Professor Mette Lauridsen of Denmark: A new approach to the treatment of non-gut-based hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome based on metabolic disorders and varying severity due to acute and chronic severe liver dysfunction or various portal vein-system circulatory shunts. A serious problem with chronic hepatitis B (CHB) can progress to cirrhosis, which is a late complication of cirrhosis. From a medical and sociopsychological point of view, the treatment of hepatic encephalopathy remains challenging.

In June 2022, at the 57th Annual Meeting of the European Society for the Study of Liver Diseases (EASL2022) and the International Liver Congress ™ 2022 (ILC 2022), the 2022 EASL Clinical Practice Guidelines for Hepatic Encephalopathy were released. At the meeting, Professor Mette Lauridsen of Denmark, Secretary-General of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN), gave a presentation entitled "New Therapies for Non-Intestinal-Based Hepatic Encephalopathy" at the Forum on "New Treatments for Hepatic Encephalopathy". International Liver Disease had the honor of interviewing Professor Mette Lauridsen on the spot, and discussed hemotherapy from the perspectives of drug therapy for HE, management of mild hepatic encephalopathy, and emerging HE therapies.

EASL Interview 丨Danish Professor Mette Lauridsen: A new approach to the treatment of non-gut-based hepatic encephalopathy

Click on the link above to view the video of the interview

International Liver Disease

At present, the drug treatment of hepatic encephalopathy is based on ammonia reduction, supplemented by a strategy of improving the nervous system. With the revelation of the mechanism of ammonia-induced brain cell damage in recent years, some new HE treatment targets and related drugs have been discovered. Please briefly introduce the current progress of HE treatment drugs.

Professor Mette Lauridsen: For a long time, we have been using lactulose, which works in the intestines by acidifying feces and helps to reduce the production of ammonia and other toxins in the intestines. Rifaximin is also seen as a drug that targets the intestines and reduces ammonia production. You could say that rifaximin is a new drug, but we are already exploring further whether there are more possibilities. Some of these are ammonia scavengers that can help lower blood ammonia. Both lactulose and rifaximin play a role in the intestine to reduce the production of ammonia in the intestine, but there is still some ammonia that reaches the intestine, all of which may be further reduced. Glyceryl phenylbutyrate (GPB) is a nitrogen conjugate used to treat disorders of the urea cycle and can directly lower ammonia by converting to urea, helping the body to clear ammonia.

In addition, exercising and maintaining skeletal muscle health are also good strategies for lowering ammonia. In chronic liver disease, when the liver fails, the muscles can actually take over part of the ammonia detoxification. Therefore, I think it is important to help patients maintain healthy muscle mass by ensuring nutrition and exercise.

Bibliography:

<Hepatology Digest>: 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.

International Liver Disease

Treatment of mild hepatic encephalopathy remains a huge unmet need to work together to better define the disease and thus develop new treatments. What are your experiences and suggestions regarding the management of MHE?

Professor Mette Lauridsen: The first step is to identify MHE patients through various test methods. Once mHE patients or significantly high-risk patients have been identified, they should be treated like other severe hepatic encephalopathy. The pathophysiology of minor lesions and obvious lesions is the same, so lactulose is used and followed up with a new psychometric method. If lactulose does not work, add rifaximin or branched-chain amino acids, which are also drugs that can strengthen the skeletal muscle ammonia detoxification.

Bibliography:

<Hepatology Digest>: 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.

International Liver Disease

There are currently some innovative and emerging HE therapies in the preclinical and clinical research stages, please tell us about the corresponding progress.

Professor Mette Lauridsen: There are some drugs that are under development, but as I mentioned earlier, GPB is actually a drug that can help clear ammonia and is already on the market. Some interesting new drugs are being developed that act in the brain to protect the brain from neurotoxic substances in the blood, and it can bind to γ-aminobutyric acid type A receptors (GABA-A receptors) without the neurodepressive effects that GABA normally have. Instead, it simply blocks the receptor, preventing it from binding to the circulating neurosteroid, which can reduce drowsiness in patients with hepatic encephalopathy. I think this drug has a lot of potential. In addition, research into albumin as a potential treatment for hepatic encephalopathy is currently underway, and it appears that it could help prevent encephalopathy.

Bibliography:

<Hepatology Digest>: 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.

International Liver Disease

Some studies argue that future studies should be focused on understanding the effects of comorbidities on patient outcomes, testing strategies for systemic and neuroinflammation, and providing guidelines for drug development and regulation with clear endpoints. What are your thoughts on the direction of research for new therapies for hepatic encephalopathy that are not gut-based?

Professor Mette Lauridsen: I think brain protection drugs are definitely promising. Other research directions we can only wait and see.

Bibliography:

<Hepatology Digest>: 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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