肝性脑病（HE）是由急、慢性肝功能严重障碍或各种门静脉-体循环分流异常所致的，以代谢紊乱为基础、轻重程度不同的神经精神异常综合征。慢性乙型肝炎（CHB）的一个严重问题是可发展为肝硬化，而肝性脑病是肝硬化的一个晚期并发症。从医学和社会心理学的角度来看，肝性脑病的治疗仍然具有挑战性。
2022年6月，第57届欧洲肝病研究学会年会（EASL2022）暨2022年国际肝脏大会TM（ILC 2022）上，2022 EASL肝性脑病临床实践指南发布。会上，国际肝性脑病和氮代谢学会（ISHEN）秘书长、丹麦Mette Lauridsen教授在“肝性脑病治疗新方法”论坛上做了题为“非基于肠道的肝性脑病新疗法”的报告。《国际肝病》有幸在现场采访了Mette Lauridsen教授，从HE的药物治疗、轻度肝性脑病管理、新兴的HE疗法等角度展开探讨。
《国际肝病》
目前肝性脑病的药物治疗采用的是以降氨为主，辅以神经系统改善的策略。随着近年来对于氨诱导脑细胞损伤机理的揭示，又发现了一些新的HE治疗靶点和相关药物。请您简单介绍目前HE治疗药物的进展。
Mette Lauridsen教授：长期以来，我们一直使用乳果糖，它通过酸化粪便在肠道中发挥作用，有助于减少肠道中产生的氨和其他毒素。利福昔明也被视为一种靶向肠道和减少氨产生的药物。你可以说利福昔明是一种新药，但我们已在进一步探索是否有更多可能性。其中一些是氨清除剂，可以帮助降血氨。乳果糖和利福昔明都在肠道中发挥作用，以减少肠道中氨的产生，但仍有部分氨会到达肠道，所有还有进一步降氨的可能。苯丁酸甘油酯（GPB）是一种氮结合物，用于治疗尿素循环障碍疾病，可以通过转化为尿素而直接降低氨，帮助身体清除氨。
此外，锻炼身体和保持骨骼肌健康也是降氨的好策略。在慢性肝病中，当肝脏衰竭时，肌肉实际上可以接管部分氨解毒。因此，我认为通过确保营养和锻炼来帮助患者保持健康的肌肉质量是很重要的。
参考文献：
: Reducing blood ammonia is currently the main therapeutic strategy for hepatic encephalopathy (HE), along with improving nervous system function. Thanks to the clarification of the mechanism underlying ammonia-induced brain cell injury in recent years, some novel therapeutic targets and related drugs have proposed. Would you please introduce the progress of HE drugs with regard to ammonia reduction, nervous system improvement, and intervention of ammonia toxicity targets（or from your own point of view）？
Prof. Lauridsen: For a long time, we have been using lactulose, which works through the gut by acidifying the stool. It helps reduce the amount of ammonia and other toxins produced in the gut. While I have been active in research, rifaximin has also been introduced as a way of targeting the gut and a way of reducing ammonia production. You could say that rifaximin is kind of new, but we are already looking further to see if there are any more possibilities for use. Some of them are ammonia scavengers that can help reduce blood ammonia. Lactulose and rifaximin both work in the gut to lower production of ammonia in the gut, but some ammonia will still reach the gut, and there are possibilities to lower ammonia further. There is a substance called glycerol phenylbutyrate (GPB) that is used in urea cycle defects that can scavenge ammonia and help the body rid itself of ammonia. Other than that, exercise and keeping skeletal muscle fit is also a good strategy for lowering ammonia. In chronic liver disease, when the liver fails, the muscle can actually take over some of the ammonia detoxification. So I think it is important that we help our patients keep a healthy muscle mass by ensuring good nutrition and recommending exercise.
《国际肝病》
轻度肝性脑病的治疗仍然是巨大的未满足的需求，需要共同努力来更好地定义这种疾病，从而开发新的治疗方法。关于MHE的管理，您有哪些经验和建议？
Mette Lauridsen教授：首先要通过各种检测方法鉴别出MHE患者。一旦确定了MHE患者或明显的高危患者，应该和其他严重的肝性脑病一样去处理。微小病变和明显病变的病理生理学是一样的，所以使用乳果糖，然后用新的心理测量法进行随访。如果乳果糖不起效，添加利福昔明或支链氨基酸，这也是可以加强骨骼肌氨解毒的药物。
参考文献：
: Treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. Could you please share us with your experience and suggestions on management of MHE？
Prof. Lauridsen: First of all, you have to find patients with minimal HE. There are various ways to test for that, so that is actually step one - to find it - but once you have identified a patient with minimal HE or a patient at high risk for overt hepatic encephalopathy, you should treat it like any other severity of hepatic encephalopathy. The pathophysiology is the same for minimal as for overt, so we give them lactulose and then follow-up with new psychometrics. If lactulose doesn’t work, we add rifaximin or branch chain amino acids, which is something that can also strengthen skeletal muscle ammonia detoxification.
《国际肝病》
目前有一些创新的、新兴的HE疗法分别处于临床前和临床研究阶段，请您介绍一下相应的进展。
Mette Lauridsen教授：有些药物正在研发中，但正如我之前提到的，GPB实际上是一种可以帮助清除氨的药物并已上市。一些有趣的新药正在研发中，在大脑中起作用，保护大脑免受血液中神经毒性物质的影响，它可以与 γ-氨基丁酸 A型受体（GABA-A受体）结合，而不会带来GABA通常具有的神经抑制作用。相反，它只是阻断受体，阻止其与循环中的神经甾体结合，可以减少肝性脑病患者的嗜睡。我认为这种药物很有潜力。此外，白蛋白作为肝性脑病潜在治疗方法的研究目前正在开展，似乎它可以帮助预防脑病。
参考文献：
: There are exciting, innovative, emerging therapies for HE that are currently being developed at the pre-clinical phase, as well as options currently being tested in clinical trials. Could you please introduce those therapies and related progress to us？
Prof. Lauridsen: There are drugs in the pipeline, but as I mentioned before, GPB is actually a substance that can help scavenge ammonia and that is already on the market. That is not really in the pipeline anymore. Something interesting that is in the pipeline are substances working in the brain to protect the brain from neurotoxic substances in the blood. That could be, for example, modulation of the GABA receptor. There is this exciting drug in the pipeline that can actually bind to the GABA-A receptor without introducing all the neuro-inhibitory effects that GABA normally has. Instead, it just blocks the receptor and prevents circulating neurosteroids from binding. That means it can reduce sleepiness in patients with HE. I think that is an interesting thing in the pipeline. Other than that, albumin is being examined at the moment as a potential treatment for hepatic encephalopathy. It seems it can help prevent encephalopathy.
《国际肝病》
一些研究认为，未来的研究应致力于了解共病对患者结局的影响，测试针对全身和神经炎症的策略，并为药物开发和监管提供明确终点的指南。关于肝性脑病不基于肠道的新疗法的研究方向，您有什么看法？
Mette Lauridsen教授：我认为脑保护药物肯定是很有前途的。其他的研究方向我们只能等等看。
参考文献：
: According to some studies, future research should be directed at understanding the impact of comorbidities on outcomes, testing strategies that target systemic and neuroinflammation and providing guidance to drug developers and regulators on clear endpoints. What’s your opinion on future research direction for new HE therapies not based on gut？
Prof. Lauridsen: I think the brain protective drugs are definitely up-and-coming. I think that is very interesting. Other than that, I don’t really know what is coming. We will just have to wait and see.
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