美国弗吉尼亚联邦大学医学院Arun J. Sanyal

新的临床研究终点探索及意义

　　传统的临床研究终点是死亡率，这是终末期肝病患者最重要的临床研究终点。除此之外，人们已经在考虑肝脏相关的转归，诸如发生肝肾综合征、严重肝性脑病、肝细胞肝癌和肝衰竭等并发症或疾病进展。然而，针对以上这些转归指标，我们往往需要随访观察很长的时间，所以评估新的转归指标具有重要意义。这些转归检测指标可被 大体分类为体现患者一般状况、器官功能和生存的指标。因此对以患者为中心的转归进行评估确实非常重要。目前，在门静脉高压症的临床试验中，人们正在评估定量肝功能试验作为转归终点的作用。

　　The classical endpoint is mortality because that is the most important endpoint when people have end stage liver disease. In addition to that, people have looked at liver-related outcomes such as the development of hepato-renal syndrome, severe encephalopathy, hepatocellular carcinoma and liver failure. But we realize that many of these outcomes take a long time to measure so there is a lot of interest in evaluating new outcome measures. These outcome measures can broadly be categorized as measures that capture how a patient feels, functions or survives. So patient-reported outcomes have increasingly become an important endpoint because we live in a world where patient-centered outcome assessment is really important. In addition, there are quantitative liver function tests that are currently being evaluated as outcomes in clinical trials for portal hypertension.

患者报告转归的利与弊

　　患者报告转归的优势是它可以从患者的角度提供建议，我们可以从中了解对患者来说什么问题是重要的，以及哪些是限制他们的生活质量和工作能力的主要因素，以此我们可以对患者的感受提供进行整体评估。另一方面，它的缺点在于，患者的感受往往受到多重因素的影响，患者报告的转归也常常失去特异性。因此，对于任何一项干预措施，我们都需要增加干预的作用效果，以便能够清楚说明患者经干预后所报告的转归是有差异的。

　　The advantage is that it provides perspective from the patient’s side. It tells us what the things are that are important for the patient and limiting their quality of life and their ability to function. It provides a holistic assessment of how the patient feels they are doing. On the other side, the difficulty is that we know how patients feel is affected by a lot of things, so you lose specificity. You need a huge effect size of any intervention in order to be able to say clearly that it was an intervention that made a difference to patient-reported outcomes.

β-受体阻滞剂在门静脉高压症中的应用减少了吗？

　　Sanyal教授认为没有，接受β-受体阻滞剂的大多数患者存在代偿期肝硬化和静脉曲张。然而，对于进展期难治性腹水患者，由于其肾血流量已存在一定的障碍，β-受体阻滞剂的应用的确有所减少。已有研究表明，β-受体阻滞剂可以进一步降低肾血流量。这一观点虽然尚存争议，但确实存在一定的顾虑，以防止β-受体阻滞剂使这一亚组患者的转归进一步恶化。

　　I don’t think so. I think most patients who are receiving beta-blockers have compensated cirrhosis with varices. Where we have seen a decline in beta-blockers has been in people who have advanced refractory ascites and where there is already some impairment in renal blood flow or where beta-blockers have been shown to further reduce renal blood flow. It is controversial, but certainly there is some concern that they may further worsen outcomes in that subset of patients.

门静脉高压症管理策略的成本效益的评估

　　门静脉高压症管理策略的成本效益不仅需要考虑对医疗资源的总体利用，即治疗干预措施有关的直接要素，例如住院频率、急诊次数、手术操作次数、药物等，同时还包括对家庭影响所组成的间接要素，例如失业和对家庭的财务影响。对管理策略成本效益的评估，未来有望建立一个评估模型，用以比较两种干预措施的临床效益，或者哪一种干预措施实际上更符合成本效益。

　　The short answer to that question is to look at the total utilization of healthcare resources – frequency of hospitalization, emergency room visits, the total number of procedures that have to be performed, drugs and in addition, the costs of loss of work and the financial impact on families. So there is a direct element associated with the direct therapeutic intervention itself, but there is an indirect element that is composed of the total healthcare resources utilized and then the impact on families. These have to be modeled in future trials in order for us to know that if two interventions have the same clinical benefit, which one is actually more cost-effective.

治疗肝硬化的新靶点

　　Sanyal教授认为，我们在代偿期肝硬化的治疗上所取得了较大进展，在肝硬化能否逆转的问题上，我们已经看到曙光。相信未来两年内，我们将可以揭晓答案。基于对肝硬化的作用机制和现有的临床前数据，我们有证据相信肝硬化可以逆转。这对于整个肝病学界以及进展期肝病患者具有非凡的意义，因为即使患者已经进展为肝硬化阶段，我们仍有能力延缓其进展，甚至将疾病逆转为无肝硬化的状态。

　　Where we are making the greatest progress is in the setting of cirrhosis that is still compensated. The possibility of reversing cirrhosis appears to be, at least, on the horizon. I think we will know within the next two years if it is even feasible. But that gives us tremendous excitement and hope, based on mechanism of action and preclinical data, that we can indeed reverse cirrhosis. That would be extremely important for the entire field of hepatology and for patients with advanced liver disease where we know that even if they have advanced to cirrhosis, we will be able to slow the progression and even regress the disease to a non-cirrhotic state.