Vienna, June 24th – The 58th Annual European Association for the Study of the Liver (EASL 2023) and the 2023 EASL Congress are nearing their conclusion. In a special session titled “Multi-society and multi-stakeholder consensus revision of the NAFLD nomenclature: the final results,” experts and scholars from various countries engaged in heated discussions regarding whether NAFLD should be renamed as MASLD.

Hepatology Digest had the privilege of inviting Dr. Lai Wei from Peking University Affiliated Tsinghua Chang Gung Hospital to provide updates on the renaming discussion and share his insights. Additionally, we had the opportunity to invite Dr. Lai Wei to discuss his team’s exploration of the research paradigm in the field of hepatitis B and some noteworthy information from this year’s EASL Congress. Here is the summary of the related content:

Hepatology Digest: Fatty liver disease is currently one of the most prevalent liver conditions globally. However, there is ongoing debate about its nomenclature. This conference addressed the renaming of NAFLD to MASLD or MAFLD. Could you please introduce the progress of this discussion and share your personal viewpoint?

• Dr. Lai Wei: The naming and definition of nonalcoholic fatty liver disease (NAFLD), the term commonly used for what we colloquially refer to as fatty liver, have been under discussion in the liver disease field in recent years. A new term was proposed by international experts a few years ago: metabolic dysfunction-associated fatty liver disease (MAFLD). Subsequently, organizations such as the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Latin American Association for the Study of the Liver (ALEH), as well as patient organizations, formed working groups. These groups conducted surveys, held online and offline meetings, and reached a consensus. The new disease naming and diagnostic criteria were officially announced at this year’s EASL conference.

• During the discussions, a common sentiment was that liver diseases primarily characterized by fat deposition should have an overarching term. Since the term “fatty” was considered somewhat stigmatizing, the consensus group chose “steatotic liver disease (SLD)” as an umbrella term encompassing various etiologies of fat deposition, including MASLD, metabolic and alcohol-related steatotic liver disease (MetALD), alcohol-related liver disease (ALD), specific causes of SLD, cryptogenic SLD, and combinations other than MetALD.

• For the new name for NAFLD, the majority leaned towards “metabolic dysfunction-associated steatotic liver disease (MASLD).” MASLD is defined as the presence of liver fat deposition and at least one of the five cardiovascular metabolic risk factors. It’s important to note that diagnosing MASLD does not mean excluding other causes of SLD, especially in children. Before applying the MASLD diagnostic criteria, other causes of liver fat deposition must be ruled out to avoid missing dual pathology, as shown in Figure 2. Fatty liver hepatitis is still considered an important pathophysiological stage and will be referred to as Metabolic Dysfunction Associated Steatohepatitis (MASH) instead of NASH.

• In NAFLD patients who also consume alcohol, those who drink more often have a worse prognosis compared to non-drinking NAFLD patients. However, to avoid confounding factors from alcohol, such patients were often excluded from previous studies and clinical trials, creating a “the elephant in the room” scenario. Therefore, this renaming introduces the MetALD category, specifically for MASLD patients who consume larger quantities of alcohol (140 to 350 grams per week for females and 210 to 420 grams per week for males).

• For patients with liver fat deposition but no clear metabolic parameter abnormalities and no known causes, the term “cryptogenic SLD” is used. These patients may also be considered as MASLD based on clinical judgment and may benefit from regular follow-up reevaluation.

• Although there has been extensive discussion over the past two years, as the experts at the conference noted, “consensus” represents the majority opinion in the voting rather than unanimous agreement. The new disease definition and diagnostic criteria have been accepted by most liver disease academic organizations, but there are still many differing voices in the academic community. For instance, during the live discussions, some scholars pointed out that the definition of alcohol consumption levels in the MetALD category may be hasty, and the selected thresholds lack sufficient research validation. There were also voices from patient organizations expressing that patient input during the consensus development process was not extensive enough. Furthermore, how do drug regulatory agencies like the FDA and EMA view changes in disease names and definitions in terms of ongoing drug clinical development and non-invasive diagnostic tool (NIT) assessments? When will the World Health Organization assign an ICD code for MASLD?

• It’s worth noting that this consensus has not yet received the endorsement of APASL, the largest liver disease academic organization in the Asia-Pacific region. MAFLD was initially proposed by liver disease experts from the Asia-Pacific, and it fully reflects the essence of this disease and some unique features in subsequent diagnosis, treatment, and population public health management.

• In conclusion, the release of this consensus is just the first step. The impact of the new disease name and diagnostic criteria on other populations and organizations needs further evaluation.

Hepatology Digest: : Your team had a research achievement in the field of hepatitis B selected for presentation at this conference. Could you introduce the background or motivation for conducting this research and the significant impact it may have?

• Dr. Lai Wei: The title of this research is “Conceptual Study on the Safety and Efficacy of Celecoxib in the Inhibition of Hepatitis B Virus Surface Antigen in Virally Suppressed Patients with Chronic Hepatitis B Using Nucleos(t)ide Analogues.” This is a continuation of our ongoing exploration of applying artificial intelligence to liver disease research.

• In our previous studies, we used artificial intelligence and machine learning to establish a fully automated, continuous quantitative strategy and technology for liver tissue fibrosis, inflammation, ballooning degeneration, and fat deposition in nonalcoholic steatohepatitis (NASH). At this year’s EASL conference, we observed that an increasing number of NASH drug development companies are using this system to evaluate liver histological changes induced by new drugs.

• In this study, we relied on the data and language processing platform from Tianhe, China, to search for drugs among existing medications that may have an impact on the surface antigen seroconversion in chronic hepatitis B. This involves what is known as the “fourth paradigm of science,” primarily collecting and analyzing a vast amount of data to discover unknown factors and relationships related to hepatitis B. Big data technology allows for the rapid discovery of previously unknown or undiscovered data relationships related to hepatitis B seroconversion.

• First, in collaboration with Tianhe, we used language processing tools to analyze extensive data related to various medications and hepatitis B. We identified several marketed drugs associated with hepatitis B surface

• antigen seroconversion. The study presented here focuses on the research of celecoxib. Preliminary research, including studies at the cellular level, animal models, and database analysis from multiple hospitals, indicated an association between celecoxib and hepatitis B surface antigen seroconversion. Therefore, we conducted a prospective conceptual validation. The presentation here represents a mid-term analysis of this prospective conceptual validation.

• We hope that this research will serve as a starting point for more researchers and pharmaceutical companies to use this paradigm and repurpose existing drugs. One advantage of this paradigm is its ability to iterate and optimize quickly, which is something we can consider in our future work.

Hepatology Digest: : Finally, could you discuss other topics or research at this year’s EASL Congress that you found interesting? And what were your overall impressions of attending this conference?

Dr. Lai Wei: In my opinion, this conference had three significant features.

• First, based on the six main reports from the first day’s plenary sessions, it was evident that the liver disease field is making strides toward addressing unmet needs in the near future. These six reports focused on new drug development for NASH, liver cell carcinoma, complications of liver cirrhosis, the immune microenvironment within the liver, and sociological issues related to alcoholic liver disease. Two of the reports specifically addressed complications of liver cirrhosis.

• Second, new drug development for NASH is approaching clinical use. Up until now, there have been no specific drugs for treating NASH. The first report at the conference showcased the success of Madrigal’s resmetirom, a thyroid receptor beta agonist, as the first drug to achieve meaningful liver histological endpoints in clinical trials. Multiple non-invasive measures of liver fat reduction and fibrosis improvement support the evidence of histological improvement. In terms of safety, the main adverse events occurred during the initial treatment phase, primarily diarrhea and nausea, which were manageable. However, Professor Harrison, the lead investigator of this clinical trial, emphasized that a longer-term study (54 months) is ongoing to evaluate the long-term clinical outcomes, including the benefits on liver cirrhosis and liver cancer incidence.

• It’s important to mention here the world’s first large-scale clinical trial of a drug for NASH, obeticholic acid. This drug has already been approved for the treatment of non-responsive primary biliary cholangitis (PBC). The III-phase clinical trial of obeticholic acid for NASH enrolled 2,477 patients. In the interim analysis at 18 months, the 25 mg dose group showed a statistically significant difference compared to the placebo group (the 10 mg dose group did not). However, the U.S. Food and Drug Administration (FDA) expert committee believed that the clinical trial for obeticholic acid used surrogate endpoints, and obeticholic acid carries the risk of drug-induced liver injury. Therefore, during the EASL conference, on June 22, 2023, the FDA requested successful clinical data from long-term follow-up. Subsequently, Intercept Pharmaceuticals, the developer, announced the decision to discontinue all work in the NASH field. While obeticholic acid did not receive FDA approval for NASH, the research conducted throughout this process explored population selection closer to clinical drug indications and non-invasive diagnostic and monitoring methods.

• Third, the conference addressed social issues related to liver diseases. The third presentation analyzed the impact of parental alcohol consumption on offspring, including drinking habits, alcoholism, and effects on the liver and other aspects. The primary outcome was that if either the father or the mother drinks alcohol, there is a high probability that the offspring will also consume alcohol. The significance of this report lies in its sociological focus on liver disease.

• I personally felt a slight regret that, in the era of artificial intelligence, there was no conference presentation specifically dedicated to the application of artificial intelligence in liver disease health, diagnosis, and treatment. However, this indicates that more research is needed, leaving us with ample room for future development.