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Application of pathological indicators based on liver biopsy in the diagnosis of cirrhotic portal hypertension
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摘要: 肝静脉压力梯度(HVPG)是诊断门静脉高压症以及判断其严重程度的“金标准”，但因其有创性、操作技术难度大，限制了其在临床中的广泛开展。通过非侵入性方法替代HVPG是目前研究的热点，但现有的血清学及影像学方法的准确度仍有待商榷，尚不能在临床中完全替代HVPG。肝活检已在临床中广泛开展多年，是确诊某些肝脏疾病不可或缺的方法。近来研究发现肝穿刺后的病理学指标，如胶原面积、纤维间隔厚度、结节大小、微血管密度及胆管、淋巴管密度和面积等，不仅能判断肝纤维化的严重程度，而且与门静脉压力也有良好的相关性。这对诊断肝硬化门静脉高压症及评估门静脉高压症严重程度提供了新的思路。Abstract: Hepatic venous pressure gradient (HVPG) is the "gold standard" for diagnosing portal hypertension and determining its severity, but its wide clinical application is limited due to its invasiveness and difficulties in operation. The replacement of HVPG by noninvasive methods has become a research hotspot in recent years; however, the accuracy of the existing serological and imaging methods remains to be discussed, and such methods cannot completely replace HVPG in clinical practice. Liver biopsy has been widely used in clinical practice for many years and is still an indispensable method for the diagnosis of some liver diseases. Recent studies have found that several pathological indicators after liver biopsy, such as collagen area, fibrous septal thickness, nodule size, microvascular density, and density and area of bile ducts and lymphatic vessels, can not only judge the severity of liver fibrosis, but also have a good correlation with portal venous pressure, which provides new ideas for diagnosing cirrhotic portal hypertension and evaluating the severity of portal hypertension.
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Key words:
- Liver Cirrhosis /
- Hypertension, Portal /
- Biopsy, Needle /
- Diagnosis
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门静脉高压症是肝硬化患者死亡的主要原因之一[1]。据统计[2]，确诊肝硬化门静脉高压症患者的第一年死亡率为25%~30%，如果不经过系统治疗，两年后的死亡率可高达50%。肝静脉压力梯度(hepatic venous pressure gradient, HVPG)是门静脉和下腔静脉之间的压力梯度[3]，也是目前临床测量门静脉高压最可靠的方法[4]。然而，由于HVPG属有创操作、检查费用高、技术难度大、难以重复检查等缺点，限制了其在临床实践中的广泛应用[5]。目前，在临床中虽然涌现出了大量反映门静脉高压症的非侵入性方法，但其准确性及临床应用价值仍需进一步评估[1]。肝活检仍是目前判断肝硬化及其分期的“金标准”，如果能够寻找其他的病理特征来反映门静脉压力，利用肝活检后的病理切片不仅能够用于肝纤维化程度判定，也能用来诊断门静脉高压的严重程度。近年来，研究发现，肝活检病理学的相关指标，如胶原面积、纤维间隔厚度、结节大小、微血管密度、胆管及淋巴管微结构的变化和门静脉高压症有良好的相关性，可为评估肝硬化门静脉高压症严重程度及制订进一步诊疗策略提供新的思路。
1. HVPG与肝脏胶原面积、纤维间隔厚度及结节大小相关
胶原构成了肝脏结缔组织的细胞骨架[6]。当肝脏受损时，肝小叶内原有的网状支架塌陷，肝星状细胞活化后转变为肌成纤维细胞并产生大量胶原[7-8]，随着胶原沉积的增加，肝内阻力增大，门静脉压力也随之升高。健康人肝脏胶原约占肝质量的2%，肝硬化时可上升至8%~10%[9]。一项动物实验研究[10]发现，与门静脉压力＜10 mmHg的大鼠相比，显著门静脉高压(HVPG≥10 mmHg)大鼠肝脏的纤维面积升高了13倍。2009年Calvaruso等[11]首次提出了利用组织切片的计算机辅助数字图像分析技术来测量胶原比例面积(collagen proportionate area, CPA)，从而反映肝脏纤维化的程度，他们通过对115例丙型肝炎患者的研究发现CPA不仅与纤维化程度相关，而且发现CPA与HVPG的组织学相关性甚至优于Ishak分期。随后，Tsochatzis等[12]通过Laennec、Kuma、Nagula和Sethasine等半定量分类系统对从肝纤维化到肝硬化进行分期，发现CPA在肝硬化的所有阶段都成比例增加。随后，在一项对42例肝硬化患者进行肝活检，并在肝活检后6个月内进行HVPG测量的研究[13]也发现CPA与HVPG显著相关(r=0.636，P＜0.005)。另外，在一项纳入169例感染慢性HBV或HCV的肝移植患者的研究[14]中，在患者进行肝移植前后分别进行肝活检，发现CPA与HVPG相关(R2=0.41，P=0.01)。不仅如此，Nielsen等[15]利用CPA可靠的区分了“临床上显著的门静脉高压”，即HVPG≥10 mmHg(受试者工作特征曲线下面积：0.923，P＜0.001；OR=1.209，P=0.003)。除此之外，纤维间隔厚度及结节大小与HVPG亦相关[16]。一项回顾性研究[17]对104例多种病因肝硬化患者进行肝活检，并在活检后1个月内进行了HVPG测定，发现HVPG与肝硬化的结节大小(P＜0.001)、间隔增厚(P=0.015)呈显著正相关。Nagula等[18]通过对43例肝硬化患者测量HVPG，并评估了纤维间隔厚度及结节大小，发现小结节和纤维间隔厚度是独立预测“临床上显著的门静脉高压”的良好参数。利用胶原面积、纤维间隔厚度及结节大小来反映门静脉高压，目前仍处于研究阶段、缺乏大规模临床数据验证，不能完全替代目前临床上诊断门静脉高压的方法[19]。但其为以后的临床研究奠定了基础，为预测肝硬化的进展和预后提供了新的思路。
2. HVPG与肝内血管的变化有关
肝微血管的改变被认为是肝硬化门静脉高压症的重要病理生理特征之一[20]。在门静脉高压症的发病机制中起着重要作用[21]。门静脉高压时肝内血管的改变主要包括血管新生和血管重塑[22]。在肝硬化的发展过程中，随着胶原的沉积、再生结节的形成，组织缺氧进一步加重，肝内微血管狭窄，甚至闭塞，进而导致肝内循环阻力增加，血管的这一系列改变又加剧了门静脉高压的严重程度[23-24]。目前，对血管数量的计算主要采用“热点法”[25]，免疫组化指标主要包括CD31、CD34以及vWF[26]。有研究通过使用CD34抗体对肝组织切片进行染色，在二维层面证实了微血管密度(microvessel density, MVD)随着肝纤维化的发展不断升高(轻度纤维化的MVD为1.09%±0.26%，中度纤维化为1.92%±0.20%，重度纤维化为2.46%±0.23%)，均明显高于正常组(0.45%±0.14%) (P＜0.01)[20]。此外，一项动物实验研究[10]通过用CD34免疫染色方法测量肝硬化大鼠肝脏MVD，发现当门静脉压力升高时，新生血管数量亦增加，MVD与门静脉压力(r=0.731，P＜0.001)相关。胡春红团队[20]通过近年来逐渐发展起来的一项对肝脏内部无创、三维可视化观察的一项新技术——X射线相衬CT对肝纤维化大鼠肝脏进行检查，在三维层面发现在肝纤维化的发展过程中，血管内壁的曲线度、纹理特征、内径和MVD与纤维化面积(r≥0.729，P＜0.001)和门静脉压力(r≥0.715，P＜0.001)有很好的相关性。随后，其团队通过这项技术再次对CCl4或胆管结扎诱导的肝硬化大鼠的肝脏进行检查，发现门静脉压力与肝内血管分支形态特征显著相关(r≥0.761，P＜0.01)，证明了血管形态的改变能准确区分肝硬化大鼠的门静脉压力[27]。并提出了门静脉分支形态学特征可作为门静脉高压症检测的替代指标。目前肝硬化的微血管改变与门静脉高压症的关系仅在动物实验中进行，尚缺少临床验证。但利用肝内微血管的改变来评估门静脉压力或预测门静脉高压症是非常有潜力的组织病理学指标。
3. HVPG与淋巴管的变化有关
肝脏是产生淋巴液的最大器官[28]，肝硬化肝脏血液动力学严重异常时，淋巴系统则发挥了重要的代偿作用[29]。肝纤维化时，胶原的沉积和血管阻力的增加导致肝脏微循环障碍，从而导致淋巴系统在淋巴管新生、淋巴液产生、淋巴引流系统的扩张、淋巴液含量等方面的一系列变化[30-31]。早在1984年就有研究[32]发现肝硬化大鼠肝脏的淋巴液流量较对照组正常大鼠增加29倍，且淋巴流量与门静脉压力之间有良好的相关性(r=0.72~0.92，P＜0.01)。1997年Vollmar等[33]首次报道了肝纤维化和肝硬化时淋巴管的新生。他们使用CCl4大鼠肝硬化模型，发现在肝硬化形成过程中淋巴管密度逐渐增加，在CCl4诱导后1、2和4周淋巴管密度的平均值分别为(12.3±8.0)、(19.9±10.4)和(49.8±9.0)cm，淋巴管面积由(2.6±1.7)%逐渐增加至(6.5±3.4)%和(14.5±1.7)%，与对照组相比均P＜0.01。Tanaka等[34]对肝硬化患者的研究发现，随着淋巴管的新生，肝脏淋巴液的生成增加了30倍。在之后的临床研究[28]中，也证明了在包括肝硬化在内的多种肝病患者中，肝淋巴管的生成显著增加。Yamauchi等[35]对慢性病毒性肝炎和肝硬化患者的标本进行形态计量学分析，发现淋巴管的数量和面积均随肝纤维化程度的加重而增加。在一项纳入了28例不同病因的终末期肝病患者的研究[36]中，通过使用podoplanin标记淋巴管，INFORM软件计算淋巴管密度，发现肝硬化患者淋巴管密度显著增加(P＜0.01)。Oikawa等[37]报道特发性门静脉高压患者较健康对照组肝脏淋巴管的面积增加，推测可能与门静脉血流量减少有关。除此之外，Park等[38]通过胸部CT测量179例慢性肝病患者的远端胸导管的直径发现，胸导管扩张程度与肝硬化进展及门静脉高压症进展有显著相关性(OR=3.809，95%CI：1.172~12.458，P=0.027和OR=2.788，95%CI：1.051~7.393，P=0.039)。然而，目前对淋巴系统在肝硬化和门静脉高压症中的作用机制仍不清楚，还需要进一步的研究。
4. HVPG与胆管变化有关
肝脏除了血管、淋巴管系统，还拥有胆管这一特殊系统。目前，在多种肝硬化动物模型及不同病因肝硬化患者中均可见胆管增生[39-40]。胆管增生的激活被认为在肝纤维化的发生和发展中起着关键作用[41-42]。增生的胆管通过介导星状细胞增殖、活化，加快门静脉高压症的形成[43-44]。Rókusz等[45]分别用CK19免疫荧光标记和Picro Sirius染色后形态计量学方法检测肝硬化小鼠的胆管增生和纤维化程度，发现肝纤维化程度与胆管增生之间有很强的相关性(P＜0.001)。不仅仅在动物模型中，在一系列临床研究中，也证明了随着肝纤维化的发展，胆管数量逐渐增加。Wood等[46]在对血色病患者的研究中，发现通过CK7标记的胆管数量随着纤维化程度而增加，两者呈正相关(r＝0.803，P＜0.0001)。在慢性丙型肝炎肝硬化患者中，CK7标记的胆管面积与纤维化程度亦呈正相关(r＝0.453，P＜0.000 1)[47]。此外，在非酒精性脂肪性肝硬化中，随着肝纤维化程度的加重，CK7标记的胆管面积也呈现动态变化并且两者有密切相关性(r＝0.51，P＜0.000 1)[48]。在丙型肝炎肝纤维化形成过程中，胆管的数量与肝纤维化阶段之间也呈正相关(r=0.53，P＜0.000 01)。胆管的数量随着肝纤维化的发展而增加[40]。虽然肝硬化时胆管的形态数量改变的研究仍处于理论阶段，但通过计算病理切片中胆管的面积，能够反映肝纤维化程度。为胆管形态和数量的变化预测门静脉压力提供了理论基础，也将成为一项非常有潜力的病理学指标。
5. 研究现状及展望
肝硬化在病理上不仅表现为胶原沉积、血管新生，同时也伴有胆管和淋巴管的增生。而门静脉高压症是肝硬化失代偿期患者死亡的重要原因。近年来，许多研究已经证明肝硬化门静脉高压症时，肝内胶原面积、纤维间隔厚度、结节大小、微血管密度及淋巴管、胆管密度和面积与门静脉高压症有良好的相关性，并且通过二维病理及其三维结构证实了这些发现。这是对肝硬化的病理形态学特点的补充，不仅为肝脏穿刺活检提供了更多的临床价值，为肝活检评估肝硬化严重程度提供了一个新的病理指标，也为门静脉高压症的诊断提供了新的思路。
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