酒精性肝病和非酒精性脂肪肝发病机制和治疗新进展

liver411

-Craig J McClain访谈
引文英文录像略去
来源：国际肝病作者：发布时间：2008-11-12阅读：110
导读：在过去的10年，我们在治疗酒精性肝炎方面已经取得了很大的进步。我们知道戒酒至关重要，不论代偿性或失代偿性肝病患者，戒酒均可以改善酒精性肝病的严重程度。此外，研究表明即使无法完全戒酒，减少饮酒也是有好处的。

Hepatology Digest：You published the article Inhibition of Adiponectin Production by Homocysteine: A Potential Mechanism for Alcoholic Liver Disease in Hepatology in March of this year. In that paper you mentioned that chronic alcoholism caused abnormal accumulation of homocysteine in adipocytes, which contributes to decreased adiponectin production in ALD.  Would you please speak further the progress of the pathogenesis of ALD.

国际肝病：今年3月，您在肝脏杂志上发表了一篇文章，篇名为《采用同型半胱氨酸抑制脂联素产生：发生酒精性肝病的可能机制》，在这篇文章中您提到慢性酒精中毒能引起脂肪细胞同型半胱氨酸的异常累积，进而导致酒精性肝病（ALD）患者脂联素产生减少。您能进一步谈一下ALD发病机制的研究进展吗？

Craig J McClain：I would point out that this research actually was done by one of my colleagues, Dr. Song, who has recently been back to China to present this article. What he showed was that there was increased homocysteine production that played a important role in decreased adiponectin in an animal model of liver disease.  Adiponectin is an important, fat-derived adipokine or cytokine that is good, or, anti-inflammatory.  It is well documented that there are increased homocysteine levels in alcoholic liver disease.  The homocysteine was driving down the adiponectin made in fat, and so that caused more inflammation and liver injury.  What this really does is for the document the critical interaction between fat-stores outside the liver and liver injury.  So, as hepatologists we are going think not only about the liver, but fat tissue, muscle tissue and other organs and how they interact and cross-talk between those organs.

Craig J McClain教授：我要指出的是这项研究主要是有我的同事宋博士完成的，他最近回中国对这项研究做了报告。他的研究结果显示在动物肝病模型中，同型半胱氨酸产量增加在脂联素下降中具有重要作用。脂联素是来自脂肪的重要脂肪因子或细胞因子，有抗炎作用。有研究显示在酒精性肝病同型半胱氨酸水平增加。同型半胱氨酸可以降低来自脂肪的脂联素，进而导致炎症加重和肝损伤。其真正意义在于揭示了肝外储存的脂肪和肝损伤之间有重要的相互作用。因此，我们不仅要考虑肝脏本身，还要考虑脂肪组织，肌肉组织和其它器官，要弄清楚它们之间是如何相互作用的。


Hepatology Digest：NAFLD is affecting more and more children both in China and America. In your paper Nutrition and nonalcoholic fatty liver disease in children in Current Gastroenterology Reports, you mentioned that it does not appear that overweight children with NAFLD have an unusual diet compared with their overweight counterparts without NAFLD.  It is more likely that an increased genetic susceptibility plays a role in the NAFLD.  Will you please give your opinion about diet therapy being useful for these children with increased genetic susceptibility.

国际肝病：非酒精性脂肪肝（NAFLD）正在影响越来越多的中国和美国儿童。在您的一篇关于儿童营养和非酒精性脂肪肝的文章中，你提到和无NAFLD的超重儿童相比，患有NAFLD的超重儿童饮食似乎没有明显的特别之处。很可能是强的遗传易感性在NAFLD中具有重要作用。您能谈一下对于遗传易感性强的儿童，是否有对他们有益的饮食疗法？

Craig J McClain：It is absolutely clear that there are different ethnic susceptibilities, and, probably, genetic susceptibilities. My coworker here – who actually did all the work – Doctor Voss who is at Emory University and a pediatric gastroenterologist first showed that Hispanic children are highly susceptible to fatty liver disease.  Caucasians such as myself are intermediate, and then African-Americans are a little more resistant. There are probably going to be things called SNPs – Genetic abnormalities – that predispose or make one more resistant to fatty liver disease.

Dr. Voss is also interested in dietary components -- specifically fructose – in the development of fatty liver disease.  She has actually done some very interesting fructose feeding studies in children, and also withdrawal studies. She has a recent paper showing that when she took fructose out of the diet of children they had less oxidized stress.  Oxidizing stress is one of the precipitating factors in the development of liver disease.  So, we feel all the fructose we see – especially in soda-pop – is a bad thing.  So we are trying to get that out of the school system and have children eat a more balanced diet.

Craig J McClain教授：不同种族间的易感性有差异，这点是很明确的，很可能就是遗传易感性的差异。实际上这项工作主要是我的同事Voss医生做的，她现在埃默里大学工作，是儿童胃肠病学专家。她最早研究发现西班牙裔儿童对脂肪肝高度易感；高加索人，比如我就是高加索人，属于中度易感；而非裔美国人对脂肪肝有一定的抵抗性。这可能是由于单核甘酸多态性（遗传异常）的差异导致机体对脂肪肝更易感或具有抵抗性。Voss医生也对饮食组分特别是果糖在脂肪肝中的作用感兴趣。她实际上已经进行了一些儿童果糖方面实验。最近她在一篇文章指出当把果糖从儿童食谱中去掉时，他们产生氧化应激减少。而氧化应激是肝病的一个参与因素。因此我们觉得果糖，特别是汽水中的果糖对人体是不利的。因此我们将努力把它从学校饮食系统中去掉，从而让儿童有更均衡的饮食。


Hepatology Digest：You had mentioned some other ethnicities; do have information how China or the Asian population fits into that?

国际肝病：您刚才提到其它一些种族，您有关于中国或亚洲人群这方面的相关信息吗？

Craig J McClain：Yes, actually the Asian population is very interesting because some of my co-workers are from China.  I think that fatty liver disease is going to be a huge problem there, probably precipitated, in part, by the American diet. Chinese don’t become nearly as overweight as Americans, but still do develop fatty liver.     

Craig J McClain教授：是的，实际上我对亚洲人群很感兴趣，我的一些同事就来自中国。我认为脂肪肝也会成为中国很大的一个问题，一定程度上可能与美国化饮食有关。虽然中国人超重程度还没达到美国人的水平，但是也有很多脂肪肝发生。


Hepatology Digest：In your nutrition paper you recommended initiating sustainable family-oriented lifestyle changes in all children with NAFLD. Please introduce to our audience your ideas about this.

国际肝病：在您的一篇关于营养的文章中您推荐在所有患有NAFLD的儿童开展持续的以家庭为导向的生活方式的改变。您能给我们介绍一下您的观点吗？

Craig J McClain：Again, this was work that Doctor Voss did, and when she was instructing children, obviously they are not going to be doing the cooking.  So, the parents were brought along.  This was changing dietary habits, especially getting the fructose out of the diet.  What she found is that when parents actually understood that there were critical dietary components that are likely causing liver disease in their children, they were likely to change their cooking habits.  One of the things that they really did first was to eat-out much less and start cooking at home, cooking a much more balanced diet.

Craig J McClain教授：这项工作也是由Voss医生做的，她曾指导儿童改变家庭饮食习惯，很明显儿童不会自己做饭，因此需要父母参与进来。目的是为了改变饮食习惯，特别是将果糖从饮食中去掉。她发现当父母知道一些危险的饮食成分可能会引起儿童肝病时，他们很愿意改变烹饪习惯。而我们首要要做的事情就是少到外面就餐，而开始在家里自己做更健康的均衡饮食。


Hepatology Digest：When you mention fructose, are you talking about going to the grocery store and label reading and making sure there is no fructose in the product?

国际肝病：当我们到食品店买东西时，是否应该看看标签以确定该食品中没有果糖呢？

Craig J McClain：Yes, that is one of the things – label reading.  Fructose, unfortunately, is in almost in everything.  The first critical thing you can do is to stop drinking three or four cans of soda pop per day, and we feel that is the most important thing.   

Craig J McClain教授：是的，看标签是我们要做的事情之一。而果糖几乎存在于各种食品中。首要要做的事是停止每天喝3-4瓶汽水的习惯。


Hepatology Digest：Recently, the clinical trial result for the use of Etanercept for alcoholic hepatitis was published in Gastroenterology, and you were one of the authors. It appears that in patients with moderate to severe alcoholic hepatitis, Etanercept was associated with a significantly higher mortality rate after 6 months.  Do you think Etanercept has a possible mechanism for that increased mortality?

国际肝病：最近在胃肠病学杂志上发表了酒精性肝炎使用依那西普的临床试验结果，您是作者之一。研究结果提示使用依那西普治疗中度酒精性肝炎患者，与较高的6个月死亡率有关。您认为依那西普导致死亡率升高可能的机制是什么呢？

Craig J McClain：This really goes back to work that was done by our group and doctor Deal’s group over a decade ago. Where we showed that a lot of TNF damaged liver, that she showed a little TNF was necessary for liver regeneration and liver protection.   We certainly know that alcoholic liver disease is highlighted by abnormal TNF metabolism – with way too much TNF being produced – and in experimental animals you can block the liver entry by giving drugs like Etanercept.  Unfortunately in humans, wiping out all the TNF is not good, which is what Etanercept does.  Instead a better rational is to decrease the excess production.  So, bring it down to the normal basal level.  And that is what our group, and others, are working on now.  And one of the things were looking at is specific phosphodiesterase inhibitors to block the endotoxin or LPS-stimulable TNF.

Craig J McClain教授：这是我们和Deal医生研究小组10年前的一项研究成果。我们的研究结果提示过量的肿瘤坏死因子（TNF）会引起肝脏损伤，而少量的TNF是肝脏再生所必需的，并对肝脏具有保护作用。我们知道酒精性肝病患者TNF代谢异常特别明显，有大量的TNF产生，在实验动物可以通过给予像依那西普这类的药物阻断肝脏大量TNF输入。然而在人类，用依那西普阻断所有的TNF产生并非是件好事。正确合理的做法是减少TNF过量产生。应该让其降到正常的基线水平。目前我们的研究组以及其它一些研究组正在做这方面的工作。目前正在做的一项工作是用特异性磷酸二酯酶抑制剂来阻断内毒素或LPS脂多糖刺激TNF的产生。


Hepatology Digest：Will you please give us your general over-view of the current progress in the treatment of alcoholic hepatitis?

国际肝病：您能给我们概括介绍一下目前治疗酒精性肝炎的进展吗？

Craig J McClain：I think we have gotten much better at treating alcoholic hepatitis over the past decade.  We know that abstinence is critical now, and notdrinking will improve any level of alcoholic liver disease – whether you are compensated or decompensated.  Moreover, If you don’t stop drinking completely, we know from VA cooperative studies, that just cutting back drinking will help out.   We know that nutrition support, especially a bed-time snacks, is helpful in maintaining nitrogen balance in people who have liver disease.  So they go into a starvation mode very quickly and that night-time snack helps out.  People in the hospital we aggressively work on enteral feeding if they are not taking in enough by mouth.

In patients with severe alcoholic hepatitis we now use Prednisone.  I am kind of a born-again Prednisone person and I used to not use it that much.  But in our bad patients now we do use it, because of work from France showing there is an early decision you can make at the end of one week on whether patients are responding.  So, if their bilirubin drops, that means they are responding and we continue the Prednisone; if their bilirubin does not drop at all at the end of the week, then we discontinue it.

I also use a medicine called Trental or Pentoxifylline as a phosphodiesterase inhibitor.  It is very safe and it is especially good for people with marginal renal function.  We also give Zinc to everybody.  It is total non toxic.  It stabilized gut-barrier function and it does a lot of other favorable things.

Some interesting things that we are looking at is Adenosyl-L Methionine, probiotics, other ways of stabilizing gut bacteria and caspase inhibitors for patients with bad hepatitis.

So we know more about mechanisms and those mechanisms now give us novel targets for intervention.

Craig J McClain教授：在过去的10年，我们在治疗酒精性肝炎方面已经取得了很大的进步。我们知道戒酒至关重要，不论代偿性或失代偿性肝病患者，戒酒均可以改善酒精性肝病的严重程度。此外，研究表明即使无法完全戒酒，减少饮酒也是有好处的。我们知道营养支持，特别是夜间小吃，对于维持肝病患者氮平衡是有利的。由于肝病患者很快会饥饿，给予夜间小吃是有利的。如果患者无法通过口进食，则要采取侵入性的肠道喂养。对于重度酒精性肝炎患者，我们现在给予泼尼松治疗。我习惯于更多的使用泼尼松进行治疗。对于病情很重的患者，我们也确实在使用泼尼松进行治疗。来自法国的一项研究指出不论患者在治疗1周时是否有应答，泼尼松可以作为早期的治疗选择。因此，如果患者血清胆红素下降，表明该治疗有应答可以继续给予泼尼松治疗；但如果治疗1周胆红素不下降，我们就终止该疗法。

我也使用磷酸二酯酶抑制剂如巡能泰或己酮可可碱进行治疗。它们的安全性很好特别是对肾功能较差的患者。我们也给予患者锌剂治疗。这是完全无毒的。它可以稳固肠道屏障功能，此外也有许多其它的好处。

我们正在研究腺苷-L-蛋氨酸，益生菌，其它一些稳固肠道菌群的方法以及caspase抑制剂在治疗病重患者中的疗效。

由于我们知道了更多的发病机制进而给我们提供了更多新的干预靶点。


翻译：北京大学第一医院感染疾病科吴学杰
审校：北京大学第一医院感染疾病科吴学杰