综述。

关键词乙型肝炎，慢性；肝硬化；诊断

肝纤维化是肝硬化和肝衰竭的早期信号，亦是抗病毒治疗的指征。肝活检是诊断肝纤维化的金标准，但其为有创性检查，有发生胆汁性腹膜炎、气胸、腹腔内出血等并发症的风险，且肝活检不便于动态监测肝纤维化的进展过程。因此，需要探索诊断肝纤维化的无创方法。本文就慢性乙型肝炎(chronic hepatitis B, CHB)肝纤维化的无创诊断进展作一综述。

一、超声弹性成像技术

1. 瞬时弹性成像(transient elastography, TE)：TE是一项通过测量肝脏硬度间接反映肝纤维化的超声技术[1]。检测的肝实质相当于整个肝脏的1/500，为肝活检样本的100倍，更具有代表性[2]。目前欧洲肝病研究协会(EASL)临床指南[3]推荐将TE作为诊断CHB肝纤维化的方法。国内Jia等[4]发现，当肝脏硬度测定值(LSM)为7.3 kPa时，TE诊断CHB明显肝纤维化的受试者工作特征曲线下面积(AUROC)为0.82；临界值为10.7 kPa时，诊断肝硬化的AUROC达0.90。TE还可用于监测CHB患者抗病毒治疗后肝纤维化的改善情况[5]，评估食管胃底静脉曲张、肝癌等并发症发生的风险以及预后[2]。近期研究发现，M型探头TE可测量受控的衰减参数，对CHB患者肝脂肪变的评估具有较高的敏感性和特异性[6]，而CHB患者发生肝脂肪变可影响抗病毒的疗效，增加肝硬化和肝癌的发生风险[6-7]。

体重指数(BMI)可影响TE对肝纤维化的诊断。对BMI≥30 kg/m2的患者，M型探头诊断肝纤维化的失败率达29.1%。XL型探头(2.5 MHz)的频率较M型探头更低，振幅更大，穿透力更强，其诊断BMI≥30 kg/m2者的肝纤维化失败率仅6.8%[8]。此外，肝血管瘤、肝衰竭、肝右叶占位、腹水、血清总胆红素、肝脏炎症程度亦可影响TE对肝纤维化的诊断[4,8-9]。进食亦可能影响TE对肝纤维化诊断的准确性[10]，建议行TE前至少空腹2 h[8]。

2. 实时组织弹性成像(real-time elastography, RTE)：与TE相比，RTE是二维图像，不受腹水、肋间隙狭窄、肝脂肪变、肝萎缩等因素的影响[8]。Xie等[11]发现，肝脏弹性指数的临界值为1.10时，RTE诊断CHB患者≥S2期肝纤维化的敏感性为77.8%，特异性80.0%，阳性预测值(PPV)80%，AUROC为0.863；临界值为0.60时，诊断肝硬化的敏感性50.0%，特异性96.7%，阴性预测值(NPV)92.2%，AUROC为0.797。

3. 声脉冲辐射力成像(acoustic radiation force impulse, ARFI)：ARFI通过向肝组织发出高强度的声脉冲，对组织进行短时间的机械刺激，从而产生剪切波。剪切波的速度(shear-wave velocity, SWV)与肝脏硬度有关[12]。Friedrich-Rust等[13]首次应用ARFI评估CHB患者肝纤维化程度，SWV临界值为1.39 m/s时，诊断明显肝纤维化的特异性为90%，PPV 67%，AUROC 0.75。ARFI在B超引导下选择感兴趣的区域进行测量，可避免周围组织(如血管)的干扰[14]。对合并腹水或肝右叶占位的CHB患者亦适用[8]。但SWV的范围值较窄(0.5～4.4 m/s)，对肝纤维化分期临界值的界定带来了一定困难[8]。肥胖、ALT、进食、胆汁淤积可影响ARFI对肝纤维化分期的诊断[15-17]。

4. 剪切波弹性成像：二维剪切波弹性成像(2D-SWE)可测量SWV，与普通超声设备联合使用具有较好的重复性，可用于长期随访，此外，2D-SWE能建立一个实时、二维的量化图[12,18]。当LSM临界值分别为7.2 kPa、9.1 kPa、11.7 kPa时，诊断CHB明显肝纤维化(F≥2)、重度肝纤维化(F≥3)、肝硬化(F=4)的准确性高，NPV分别为82.6%、95.1%、97.4%，AUROC均达0.900以上，但BMI、GGT、血清白蛋白可影响2D-SWE对肝纤维化分期诊断的准确性[18]。点剪切波弹性成像(PSWE)对CHB肝纤维化分期亦有诊断价值，且重复性好[19]。

二、影像学技术

1. 磁共振弹性成像(magnetic resonance elastography, MRE)：MRE可测量整个肝脏，对F≥1、F≥2、F≥3、F=4期肝纤维化诊断的准确性较高，AUROC达0.960以上。且不受肥胖、腹水的影响，同时可定量诊断肝脏脂肪化、铁沉积的程度。但当LSM的临界值为3.61 kPa时，MRE诊断F≥1的肝纤维化的NPV较低(0.677)，提示MRE将肝纤维化F≥1的患者误诊为F=0的概率较大。对F≤2期的CHB患者，炎症可使MRE高估或低估肝脏纤维化的程度[20]。

2. 磁共振扩散加权成像(diffusion weighted imaging, DWI)：DWI可显示肝纤维化时水在肝脏扩散的情况，然而，由于扫描设备、序列和b值的选择等因素的不同，DWI的表观扩散系数(ADC)在各期肝纤维化间存在较多重叠，目前未发现诊断肝纤维化的最佳临界值[21]。

3. 其他磁共振技术：增强磁共振显示肝纤维化时肝脏血流动力学改变，核磁波谱分析(MRS)从功能方面评价肝纤维化时肝脏代谢的变化，对肝纤维化的临床有一定价值，但MRI对肝纤维化的诊断易受呼吸、胃肠道运动的影响。目前扫描序列、成像参数的选择和数据的获得均缺乏统一标准[22]。因此，磁共振技术对CHB肝纤维化的诊断价值仍有待研究。

4. CT灌注成像：可应用定量参数反映肝纤维化血流灌注情况，肝脏血流灌注变化与病变严重程度有关，但参数受呼吸运动的影响较大，不同灌注模型设计和计算方法对结果亦有一定影响，目前的研究尚缺乏严格的灌注参数与病理对照[23]。

三、血清学指标

1. 平均血小板体积(MPV)：肝纤维化时，血小板生存周期缩短以及白细胞介素(IL)-6增加均可刺激骨髓产生血小板，使释放至外周血的新生血小板增加，从而导致MPV明显升高[24]。MPV临界值为8.15 fl时，诊断重度肝纤维化的AUROC为0.677，敏感性67%，特异性63%[25]。

2. 红细胞分布宽度(RDW)：CHB患者由于炎症、营养物质缺乏、骨髓抑制、氧化应激，可致RDW升高[26]。Karagoz等[25]发现RDW≥12.6%诊断重度肝纤维化的AUROC为0.672，敏感性91.5%，特异性42.5%。

3. 其他血清学指标：血清转铁蛋白[27]、血清铜蓝蛋白[28]可反映CHB肝纤维化的严重程度，有望成为评估CHB肝纤维化的血清学指标。

4. RDW与血小板计数比值(RPR)：Chen等[29]的研究结果显示RPR与肝纤维化相关(P<0.001)，RPR的临界值分别为0.10、0.16时，诊断CHB明显肝纤维化、肝硬化的AUROC分别为0.825、0.884，敏感性分别为63.1%、73.7%，特异性分别为85.5%、93%，PPV分别为77.4%、60.8%，NPV分别为74.7%、96%。

5. 球蛋白/血小板计数(GP)模型：GP模型与肝纤维化严重程度相关(P<0.001)，GP值<1.68，诊断轻微肝纤维化的AUROC为0.762，敏感性72.4%，特异性69.6%；GP值>2.53，诊断肝硬化的AUROC为0.781，敏感性72.7%，特异性84.5%[30]。

6. 白蛋白、Ⅳ型胶原、脾脏纵向直径构成的评分系统：该系统评分<3分，排除明显肝纤维化的NPV 86.1%，敏感性86.8%；评分>6时，诊断明显肝纤维化的AUROC为0.79，PPV 73.6%，特异性87.6%；该系统可使53.4%的患者避免行肝穿刺[31]。

7. REAL TEST公式：REAL TEST公式值≥1.37时，诊断CHB明显肝纤维化的AUROC为0.852，敏感性78%，特异性79%，NPV 85%，PPV 70%；该公式值≥0.64时，诊断轻微肝纤维化的AUROC为0.724 2，PPV 94.58%，敏感性71.75%，特异性56.94%[32]。

8. FibroTest模型：该模型的临界值分别为0.32、0.68时，诊断CHB明显肝纤维化、肝硬化的敏感性分别为79.3%、80.0%，特异性分别为93.3%、84%，PPV分别为98.5%、75.9%，AUROC分别为90.3%，86.6%[33]。但由于该模型包含触珠蛋白、胆红素、γ-GGT，患者发生溶血、胆汁淤积或近期有饮酒史时，可出现假阳性结果[34]。

9. APRI模型：Zhu等[35]发现，APRI的临界值分别为0.5、1.0时，诊断ALT≤2倍正常值上限(ULN)的CHB患者发生明显肝纤维化、肝硬化的AUROC分别为0.81、0.83，敏感性分别为82%、75.9%，特异性分别为83.3%、69.2%，NPV分别为89.9%、93.5%。

10. FIB-4模型：Zhu等[35]还发现，FIB-4的临界值为1.7时，诊断ALT≤2×ULN CHB明显肝纤维化的敏感性74%，特异性84.4%，PPV 71.2%，AUROC为0.86；临界值为1.9时，诊断肝硬化的AUROC为0.77，敏感性为69%，特异性75.3%，NPV 92.4%。

11. Forns指数：Forns指数对CHB肝纤维化的预测价值鲜见报道，饶建国等[36]对361例接受肝穿刺检查的CHB患者行Forns指数预测。临界值分别为4.873、5.432、6.289，诊断CHB显著肝纤维化、严重肝纤维化、肝硬化的AUROC均>0.7，提示Forns指数可作为评估CHB肝纤维化的无创方法。

四、血清学指标联合弹性成像技术

由于血清学指标与弹性成像技术可从不同的侧面对肝纤维化进行诊断，因此，两者联合可起到互补的作用，提高诊断肝纤维化的准确性。ARFI、TE、APRI联合诊断明显肝纤维化、肝硬化的准确性可分别升至83.86%、91.88%，敏感性和NPV亦明显提高[14]。Forns指数与ARFI或TE联合以及FibroSURE与AST联合亦可提高诊断CHB肝纤维化分期的准确性[37-38]。

五、结语

TE对CHB肝纤维化分期具有诊断价值，但对肝纤维化早期的诊断价值较低。目前ARFI、RTE、MRE、剪切波弹性成像对CHB肝纤维化也具有诊断价值，但缺乏充分的临床数据支持[39]。血清学指标具有重复性高、容易获得等优点，但需多中心大样本的临床研究来进一步评估其诊断价值。血清学指标联合弹性成像技术可提高诊断的准确性，但如何联合为一大难题[14]。

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(2015-08-11收稿；2015-09-18修回)

DOI:10.3969/j.issn.1008-7125.2016.06.013

Progress in Noninvasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis B

XURui,CHANGJiang,HUANGHua,JIYangyang,DENGZhenhua.

DepartmentofGastroenterology,theSecondAffiliatedHospitalofKunmingMedicalUniversity,Kunming(650101)

Correspondence to: CHANG Jiang, Email: cjcjchangjiang@sina.com

AbstractChronic hepatitis B (CHB) is one of the most commom cause of liver fibrosis. Accurate assessment of liver fibrosis is essential for the strategy of treatment and judgement of prognosis . Liver biopsy is the gold standard for staging fibrosis, but it is invasive with high cost, low reproducibility and poor acceptance by patients. Therefore, it is urgent to explore a noninvasive modality for the assessment of liver fibrosis. Recent evidence highlights that elastographic techniques, biochemical markers and the diagnostic model consisted of several serum markers have the potential for the diagnosis of liver fibrosis. This article reviewed the progress in noninvasive assessment of liver fibrosis in patients with CHB.

Key wordsHepatitis B, Chronic;Liver Cirrhosis;Diagnosis

*本文通信作者，Email: cjcjchangjiang@sina.com