Editor's note
Acute-on-chronic liver failure (ACLF) is a complex syndrome of acute liver function deterioration based on chronic liver disease, accompanied by high mortality rate of liver and extrahepatic organ failure, and the short-term mortality rate of comprehensive medical treatment is as high as 50%~90%. Due to the high mortality rate and complex pathogenesis, research and treatment strategies for ACLF are particularly important. On June 5-8, 2024, at the annual meeting of the European Association for the Study of the Liver (EASL) held in Milan, Italy, the team of Professor Li Jun from the First Affiliated Hospital of Zhejiang University School of Medicine presented five ACLF-related research results. Professor Jun Li was invited to introduce the highlights and significance of these five studies, share his experience and thoughts on the future development of the ACLF field.
International Liver Disease
What unique peripheral immune signatures have your team revealed through longitudinal single-cell transcriptomic analysis over the progression of ACLF during ACLF progression? How do these features influence the course of the disease and provide potential targets for future therapies?
Prof. Jun Li: At this EASL Annual Meeting, we are honored to have 5 studies selected for the conference presentation. In one of the studies, we dynamically observed single-cell data on ACLF during disease progression and prognosis. In fact, this is a further in-depth exploration based on our 2022 research. At that time, we studied peripheral blood mononuclear cells (PBMCs) through transcriptome and found that in the process of ACLF progression, there was activation of innate immunity in the early stage, and there was a serious imbalance in immune metabolism in the later stage, which may be one of the reasons for the death caused by ACLF.
In this latest study, we dynamically observe the disease progression and recovery of ACLF and delve into which immune cells play a key role in the dynamic changes of the disease at the cellular level. A large, prospective cohort study we conducted identified a population of low-density neutrophils, specifically chemokine receptor 2 (CXCR2)-positive neutrophils. These cells are less common in normal people but are highly expressed in patients with rapid ACLF progression and poor prognosis. At the same time, we also found that other immune cells, such as CXCR2+ neutrophils with low density and high inflammation and M2 macrophage-like CD163+ monocytes, play an important role in patients with progressive ACLF, and some NK cells and cytotoxic T cells are highly expressed in patients with ACLF improvement, and some are highly expressed during the deterioration of the disease.
Through this series of studies and integrated analyses, we have identified a clinically translational immune cell atlas that is divided into 6 different cell modalities. In particular, we found a 3rd group of specific immune cells. When the 3rd cell pattern emerges, it provides us with a therapeutic window within which intervention will have a positive impact on the prognosis of ACLF, a finding that is expected to guide clinical application in the future.
International Liver Disease
How does SEMA6B trigger macrophage-mediated systemic inflammation during the pathogenesis of ACLF? What is the specific impact of this inflammatory process on the progression of ACLF?
Prof. Jun Li: Our research has gradually deepened, and finally achieved clinical translation. In the process, we discovered a very interesting molecule - SEMA6B. In fact, in 2022, we discovered the molecule, and the related research results were published in Gut. With the in-depth study of each molecule, we found that when the SEMA6B molecule interacts with other proteins, it can activate the inflammatory response of macrophages, and the levels of IL-10 and TNF-α are significantly increased. In other words, when the microenvironment is disturbed, SEMA6B will promote the inflammatory response of macrophages during interaction, which may be closely related to the cytokine storm. SEMA6B is an important target for the clinical treatment of ACLF. At present, we are still working on this part in depth, and the relevant work is nearing completion, and has been accepted for revision by a high impact factor journal. It is expected that the results of the study will be shared with you in the second half of this year.
International Liver Disease
In addition to the above two studies, your team also included 3 studies at this year's EASL Annual Meeting, can you tell us about the main results of these studies and their potential clinical value and significance?
Prof. Jun Li: All of our team's research closely focuses on ACLF, including the diagnosis and treatment of acute liver failure. In doing so, we not only focused on early diagnosis and pathogenesis, but also delved into treatments.
In terms of early diagnosis, we have made important progress in three other studies. In one of the studies, we deeply explored the relationship between miRNA and mRNA in cell interactions, and introduced a topology-based analysis method in the miRNA and mRNA regulatory network of ACLF for the first time, which is one of the characteristics of our group and the result accumulated over the years. The study will be published in a more detailed manner, including the multiple targets we have identified that have clinical translational value.
In addition, we conducted a study from a clinical perspective. Patients with ACLF often do not respond well to treatment in the terminal stages of the disease. In particular, when ACLF is associated with circulatory collapse, the mortality rate is extremely high. This begs the question: Can such a patient have a liver transplant? In previous Asia-Pacific guidelines, liver transplantation in the setting of ACLF and circulatory failure was not advocated, but this was only based on the experience of experts and lacked evidence-based medical evidence. European guidelines suggest that transplants can be tried, but there is no evidence-based evidence to support them.
Through a prospective, large cohort, retrospective study analysis of COSSH, we found that many patients with HBV-ACLF received transplantation when they had circulatory collapse, and these transplanted patients survived significantly longer than those who did not receive transplantation. This result shows that liver transplantation is still highly valuable even in the presence of circulatory failure.
In our discussions with EASL experts at the meeting, they spoke highly of our work, arguing that our research is in line with European advocacy and providing them with new evidence. They look forward to the publication of our study as soon as possible so that doctors can have more options, especially for severe patients with ACLF and circulatory failure, who should be given the opportunity to transplant. I think this study is very interesting.
In addition, our team has a study involving stem cell intervention. Stem cell research has always been an important direction of our group. As we all know, in addition to conventional methods such as internal medicine treatment and liver transplantation, there is a lack of new treatment methods for ACLF in the later stage. Our previous animal trials, both in pigs and rats, have observed significant efficacy from stem cell transplantation.
In the early stage, we have successfully treated pigs, a large animal model of liver failure, with remarkable results using human bone marrow mesenchymal stem cells, and the results of this research were published in Hepatology, which received wide attention. We were the first team to conduct such research on large animals, and the work has had a profound impact. At present, stem cell therapy for liver failure has been applied in clinical practice, and a number of clinical trials are underway. However, on this basis, we found that there was a large difference in the effectiveness of stem cell therapy, with some patients achieving significant results while others had mediocre results.
After in-depth research, we found that stem cells contain multiple subsets of cells, and these subsets of cells have different efficacy. Some subsets of cells have a good therapeutic effect, while others may not work well and may even trigger side effects such as fibrosis and promoting an inflammatory response in the microenvironment of different hosts. In our new study, we screened cells for specificity and trained them under conditions that mimicked in vivo microenvironment disturbances, which we call training immunity. Specific cells are trained to be more "combative" and are able to specifically inhibit overactivated macrophages and prevent them from releasing inflammatory cytokines.
In this way, we can improve the immune microenvironment and modulate the cytokine storm, thereby increasing the survival rate of animals. We are now nearing the end of this new work, and we look forward to sharing the final findings with our peers as soon as possible.
International Liver Disease
What hot issues or highlights in the ACLF field did you pay more attention to at this EASL conference?
Prof. Jun Li: At present, there are four major diagnostic criteria for ACLF, namely EASL-CLIF criteria, APASL criteria, NACSELD criteria in North America, and COSSH criteria later proposed by mainland China. In view of the differences in etiology and populations around the world, a new question was raised at this meeting: is there a need for a uniform diagnostic standard? These existing criteria are based on different etiologies, different races, and different populations, so it is particularly urgent to develop a globally unified diagnostic criteria applicable to various etiologies.
A unified diagnostic criterion is essential to understand the pathogenesis of the disease, assist in clinical management, improve the cure rate, and reduce the case fatality rate, which was also reflected at this conference. At the same time, a new trend has caught our attention. The traditional major causes of ACLF include HBV, alcoholic fatty liver disease (AFLD), and metabolic-associated fatty liver disease (MAFLD), especially in Western populations, where AFLD and MAFLD are important causes.
However, a new situation has now emerged: in the clinic, immunotargeted therapy for non-liver tumors, such as lung cancer, gastric cancer, and gastrointestinal cancer, may lead to acute liver injury. Immunotargeted therapy in addition to chronic liver disease may even trigger liver damage, which in turn can lead to ACLF.
Because targeted therapies are becoming more common, this new cause will need to be focused on in the future. At the same time, the hepatology department should also pay close attention to ACLF caused by damage caused by new specific drugs.
International Liver Disease
What are the biggest challenges in the current effort to roll out harmonized diagnostic criteria for ACLF?
Prof. Jun Li: The biggest challenge in this work is to achieve global cooperation. The COSSH cohort is a cooperative project of 21 centers in China, but now this is not just a matter of China. We need collaboration with Asia-Pacific and even with researchers in Europe. Currently, two of the most impactful evidence-based sources are CLIF C ACLF and COSSH ACLF. The next task is to unite the research forces of North America to jointly understand the characteristics of diseases in different regions and different etiologies. On this basis, we also need to verify the applicability of diagnostic criteria in each region and explore the need for a new diagnostic definition, diagnostic criteria, or prognostic scoring system. Work is currently underway and we are also discussing how to work with the CLIF cohort for validation during the EASL.
International Liver Disease
You mentioned that targeted immunotherapy for lung cancer, gastric cancer, digestive tract tumors, etc., can cause liver damage with specific drugs, so what do you think hepatologists should pay attention to in their daily work and clinical practice?
Prof. Jun Li: This is a process that requires multidisciplinary teamwork. In the past, patients who developed liver damage after receiving targeted immunotherapy were treated at the hepatology department. However, from the current perspective, we in the Department of Hepatology should give early warning and prediction to patients before they receive targeted immunotherapy. We hope to be able to discover specific targets and molecules that cause liver damage with targeted immunotherapy, and to infer from this information which patients are candidates for targeted immunotherapy and which are not, and need to be replaced with other treatments. Hepatology can play an important role in this process. Of course, we must first identify which populations are sensitive to liver damage caused by targeted immunotherapy and which are not, so that we can achieve precise treatment. This is a global concern, and we have already started to study it, and we believe that we will achieve some results.
International Liver Disease
What are your thoughts and takeaways from participating in this EASL2024?
Prof. Jun Li: I have gained a lot from staying at the venue every day. The three-year pandemic has changed many of our habits, for example, attending meetings online saves the fatigue of traveling. However, since the resumption of in-person activities last year, I attended last year's EASL and American Association for the Study of Liver Diseases (AASLD) Annual Meeting, this year's Asia-Pacific Association for the Study of the Liver (APASL) Annual Meeting in Japan, and this EASL Annual Meeting in Milan. In these four hepatology conferences, my biggest feeling is that I can have face-to-face communication with my international counterparts, especially the world-class team, which is irreplaceable by online communication. At the scene, I had in-depth exchanges with several EASL experts and learned a lot from them. They have provided many valuable suggestions and opinions on our COSSH research, and we have benefited a lot. I hope that our peers, especially domestic experts, will be more involved in international exchanges.
Highlights of the venue