Scott Friedam教授在APASL2009会议上接受国际肝病专访

Hepatology Digest: I’m here at APASL 2009 with Professor Scott Friedman, it’s an honor to interview you today Professor Friedman. Thank you for joining us.

国际肝病：我现在在2009年APASL年会采访Scott Friedman教授。今天很荣幸采访到您，Friedman教授。非常感谢。

Prof. Friedman: My pleasure.

Friedman教授：这也是我的荣幸。

Hepatology Digest: First question I have for you today, obviously with a memorandum of understanding between AASLD and APASL, there’s going to be some cooperation, can you talk a little about that cooperation, what form it will take and what you hope to achieve.

国际肝病：今天我向您请教的第一个问题是，AASLD与APASLD签订合作备忘录后，将会有很多合作，您能不能谈一下有关合作事宜？合作将采用的方式及有哪些收益？

Prof. Friedman: First of all, we’re delighted at the opportunity to partner officially with APASL.  This is a vital part of the world particularly with respect to liver disease. Many new treatments and approaches are being pioneered here, and of course the prevalence of liver disease in the Asian Pacific, and in particular hepatocellular carcinoma, are larger than they are in the United States.  So in many ways we need to learn from our Asian colleagues. The memorandum of understanding is really an effort to align our interests, to create synergies between the two associations in whatever form that might take; including joint programming and conferences, joint efforts in lobbying for funding from government agencies, and greater awareness of liver disease in terms of screening, as well as trying to develop new treatments together possibly including joint clinical trials. So we are very open minded about how this memorandum of understanding will be realized over the subsequent years, and that’s really for each of the associations to develop as they see fit.  But it really solidifies our relationship officially so that we can embark upon joint projects that ultimately will accelerate the development of drugs and improve the health of our patients, both in the United States as well as the Asia-Pacific region.

Friedman教授：首先，我们很高兴有机会与APASL进行官方合作。APASL关系着全球很大一部分人口，尤其从罹患肝病人群的角度来看。很多新的治疗方法和途径都是从这里发源的。当然，亚太地区的肝病患病率，特别是肝癌的患病率，都比比美国多。因此从很多方面我们都要向亚洲同行学习。不论采取什么形式的合作，合作备忘录都确实能联合两个协会共同的利益，建立一种互补关系。可以采取的合作方式也有很多，包括联合规划方案和联合会议；政府研究基金联合申请；在肝病筛查方面的更多共识；联合开发新疗法，或许可以进行联合临床试验。因此，接下来的几年中如何合作，我们的思路很开阔，而且将采用适合双方的发展模式。这确实能巩固我们的官方友谊，即将开始着手进行的合作计划也会从根本上加快美国——当然还有亚太地区药物研究的发展，并改善患者的健康状况。

Hepatology Digest: You mentioned a lot of the new innovations and things coming out of Asia Pacific. How about China specifically, how about the recent developments and contributions from researchers and clinicians in China?

国际肝病：您提到了很多亚太地区的创新，那么最近中国的临床医师和研究学者有什么新发现和新贡献？

Prof. Friedman: China represents the largest concentration of both patients but also experience in chronic liver disease anywhere in the world. And so we are working as much as possible with Chinese physicians to understand the Asian approach to managing liver disease, also keeping an open mind about herbal and traditional Chinese medicines. In many ways the Chinese experience is about 10 years ahead of what we’re seeing in the United States in terms of levels of chronic liver disease and the risk of hepatocellular carcinoma. And so we really have a lot to learn from China in terms of their approach. Moreover, the growth in China, technologically and scientifically, is absolutely staggering. We’re really quite excited about partnering with China in particular, to learn more about their approaches and of course share our ideas and develop programs together to accelerate advances.

Friedman教授：中国有世界上最集中的慢性肝病患者和慢性肝病研究专家。因此，我们尽可能与中国医生合作，了解亚洲肝病的治疗方法，也了解中草药及传统中医的应用，开拓思路。但其中最重要的是经验的借鉴，在很多方面，比如以慢性肝病严重程度和肝癌发生的危险因素方面来说，中国的经验要先于美国将近10年。我们实在有太多东西要向中国学习。此外，中国的科学和技术的发展也令人震惊。我们非常高兴能与中国合作，更多地学习他们的治疗方法，同时分享我们的经验，发展合作项目，共同促进肝病治疗的进展。

Hepatology Digest: I’m curious, obviously with some of the changes going on especially in China, people getting wealthier and its life changing. How about the incidences of non-alcoholic fatty liver disease? You talk about how is it ten years, and how is that the experience that’s happening in Asia Pacific and China, how does that mirror what perhaps happened in the US and other western countries? Are their experiences similar in what’s happening? Are they following a similar trend in that case?

国际肝病：随着中国的变化，人们生活富裕了，生活方式也随之改变，那么非酒精性脂肪性肝病的发生率有变化吗？在亚太地区和中国，这种变化的发生是怎样的？在美国和欧洲也曾经发生这样的变化？这两者的经历有相似点吗？他们发展的趋势是否接近？

Prof. Friedman: Yes, it’s a very important point. Unlike for the viral hepatitis paradigm we are ahead of China in our experience with NASH, but for all the wrong reasons because the prevalence of obesity and metabolic syndrome is greater and is accelerating faster in the west than it has been in China. Having said that, the change in the diet and the activity of Chinese and Asians in general and the prevalence of obesity are also increasing in Asia. Perhaps most importantly, it seems that Asian populations are at more risk for metabolic liver disease and fatty liver at lower levels elevated body mass index than in the west. So where as we are looking to patients who are of a body mass index of greater than 25 before we’re concerned about the prevalence of NASH (nonalcoholic steatohepatitis), in Asians,, the development of fatty liver and NASH can occur at much lower levels of obesity. Of course the Chinese and the Asia-Pacific region are grappling with this just as we are because we’re still learning about the natural history of the disease, the risk of inflammation and fibrosis, and of course better more sensitive and more accurate tests for both diagnosis and approaches to treatment. So we’re really in the early stages of this epidemic and again, sadly, we are – meaning the west – Western Europe and the United States, are grappling with obesity to a greater extent but the expression of this disease in Asian populations may be a little different. We will learn from each other in terms of the genetic and ethnic factors that may influence this disease.

Friedman教授：是的，这一点很重要。和病毒性肝炎不同，我们在非酒精性脂肪性肝病方面的经验要领先于中国，这要归咎于肥胖以及代谢综合征在西方的流行，其加速进展的速率要超过中国。提到这点，中国以及整体亚洲人的饮食习惯和生活方式的改变也使亚洲肥胖人群数量有所增加。或许最重要的，即使亚洲人群只有低水平的体重指数增加，他们患代谢性肝病以及脂肪肝的风险似乎也高于西方人群。过去我们只关注那些体重指数高于25的患者，直到我们发现，在亚洲，特别是南亚和东亚，脂肪肝及非酒精性脂肪性肝病也发生在远远低于肥胖水平的患者身上。就像我们一样，中国及亚太地区正在研究这个问题。目前，我们还在研究这种疾病的自然史，发生炎症和纤维化的危险因素，当然还包括用于诊断及评价疗法的更敏感、更精确的检测方法。因此，我们还处于对这种流行病的早期研究阶段，而且遗憾的是，西方国家包括欧洲和美国，对肥胖的定义更高，但这种疾病在亚洲人群中却有不一样的表现。我们在可能会对疾病造成影响的基因和种族因素方面需要互相学习。

Hepatology Digest: And you just mentioned fibrosis, the understanding of hepatic fibrosis, or the liver’s scarring response, has emerged as a major focus of current research in hepatology.  Could you please talk about a little bit of the progress in these fields?

国际肝病：您提到了纤维化，对肝纤维化或者肝脏瘢痕反应的理解已经成为肝病学研究的主要目标。您能否谈下这个领域的进展？

Prof. Friedman: Progress in understanding fibrosis has really been astonishing over the last ten to twenty years. I’m old enough to remember that twenty years ago the dogma was that once you had scarring on the liver, it would simply get worse. In part that’s because we had no way to treat the underlying liver disease that led to that scarring. One of the most important series of observations that have emerged in the last ten to five years is now that we have effective treatments for viral hepatitis, both clearance of hepatitis C and long term suppression of hepatitis B, we begun to appreciate that the liver has an incredible capacity to resorb scar. There is a large amount of evidence, both in hepatitis C and B, that if you control or eradicate the viral infection much of the scar will resorb, even in patients who are cirrhotic. That has really led to a completely different appreciation for the dynamic nature of fibrosis, not only in its ability to develop in patients who have chronic liver disease but also in its ability to regress in those in whom we can suppress the underlying liver disease. Trying to understand the mechanisms by which the liver naturally resorbs scar really creates opportunities to exploit those pathways in the form of therapies that will regress scar even when the underlying liver disease is persistent, for example viral hepatitis or fatty liver disease. So with that new understanding of mechanisms of regression, we’re really at a point now where we’re beginning to develop meaningful therapies, certainly in animal models. We hope over the next five years, in good clinical trials, that we will really establish that we can treat the fibrosis without affecting the underlying liver disease and still anticipate improvement in fibrosis, prolongation of health, and ultimately decrease mortality and complications.

Friedman教授：在过去的10到20年间，有关纤维化进展方面的消息很令人吃惊。我还记得20年前，人们教条性地认为如果肝脏有瘢痕出现，预示着疾病的加重。部分原因是因为我们没有方法治疗那些导致瘢痕产生的潜在性疾病。在近5到10年一些最重要的发现中，我们看到，已经出现了针对病毒性肝炎的有效治疗手段，这些治疗能清除HCV或长期抑制HBV，我们开始认为肝脏有难以置信的修复瘢痕的能力。大量证据表明，不论是HBV还是HCV，如果控制或根除病毒，大部分瘢痕能被吸收，即使是已经发生肝硬化的患者。因此对纤维化程度的动态变化会有完全不同的评价：在慢乙肝患者，它会进展；但在那些能抑制其潜在肝病的患者，它却能减轻。了解和探究肝脏自然重吸收瘢痕的机制有助于开发减少瘢痕新治疗方法，即使在有潜在肝病的情况下，例如病毒性肝炎或脂肪肝。因此，通过对瘢痕减轻机制的新理解，我们现在要做的是如何开展新疗法的研究，当然首先是动物试验。我们希望在接下来的5年，通过理想的临床试验，真正找到一种治疗肝纤维化而不影响潜在肝病的治疗方法，它能改善纤维化，延长健康状态，最终降低死亡率和并发症的发生。

Hepatology Digest: You mentioned on the treatment side, how about on the imaging side of diagnostics. I know it seems some of the non-invasive methods, FibroScan and such have helped.  How do you foresee we will be able to use these non-invasive methods. When will we really be able to tell between very close stages of fibrosis because obviously now it’s not really there. Can you talk about that?

国际肝病：您提到了治疗方面，关于诊断方面又怎样呢？我知道有非侵入性检查方法——瞬时弹性成像技术和其他一些有用的方法。您对非侵入性检查方法的应用有什么看法？我们现在还不能把纤维化程度非常接近的几个阶段区分开，什么时候能真正做到这点？就这方面能不能谈一下您的看法？

Prof. Friedman: Well I think that’s a fair point. Before we get to new modalities of diagnosis I think it’s fair to acknowledge that liver biopsy is not an ideal test. It’s certainly very invasive, we’re only sampling about one fifty-thousandth (1/50000) of the liver and so there is some sampling variability among different regions of the liver. It does not really tell us anything about the function of the liver or the rate of change of scar accumulation or regression, and we can only do biopsy between long intervals – maybe a year or two at the most, and even then it is probably being somewhat aggressive. So that has really set the stage for us to take a completely new evaluation of how we assess not just scar formation but also the integrity and the metabolic reserve of the liver. Some of those advances are in fact coming with things like FibroScan and serum markers, but there’s a whole new generation of tests that are under development that assess liver blood flow, metabolic reserve, and overall integrity of the liver in a way that really is complementary to the biopsy. In other words, tests that will measure the functional reserve of the liver as an indication of when the patient is beginning to accrue risk of liver failure, as well as non-invasive methods that ultimately will assess the portal gradient and other measures of liver function as well as the likelihood of liver decompensation. So I would say that we’re really just turning the corner now in appreciating both the limitations of biopsy on the one hand, and the many complementary ways we can assess the status of the liver and the likelihood of decompensation going forward.  I think it’s such a tremendously exciting time.

Friedman教授：我认为这是很公正的观点。公平地说，在新的诊断形式出现之前，肝活检并不是很理想的检测方法。当然，它是具有侵入性的；采集到的样本只是肝脏的1/50000，因而在肝脏的不同部位就存在取样差异。这样一来，我们就无法真正了解肝脏的功能、瘢痕累积的速率、衰退的速率等情况。而且肝活检要求很长的时间间隔，一年或最长两年，到那时患者的疾病很可能有或多或少的进展。这就使得我们需要一种全新的评估方式，来评价瘢痕形成、整体功能、代谢储备等情况。实际上现在已经有一些先进的评估手段，像瞬时弹性成像以及血清标志物等，还有一套全新的检测方法正在研制中，这种检测方法能评价肝脏血流、代谢储备、整体功能等情况，确实能作为肝活检的补充。换句话说，这些检测手段能检测肝脏的功能储备——是否有肝衰竭风险发生的指征。非侵入性检测方法可以作为最终对门静脉（压力）梯度和肝功能失代偿的可能性评估以及其他一些肝功能指标的评估。因此，我得说，我们现在处在一个十字路口：一方面是有利有弊的肝活检；一方面是展示诸多优势的新的检测方法，通过它们我们能评估肝脏的状态和失代偿发生的可能性。我想，这是个令人兴奋的时刻。

Hepatology Digest: Obviously the link between cirrhosis and hepatocellular carcinoma is a real concern. What can we do to prevent those patients who have cirrhosis from developing HCC?

国际肝病：最后一个问题是关于肝硬化的。肝硬化和肝细胞癌之间的联系是倍受关注的问题。我们如何预防肝硬化患者向肝癌方向发展？

Prof. Friedman: That remains one of the great mysteries of our field. It’s well established that hepatitis C patients really aren’t at high risk for hepatocellular carcinoma until they’re cirrhotic.  In hepatitis B we recognize that patients are at risk at any point in their disease although good viral suppression of Heptitis B will reduce greatly the risk not only of cirrhosis but also of hepatocellular carcinoma. But to return to the fundamental issue, we have no understanding of why the cirrhotic liver is so permissive for the emergence of cancer. What is there about the scar in the liver that makes cancer so much more likely? This really presents a new frontier for research about which we really have very few answers and really no practical insights. We know from a clinical perspective that once a patient is cirrhotic we must screen them very aggressively, at least every six months for the emergence of small cancers so that therapies can be curative. But we really have no way of reducing the risk of cancer once a patient is cirrhotic short of treating the underlying disease. So if we think about it, if we can reverse cirrhosis with good antiviral therapy, then we would anticipate then the risk of cancer goes down, and in fact early data supports this idea. We’re not yet at the point where we can treat with an antifibrotic, reduce the scar, and decrease the incidence of hepatocellular carcinoma. That really represents the next frontier, linking the mechanisms of cancer to the presence of fibrosis and then intervening in some way so we can attenuate or reduce the risk of cancer in patients who are already cirrhotic. That’s perhaps what our trainees in the next generation can grapple with, although it is certainly something I really wrestle with a lot in trying to identify the new frontiers both of research and also of clinical care.

Friedman教授：这在我们的领域里还是个比较值得探究的问题。HCV患者如果没有发展为肝硬化，那他们发生肝细胞癌的风险就很小。但HBV患者在疾病的任何一个阶段都有发生肝癌的风险，尽管良好的病毒控制能显著降低发展为肝硬化甚至肝细胞癌的风险。回到基础的问题，我们不知道为什么肝硬化会增加肝癌发生的风险。是因为肝脏内的瘢痕而增加了肝癌的发生风险吗？这确实是一个比较前沿的课题，我们目前对答案还知之甚少，也没有实际的资料。从临床展望来说，一旦患者发展到肝硬化，我们就要对他进行积极的筛查，至少每6个月检查一次，以便早期发现小肝癌，这样才有治愈的希望。但如果患者发展为肝硬化，我们除了治疗基础疾病外，实在没有办法减少肝癌发生的风险，因此，如果通过理想的抗病毒治疗逆转肝硬化，我们就能预期——实际上前期的数据也证明了这个观点，肝癌的发生风险也会降低。我们现在还达不到抗纤维化治疗、减少瘢痕、降低肝细胞癌发生率的程度。诸如肝纤维化与肝癌之间的联系机制、如何对肝硬化患者进行干预从而降低肝癌的发生风险等等，这些都是以后待开发的课题。虽然在临床治疗和研究中对这个新领域我已经探究很久，但这可能是我们下一辈接班人需要解决的主要问题。

Hepatology Digest: Once again, Professor Friedman thank you for joining us today. It’s a great pleasure.

国际肝病：再次感谢您接受我们的采访，Friedman教授。非常高兴与您交谈。

Prof. Friedman: The pleasure is mine. Thank you.

Friedman教授：我也非常高兴，谢谢。