《国际肝病》：肝纤维化程度的不同，其治疗策略和预后差异很大，因此肝纤维化的准确分期十分必要。目前主要的肝纤维化非侵入检测方法有哪些？ 

 

Castera教授：肝纤维化是肝病发展的重要预后因素。目前有两大类不同的非侵入性检测肝纤维化的方法。一是血清指标检测。另一种是使用多种技术检测肝脏硬度，这方面瞬时弹性成像（TE）较为先进且应用最为广泛，也有其他新技术如ARFI（剪切波成像技术）及MR成像技术。此外，一些血清学治疗及联合模型的诊断价值也得到了临床验证，如FibroTest、FIB-4或APRI等。

 

这些方法虽然应用广泛，但是诊断肝硬化的准确度却不如TE。TE的主要优点是作为点对点技术能够快速获得检查结果（仅需约5min）。医生或护士都能操作，也可在床旁实施。此外，肝硬度值处于12～75 kPa范围时，TE诊断肝硬化具有极高的准确度，而且用于肝硬化患者的预后价值也较高。TE的主要缺点是在肥胖、腹水时准确度有所下降，而操作者的经验技术也会影响检测结果。此外，可导致假阳性结果的肝脏炎症也需要加以注意。

 

Dr Castera: You are right. Liver fibrosis is the main prognostic factor in liver disease. Currently, we have two different but complementary approaches among the non-invasive tests. One is the level of serum markers. The other is based on the measurement of liver stiffness using different techniques, of which transient elastography has been the pioneer, but there are new techniques like ARFI (shear wave elastography) and MR elastography. So far, I have to say that transient elastography is the most widely available, validated and used, including in China. Regarding serum markers, there are mathematical formulae that have been validated against liver biopsy. Some of them are proprietary, such as FibroTest, while others are free like FIB-4 or APRI. They have high applicability, wide availability (according to whether they are patented or non-patented), but their performance for cirrhosis is not as good as transient elastography. On the other hand, the main advantage of transient elastography is that it is a point-of-care technique, meaning that results are immediately available (five minutes). It can be performed by a nurse as well as a doctor, or at the bedside. In the range from 12-75 kPa, there is very high accuracy (probably the highest for cirrhosis), and there is also prognostic value in the context of cirrhosis. The main disadvantage of this technique is its reduced applicability in cases of obesity or ascites, and where there is a lack of operator experience. Those are the main drawbacks. You also have to be cautious with inflammation, as there is the risk of false positives.

 

《国际肝病》：非侵入的检查方法已经越来越多地用于非酒精性脂肪性肝病患者的诊疗中，那么目前非侵入的检查方法能否代取代传统的肝组织活检？

 

Castera教授：非侵入性检查不能替代肝活检，尤其是对于非酒精性脂肪性肝病（NAFLD）患者。诊断如非酒精性脂肪性肝炎（NASH）的病变时，患者存在病情快速进展风险，也可能存在并发症、肝硬化及肝细胞癌（HCC），这都需要肝活检来确诊。因此，目前尚无非侵入性检查方法（包括血清指标及影像学技术）能够确诊NASH。

 

病毒性肝炎中应用非侵入性检查诊断肝硬化是相当准确的。但在评估亚组患者时需要进行肝活检。例如，目前所有进行中的全球性Ⅲ期临床试验均需要肝活检结果来进行评估。在审批新药（肝病相关）时，肝活检结果也是十分必要的。非侵入性方法能够有效地筛选高危人群中处于肝病进展高风险状态（存在NASH及进展性肝纤维化）的亚组患者，从而及时转诊患者到专业医疗中心来进行肝活检并接受药物治疗或参与临床试验。

 

Dr Castera: I don’t think that non-invasive tests are going to replace liver biopsy, especially for NAFLD, because diagnosis of some of the lesions like NASH, where patients are at risk of no return and there is the potential for complications, cirrhosis and hepatocellular carcinoma, depends on liver biopsy. So far, none of the non-invasive methods, including serum markers and imaging techniques, can confidently diagnosis NASH. As for fibrosis, it has already been shown in the field of viral hepatitis that these techniques are quite reliable, especially for the diagnosis of cirrhosis. I think liver biopsy will still be needed in a subset of patients. For instance, all the current ongoing global phase III clinical trials are based on liver biopsy. The eligibility criteria rely on liver biopsy and follow-up also relies on liver biopsy. It is very likely that as new drugs are approved, liver biopsy will still be necessary. The challenge will be to identify patients in at-risk populations who are most at risk of progression (these are the patients with NASH and advanced fibrosis), and there the non-invasive methods can be useful to identify and select those subsets of patients for referral to expert centers for liver biopsy and to benefit from clinical trials and drugs.

 

《国际肝病》：瞬时弹性成像在肝硬化患者的诊断和随访中有什么优势？还有哪些需要进一步提高的方面？

 

Castera教授：TE是目前诊断肝硬化最准确的方法。而且对于肝硬化患者，肝硬度值（TE检测）还具有一定的预后价值。如果cut-off＞15 kPa，肝硬化的可能性就相当高。在15～75 kPa之间时，肝硬度值与并发症（包括病死、肝移植需求及HCC发生）之间存在相关性。

 

另一方面，随着丙型肝炎的治愈，且绝大多数HCV相关肝硬化患者能够从直接抗病毒药物（DAAs）治疗中获益，也提示了可以使用TE来进行患者的随访。获得SVR后，肝硬度显著降低。

 

是否能够使用肝硬度值降低来代表纤维化程度或肝硬化缓解，还需要进一步的探讨，相关的研究数据还十分匮乏。因此，需要对这类患者进行长期随访，即使肝硬度值降低也要持续监测门静脉高压及HCC的发生。

 

Dr Castera: For the diagnosis of cirrhosis, I think transient elastography is currently the most accurate method. The other point is that, in the context of cirrhosis, liver stiffness as measured by transient elastography has prognostic value. If the cut-off is >15 kPa, the probability of liver cirrhosis is quite high. But within the value range of 15-75 kPa, we know that there is a correlation between the liver stiffness value and occurrence of complications, including death, the need for liver transplantation and hepatocellular carcinoma. In this context, I think that transient elastography is very valuable. On the other hand, with the curability of hepatitis C, most of our cirrhotic HCV patients will benefit from DAAs, and the question arises of whether we can use transient elastography for follow-ups. After SVR, liver stiffness significantly decreases, but we need to know if we can use liver stiffness as a surrogate of fibrosis regression or cirrhosis regression. There is still room for improvement, because we have very little data and I think we need to be cautious. We need more data before we can recommend that a decrease in liver stiffness is a good surrogate for cirrhosis regression. So the take-home message is that we need to follow-up these patients and not stop monitoring for portal hypertension and HCC despite the decrease in liver stiffness.