第54届欧洲肝脏研究学会年会（EASL2019）期间，比利时安特卫普大学医院Sven Francque教授应大会邀请主持并参与了多场非酒精性脂肪性肝病（NAFLD）专题的讨论。在接受《国际肝病》采访时，Francque教授介绍了如何管理NAFLD，并结合此次年会上公布的NAFLD新药研究进展（详见文末列表）对进一步的研发方向及前景发表了个人观点，他认为可发挥多重作用的NAFLD新药或联合用药策略将更具前景。

 

Sven Francque教授

 

比利时安特卫普大学医院

 

Sven Francque博士，比利时安特卫普大学医院消化内科主任、安特卫普大学医学与健康科学学院医学教授，比利时佛兰芒政府研究基金的高级临床研究员。他的研究兴趣为非酒精性脂肪性肝病（NAFLD），长期致力于NAFLD的基础研究和临床研究；重点关注脂肪变性所致血管变化及其对疾病进展的影响、非酒精性脂肪性肝炎（NASH）的病理生理机制；作为科学委员会成员参与了数项NAFLD临床试验的Ⅱ期和正在进行中的Ⅲ期研究的设计。

 

在管理NAFLD患者的日常实践中，如何评估肝病严重程度?

 

Francque教授：如果我们以肝脏为中心来看待并想知道NAFLD的肝功能损害得有多严重，那么首先应该仔细询问患者是否有疲劳、瘙痒等症状。虽然患者症状可能不典型，但他们并非没有症状。

 

当考虑更客观的参数时，需要注意查看肝功能相关的一系列参数，因为没有任何单一的参数可以告诉我们肝脏疾病有多严重，需要考虑肝脏检查和晚期肝病的经典指标（如低白蛋白和血小板等）。

 

使用以上这些指标，我们只能发现晚期疾病患者，但NAFLD不仅仅是与肝硬化甚至失代偿有关，我们需要在疾病早期阶段发现患者，并结合超声、组织学、生化参数和评分明确潜在的肝脏炎症和纤维化实际上有多严重。同样，这不是一个参数能够实现的，我们需要了解参数组合，这些系列相关参数将有助于确定患者是否具有潜在的重大肝脏疾病。

 

从本届EASL年会看，哪些正在进行临床试验的NAFLD新药令您印象深刻？

 

Francque教授：我们开始看到某些治疗策略比其他策略更好。已经有一些试验因失败而终止，包括大型试验。这些失败告诉我们，不应过分强调单一途径来治疗这种疾病。

 

虽然逆转纤维化非常重要，但我们也不能忘记NAFLD背后的代谢和炎症驱动因素。我们需要可对疾病的不同方面发挥作用的新药物，包括驱动因素和疾病所致进展表现（主要是纤维化）。我们需要的药物，本质上应具有复杂的作用模式，可以解决不同方面的病理生理学问题，或者我们需要组合用药。

 

在本届EASL年会上，我们看到了关于奥贝胆酸（OCA）的研究数据，该研究显示使用OCA后脂肪性肝炎有所改善。虽然这种改善未能达到消除NASH的终点，但从细节看，脂肪性肝炎的几个方面都有所改善，而且纤维化有所改善（采用非常严格的终点，仅比安慰剂组高10%～12%）。从更广泛的意义上看，与安慰剂相比，如果药物能有超过12%的改善，则可以取得明显的获益，所以OCA还是很有前景的。这是一个非常好的开始，也是向前迈出的重要一步。

 

还有其他药物将有关键进展，我相信像elafibranor这样可以解决新陈代谢、炎症和纤维发生问题的药物也将显示出有益的效果。当然，需要我们拭目以待。对能量消耗和新陈代谢有重要影响的THR-β激动剂也非常有前景。

 

我们可能会看到来自具有影响代谢、炎症和纤维化发生多重作用的药物治疗的研究进展，这些药物很可能会带来实质性获益。

 

本届EASL年会公布的NAFLD新药研究汇总：

: When talking to the new clinician and advising them on NAFLD, how do you assess the severity of liver diseases and help them define the endpoints for managing NAFLD?

 

Prof. Francque: If you look at it from a liver-centered approach and want to know how severe the liver impairment is, firstly you should carefully interrogate the patient, because they do sometimes have symptoms like fatigue or pruritus, which you would probably not link to the liver because they are not very specific. But the patient may not be asymptomatic and that is the first point to take into account. When it comes to more objective parameters, you first look at the constellation of parameters. There is no one single parameter that can tell you how severe the liver disease is, so you do need to consider liver tests and classical indicators of advanced liver disease (low albumin, platelets, etc.), but that is not the complete picture. You will only capture those with very advanced disease with those parameters. But it is not just about cirrhosis, or even decompensation. You need to catch them in earlier stages, and combine ultrasound and histometry, biochemical parameters and scores that will help indicate how severe the underlying liver inflammation and fibrosis actually is. Again, it is just not one parameter. You need to get familiar with the combinations of parameters. It is the constellation of those parameters that will help to define whether the patient has potentially significant underlying liver disease or not.

 

: Of the drugs on the NAFLD horizon, which of those are most impressive to you?

 

Prof. Francque: We are starting to see that some strategies work better than others. There have been a few failures already, including in large trials, which tells us that we should not put too much emphasis on one single pathway to cope with this disease. For sure, tackling fibrogenesis is very important, but we should not forget the metabolic and inflammatory drivers behind this disease. We need drugs that act on different aspects of the disease to encompass the drivers as well as the consequences of disease, mainly fibrosis. We will need drugs that intrinsically have complex modes of action that will tackle different aspects of the pathophysiology, or we will need to combine drugs. Yesterday, we heard a presentation about the obeticholic acid (OCA) data, which showed us that there is an improvement in steatohepatitis (although it did not match the endpoint of the resolution of NASH). But looking at the details, there are improvements in several aspects of steatohepatitis, and there are improvements in terms of fibrosis (only 10-12% above placebo using very strict endpoints). Looking more broadly, more than 12% compared to placebo see benefit. There is something happening there that is promising. It’s a very good start and an important step forward. There are other drugs coming on, and I am quite confident that drugs like elafibranor that also