Editor's Note: Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute liver function deterioration based on chronic liver disease, accompanied by high mortality rates of liver and extra-hepatic organ failure. The short-term mortality rate of comprehensive internal medicine treatment ranges from 50% to 90%. Due to its high mortality and complex pathogenesis, research and treatment strategies for ACLF are particularly crucial. From June 5-8, 2024, the European Association for the Study of the Liver (EASL) Annual Meeting was held in Milan, Italy, where Professor Jun Li 's team from the First Affiliated Hospital of Zhejiang University School of Medicine presented five research findings related to ACLF. Hepatology Digest invited Professor Jun Li to introduce the highlights and significance of these studies, share his conference insights, and discuss the future development of the ACLF field. The following is the interview transcript.Hepatology Digest: In the progression of ACLF, what unique peripheral immune characteristics related to ACLF progression have been revealed through your team’s longitudinal single-cell transcriptomic analysis? How do these characteristics influence the disease course and provide potential targets for future treatment?
Professor Jun Li: At this EASL meeting, we were honored to have five of our studies selected for presentation. In one of these studies, we dynamically observed single-cell data during the progression and outcome of ACLF. This is a further exploration based on our 2022 study. At that time, we studied peripheral blood mononuclear cells (PBMCs) through transcriptomics and found that early ACLF progression involves innate immune activation, and later stages show severe immune metabolic imbalance, which may be one of the causes of ACLF-related mortality.
In our latest study, we dynamically observed the disease progression and recovery process of ACLF, exploring which immune cells play key roles in the disease’s dynamic changes at the cellular level. In a large prospective cohort study, we identified a group of low-density neutrophils, particularly CXCR2-positive neutrophils. These cells are rare in healthy individuals but highly expressed in patients with rapid ACLF progression and poor prognosis. Additionally, we found other immune cells, such as low-density highly inflammatory CXCR2+ neutrophils and M2 macrophage-like CD163+ monocytes, playing important roles in progressive ACLF patients. Some NK cells and cytotoxic T cells were highly expressed in patients with improving ACLF, while others were highly expressed during disease deterioration.
Through this series of studies and integrated analysis, we identified an immune cell map with clinical translational value, divided into six different cell patterns. Notably, we discovered a specific immune cell group, group 3. The appearance of group 3 cells provides a therapeutic window during which intervention treatment can positively impact ACLF prognosis, offering potential guidance for future clinical applications.
Hepatology Digest: How does SEMA6B trigger macrophage-mediated systemic inflammation in ACLF pathogenesis, and what specific impact does this inflammatory process have on ACLF progression?
Professor Jun Li: Our research has progressively delved into clinical translation. We discovered an intriguing molecule, SEMA6B. In 2022, we initially identified this molecule, and the related findings were published in Gut. Further research revealed that SEMA6B interacts with other proteins to activate macrophage inflammatory responses, significantly elevating IL-10 and TNF-α levels. When the microenvironment is disrupted, SEMA6B promotes macrophage inflammatory responses, potentially related to cytokine storms. SEMA6B is a crucial target for ACLF clinical treatment. We are currently conducting further research, with the work nearing completion and accepted for revision by a high-impact journal. We expect to share the formal results with everyone later this year.
Hepatology Digest: Aside from the aforementioned two studies, your team presented three additional studies at this EASL meeting. Can you introduce the main findings and their potential clinical value and significance?
Professor Jun Li: All our research focuses on ACLF, including the diagnosis and treatment of acute liver failure. We focus not only on early diagnosis and pathogenesis but also on treatment methods.
In early diagnosis, we made significant progress in three other studies. One study explored the relationship between miRNA and mRNA in cellular interactions, introducing topological analysis into the miRNA and mRNA regulatory network in ACLF for the first time. This is one of our team’s unique features, built on years of accumulated results. The study will be formally published, and we will provide detailed results and reports, including several clinically translatable targets we identified.
Additionally, we conducted a clinical study. Patients with ACLF often have poor treatment outcomes in the terminal stages of the disease, especially when ACLF is complicated by circulatory failure, resulting in high mortality rates. This raised the question: Can such patients undergo liver transplantation? The previous Asia-Pacific guidelines did not recommend liver transplantation for ACLF with circulatory failure due to a lack of evidence, while European guidelines suggested attempting transplantation without solid evidence.
Through the COSSH prospective, large-cohort, retrospective study analysis, we found that many HBV-ACLF patients with circulatory failure who underwent transplantation had significantly longer survival than those who did not. This finding indicates that liver transplantation has high value even in the presence of circulatory failure.
During discussions with EASL experts at the conference, they highly praised our work, noting its alignment with European recommendations and providing new evidence. They anticipate our study’s publication to offer more options for doctors, especially for severe ACLF patients with circulatory failure who deserve transplantation opportunities. I believe this study is highly significant.
Moreover, our team conducted a study on stem cell intervention therapy, an important direction for our research group. ACLF has limited new treatment methods beyond internal medicine and liver transplantation. In our previous animal experiments with pigs and rats, we observed significant effects of stem cell transplantation.
We successfully treated liver failure in large animal models (pigs) using human bone marrow mesenchymal stem cells, with significant results published in Hepatology, gaining widespread attention. Our team was among the first to conduct such studies on large animals, impacting the field profoundly. Stem cell therapy for liver failure is now clinically applied and undergoing multiple clinical trials. However, we found significant differences in treatment effects, with some patients responding well and others less so.
Further research revealed that stem cells consist of multiple subpopulations with varying therapeutic effects. Some subpopulations are effective, while others may not be and could even cause side effects, such as fibrosis and inflammation, in different host microenvironments. In our new study, we screened specific cells and trained them under conditions simulating disrupted microenvironments, a process we call immune training. The trained specific cells exhibit stronger “combat effectiveness,” specifically inhibiting over-activated macrophages and preventing their release of inflammatory factors.
This approach improves the immune microenvironment, regulates cytokine storms, and increases animal survival rates. Our new work is nearing completion, and we look forward to sharing the final results with our peers soon.
Hepatology Digest: What hot topics or highlights in the ACLF field did you focus on at this EASL conference?
Professor Jun Li: ACLF currently has four major diagnostic criteria: EASL-CLIF, APASL, North American NACSELD, and the Chinese COSSH standard. Given the differences in etiology and populations worldwide, experts at the conference proposed a new topic: the need for a unified diagnostic standard. These existing standards are based on different etiologies and populations, making a global unified diagnostic standard crucial for understanding disease mechanisms, assisting clinical management, improving cure rates, and reducing mortality.
At the conference, this topic was highlighted. Another emerging trend caught our attention: traditional ACLF etiologies include HBV, alcoholic fatty liver disease (AFLD), and metabolic-associated fatty liver disease (MAFLD), especially in Western populations. However, a new situation has arisen: immuno-targeted therapies for non-liver cancers, such as lung, gastric, and digestive tract cancers, may cause acute liver injury. Immuno-targeted treatments for chronic liver disease may lead to liver injury, resulting in ACLF.
As targeted therapies become more prevalent, this new etiology requires focused attention. Hepatologists must also closely monitor ACLF caused by specific new drug-induced liver injuries.
Hepatology Digest: What is the biggest challenge in establishing a unified ACLF diagnostic standard?
Professor Jun Li: The biggest challenge is achieving global collaboration. The COSSH cohort is a domestic collaboration project involving 21 centers, but this is not just a Chinese issue. We need cooperation with the Asia-Pacific region and even European researchers. Currently, the two most influential sources of evidence are the CLIF C ACLF and COSSH ACLF. The next task is to unite North American research forces to understand disease characteristics in different regions and etiologies. We also need to verify whether diagnostic standards are applicable across regions and explore the need for a new diagnostic definition, standard, or prognostic scoring system. This work is ongoing, and we are discussing collaboration with the CLIF cohort during the EASL meeting.
Hepatology Digest: You mentioned that targeted immunotherapy for lung, gastric, and digestive tract cancers can cause specific drug-induced liver injury. What should hepatologists pay attention to in daily clinical practice?
Professor Jun Li: This requires multidisciplinary team cooperation. Previously, patients would seek hepatology treatment only after experiencing liver injury from targeted immunotherapy. From today’s perspective, hepatologists should provide early warnings and predictions before patients undergo targeted immunotherapy. We aim to identify specific targets and molecules causing liver injury from targeted immunotherapy to determine which patients are suitable for this treatment and which are not, requiring alternative therapies. Hepatologists can play a significant role in this process. First, we must identify which populations are sensitive to liver injury from targeted immunotherapy and which are not to achieve precise treatment. This is a global concern, and we have begun related research, confident in achieving promising results.
Hepatology Digest: What are your thoughts and takeaways from attending EASL 2024?
Professor Jun Li: Staying at the conference, I gained a lot. The three-year pandemic changed many of our habits, such as attending online conferences, which saved travel fatigue. However, since resuming in-person activities last year, I’ve attended last year’s EASL, the 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 meeting in Milan. My biggest takeaway from these four liver disease conferences is the irreplaceable value of face-to-face exchanges with international peers, especially top-tier teams. On-site, I had in-depth discussions with several EASL experts, learning a lot from them. They provided valuable suggestions and feedback on our COSSH research, from which we greatly benefited. I hope our peers, especially domestic experts, will engage more in international exchanges.
