Rogers Williams教授专访

Hepatology Digest: I’m here with Professor Roger Williams at APASL 2009. Welcome professor. It’s a great honour to have you here today. First， I would like to ask you about the Mars artificial support device. This device may be used as a bridge to transplantation for ALF patients. We would like to know whether artificial liver support technique， represented by Mars， could become a standard therapy for liver failure， no matter whether if there is a need for liver transplant or not?

国际肝病：我现在在2009年APASL年会采访Roger Williams教授。欢迎您教授，很荣幸采访您。我的第一个问题是关于MARS（分子吸附再循环系统）人工肝支持系统的。这种治疗可以作为急性肝衰竭患者准备进行肝移植的一个桥梁。我想知道，无论患者是否需要进行肝移植，这种以MARS为代表人工肝支持系统技术是否都可以作为肝衰竭的标准治疗方案？

Prof. Williams: It is a prototype. There are still modifications being done in terms of whether you can recirculate the albumin that is being cleansed back to the patient because the binding capacity of albumin may be affected in liver disease and may not be corrected by the Mars device. However， some form of albumin dialysis， is going to be the basis of a very efficient and safe form of liver support.  It has much more potential than devices based on modules of functioning liver cells. I do think with Mars， we do have a real advance in the terms of temporary liver support. The latest trial from the French group has shown almost statistically significant survival benefits in paracetamol overdose cases of acute liver failure. The big European multi-center trial of Mars in acute-on-chronic liver failure has just been completed.  You can show that it removes toxins from the bloodstream of these patients with liver failure and you can also show that it corrects the disturbed pathophysiology.

Roger Williams教授：这只是个雏形。由于白蛋白的结合能力可能受肝脏疾病的影响，MARS治疗设备无法纠正这种功能，所以存在能否将净化后的白蛋白回输患者体内这些方面的问题，这些技术仍需被调整。白蛋白透析将会成为肝脏支持治疗中安全有效的基础治疗措施。MARS人工肝支持系统比那种建立在替代肝细胞分泌功能基础上的治疗措施更有应用潜力。因此，我认为MARS系统在临时肝脏支持治疗方面确实有优势。法国一个研究小组最近的试验结果显示，在由于服用过量扑热息痛而导致的急性肝衰竭的患者中，这种治疗方法能明显提高生存率，有统计学差异。欧洲最近刚结束的一个关于MARS大型多中心临床试验显示，在慢加急性肝衰竭患者中，它也是有优势的。它能清除肝衰竭患者血流中的毒素，使患者被扰乱的正常生理状态恢复。

Hepatology Digest: You’ve just mentioned its use in acute-on-chronic liver failure， do you think that it could really be the treatment of choice?

国际肝病：您刚才提到了MARS在慢加急性肝衰竭中的应用，您认为它能否真正成为一种治疗选择？
 
Prof. Williams: At present， it is the treatment of choice because it is effective and although still expensive， it is much less expensive than devices which include components of functioning hepatocytes， which is being tried again in America. Albumin dialysis does remove toxins but in acute-on-chronic liver failure the prognosis is going to depend very much on the underlying disease， whether that can recover. You may correct the manifestations of liver failure but underlying disease may still not improve.

Roger Williams教授：目前，它是一种治疗选择，因为这种治疗有效，尽管价格昂贵，但与正在美国进行再次试验的以替代肝细胞合成功能为基础的治疗仪器相比，它的价格要便宜很多。白蛋白透析确实能清除毒素，但慢加急性肝衰竭的预后在很大程度上取决于基础疾病是否能治愈。肝衰竭或许能被纠正，但基础疾病却可能无法改善。

Hepatology Digest: Are there any other devices that you see on the horizon or are being tested besides the Mars device， that you feel optimistic about?

国际肝病：除了MARS，目前还有没有其他有应用前景的治疗仪器出现，或者正在检测中？

Prof. Williams: Yes， the Prometheus device. This is based on the passage of albumin (with toxins) across a larger pore membrane.  It is then cleansed by passage through adsorbent columns and then put back into the patient.  We’re also looking at a device， very similar to Mars but in which the albumin with toxins after transport across the membrane is then lost and we replace it with new albumin. There is a great deal of interest now in the binding capacity of human albumin， whether it is damaged in liver failure and， whether it can be restored by these devices.

Roger Williams教授：是的。Prometheus治疗仪，它也是以白蛋白透析为主的，不过它的白蛋白滤过膜孔要大一点，白蛋白通过吸附柱净化后重新被输回患者体内。我们还在关注另一种仪器，非常类似MRAS，但携带毒素的白蛋白在通过滤过膜以后就被丢弃，用新的白蛋白代替。现在关于人类白蛋白的结合力有很多值得研究的问题：白蛋白是否在肝衰竭过程中受到损耗？通过这些仪器的治疗，白蛋白能否可以恢复？

Hepatology Digest: So a lot of the work is based on that principle regardless of the device?

国际肝病：那么不管哪种仪器，很多工作都是以这个原则为基础和目标的？

Prof. Williams: That’s exactly right. However， we do have a device for the first time ever that has been shown and ，has been confirmed several times to restore the pathophysiology of liver failure.

Roger Williams教授：确实是这样。不过我们现在终于掌握了被多次证明能改善肝衰竭病理生理变化的仪器。

Hepatology Digest: The assessment of the need of transplantation is mainly based on the King’s or the Clichy’s criteria so could you discuss their relative advantages and disadvantages?

国际肝病：是否需要进行肝移植的评估标准主要是King’s标准还是Clichy’s标准，您能否比较一下这两者的优缺点？

Prof. Williams: There is not much more to say except that the King’s criteria has been validated particularly for acetaminophen overdose. In the latter condition they are better than the Clichy ones， and now， to the King’s criteria， are being added a number of additional prognostic features， lactic acid levels and so on. The trouble is that in acute liver failure， the negative predictive value is never going to be as high as the positive predictive. In other words， some patients who don’t show these criteria nevertheless progress and become too ill for transplantation. If the criteria are present， it means you do need a transplant but if they are not present then they may still progress.  All the efforts are to try to improve the characterization of the cases early on as to whether they are going to need a transplant.

Roger Williams教授：对King’s标准，我只有一点可说，即这个标准主要应用于对乙酰氨基酚过量导致的肝衰竭。它要优于Clichy’s标准。目前，King’s标准被加入了很多其他的预测指标，例如乳酸水平等等。现在的问题是对急性肝衰竭患者，阴性预测值从来不会像阳性预测值那样高。换句话来说，有些尚未达到移植标准的患者，因病情进展到严重程度而无法进行肝移植。如果患者达到标准，意味着需要接受移植手术；如果患者未达到移植标准，他们的疾病还会进展。不论是否需要进行移植，都需要尽力早期改善患者状态。

Hepatology Digest: We’ve just listened to the Kunio Okuda lecture and there were obviously a lot of interesting questions raised， in regards to transplantation in HCC or in other cases. What do you think about the more inclusive criteria， like the Hangzhou criteria and some of the predictive values?

国际肝病：我们听了Konia Kudo的演讲中谈到很多关于肝癌和其他病例患者肝移植方面的有趣问题。您对杭州标准以及某些预测值等更综合性的标准怎么看？

Prof. Williams: When we started liver transplantation in the UK in 1968， many of our patients had large hepatocellular carcinoma， sometimes without underlying cirrhosis. Some of those patients survived 5 years or more with no tumor recurrence. In fact， one of the patients with a very big hepatocellular cancer is still alive. Two or three of them are still alive at 20 years. I never thought that the Milan criteria should be absolute because there are patients who have large tumors， which are biologically not rapidly progressive. The patient may be clinically well. And therefore this new work， looking at other predictive criteria， particularly the work that S.T Fan just described on detecting cancer stem cells in the blood is related to the biological nature of the tumor.. These are very important findings because they may enable you to identify the case where there is a chance of recurrence much more accurately than on the Milan criteria. The Milan criteria have been very useful particularly in hepatocellular carcinoma arising in cirrhosis and continue to be useful but the new knowledge may enable you to concentrate more on the biological nature of the tumor.

Roger Williams教授：1968年我们在英国开始进行肝移植的时候，发现很多患者都患有肝细胞癌且病灶很大，有的并无肝硬化基础。没有肿瘤复发的患者能存活5年甚至5年以上。实际上，其中一个病灶很大的肝细胞癌患者现在还活着。有两、三个人在术后20年仍然存活。我从不认为Milan标准应被视为绝对标准，因为有的患者虽然肿瘤病灶大，但其生物学进展却并不是很迅速.患者临床状况好。所以发现了一些新的预测标准，特别是S.T Fan最近描述的检测血中肿瘤干细胞的与肿瘤生物学特性相关的标准。这些发现很重要，在帮助我们判断复发的概率这一点上，比Milan标准更准确。Milan标准很有用，特别对发生在肝硬化基础上的肝细胞癌的评估，它会被继续应用，但新知识的发现会让你更关注于肿瘤的生物学特性。

Hepatology Digest: I suppose when we have good criteria for selection is quite useful， There really is a shortage of organs when we talk about cadaver organs. Do you think with this increased chance of success that will really help for them to be used efficiently?

国际肝病：谈到尸体器官，我认为，当我们有了一个很好的选择标准时，我们却面临器官短缺的问题。您认为成功率的提高是否会使尸体器官得到更加有效的利用？

Prof. Williams: It is unlikely to result in a greater provision of donor organs. What it does mean is that survival is even better long-term so every organ is used for maximum overall benefit for the community. There is a desperate shortage of cadaver organs and in the UK， there is a very high refusal rate by relatives. Living-donor liver transplantation does carry some risk for the donor and it is very sad that the world， as a whole， has not somehow been able to rectify this situation， expect for Spain where they have a very high cadaver organ donation rate， none of the other countries are anywhere near this.

Roger Williams教授：这可能不会扩大供体器官的来源，它的意义是每个器官都被充分地利用，使患者生存期延长，有益于整个患者群体。然而，尸体器官非常短缺，尤其是在英国，亲属拒绝率很高。活体供肝移植对供者来说风险很大。我认为很遗憾的是，在全世界范围，这种情况都无法得到有效解决。但西班牙的情况例外，那里有很高的尸体器官捐赠率，没有其他国家能和他们相比。

Hepatology Digest: Hepatocyte transplantation is a promising new treatment for several liver diseases. Could you comment on the current situation of its usage in liver failure?

国际肝病：肝细胞移植对多种肝病来说都是很有前途的新的治疗方法。您能否对目前它在肝衰竭患者中的应用情况作出评价？

Prof. Williams: There is no evidence of significant clinical benefit in liver failure， yet， there has been in hepatocyte transplantation where it has been proven to be of some benefit is in the inborn errors of metabolism in children where you can restore some of the enzyme defects， although in the long-term liver transplantation is usually required. Most of the promising work with hepatocyte transportation is in the genetic defects in inborn errors of metabolism.

Roger Williams教授：目前在临床上还没有证据说明肝衰竭患者能明显受益于这种治疗方法。不过，肝细胞移植已经被证实对先天性代谢障碍的儿童有一定的疗效，尽管从长远角度考虑通常还是需要进行肝移植，但通过这种治疗仍可以在一定程度上恢复酶缺陷。肝细胞移植的前途主要在于治疗先天性代谢障碍性疾病的基因缺陷。

Hepatology Digest: Once again， thank you for joining us today Professor Williams. It was a real honour. Take care

国际肝病：再次感谢您接受我们的采访，Roger Williams教授，非常荣幸。再见。

Pro. Roger Williams: Thank you.

Roger Williams教授：谢谢。