Editor’s Note: Non-alcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD) is on the rise globally and has become the leading cause of chronic liver disease in China, posing a significant threat to public health. Establishing diagnostic models based on risk factors to assist clinical diagnosis and classification, or developing non-invasive assessment methods, is an important prerequisite for identifying more patients and effectively intervening in the disease process.
Assistant Professor Daniel Q Huang of the National University Hospital in Singapore has made significant contributions to the field of NAFLD/MASLD, and he presented numerous new research developments from his team at the 2023 American Association for the Study of Liver Diseases (AASLD) Annual Meeting. Dr. Yee Hui Yeo, a gastroenterologist at the Westmead Hospital in the United States, has also explored and made significant discoveries in this field. “Hepatology Digest” has invited these two young experts to discuss hot topics related to NAFLD/MASLD screening, diagnosis, and new drug development, and the content is shared as follows.
NAFLD Family Risk Score: A Feasible Screening Strategy
Hepatology Digest: At this year’s American Association for the Study of Liver Diseases (AASLD) Annual Meeting, you presented the latest research developments in your team’s development of the NAFLD Family Risk Score [1]. Could you please discuss the main research findings and their significance?
Daniel Q Huang: Non-alcoholic fatty liver disease (NAFLD) is associated with genetic predisposition for fibrosis, but it is unclear how to use family history to identify first-degree relatives at risk of advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of index cases who are at higher risk of NAFLD with advanced fibrosis.
To develop this score, we included two prospective cohorts (derived from San Diego, USA, and validated in Helsinki, Finland). We assessed the liver fibrosis status of all participants using MRI or elastography and identified key factors associated with advanced fibrosis progression.
Importantly, in this scoring system, we found that family history was a major component of the risk of advanced fibrosis progression in first-degree relatives. Therefore, we designed a simple score, including age (≥50 years), type 2 diabetes, obesity, and family history, with the aim of easily identifying first-degree relatives at high risk of advanced liver fibrosis.
Yee Hui Yeo: I want to emphasize that this family risk score is indeed crucial and very timely. According to our previous analysis, the overall prevalence of NAFLD/MASLD in 2020 has reached approximately 39%, and it is projected to approach 55% by 2040. Many predictive models suggest that there are still a significant number of cases with advanced liver fibrosis that remain undiagnosed, and the NAFLD Family Risk Score will help identify those undiagnosed patients.
Furthermore, what is especially noteworthy is that this is a relatively feasible and practical approach to easily identify or capture a sufficient number of undiagnosed patients, as they come through referrals from family members. There is no doubt that this is a feasible strategy.
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<Hepatology Digest>: At the annual meeting of the American Association for the Study of Liver Disease, you introduced the latest research progress of the NAFLD Familial Risk Score developed by your team. Could you please talk about the main research results and its significance?
Daniel Q Huang: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with fibrosis.
To develop this score, what we did was we leverage on two prospective unique formula cohorts (derivation, validation). We assess liver fibrosis status in all participants by either MRI or elastography. We identify key factors that were associated with advanced fibrosis.
Importantly, in this score, we found that family history is a major component of the risk of advanced fibrosis in first-degree relatives. So, we devised a very simple score comprising of age, diabetes status, obesity, and family history that we hope can easily identify first-degree relatives of people who already are going to have advanced fibrosis that are higher risk themselves.
Yee Hui Yeo: I would like to emphasize that this family score is really important and the finding is timely. The main reason is that our previous analysis shows that the overall prevalence of MASLD currently, even in 2020, the modeling shows that it’s almost 39% and is forecast to be almost 55% in 2040. And there are just so many undiagnosed cases around with more scores like this. It will help to identify those who are undiagnosed.
This is a relatively feasible, actionable way to identify or capture patients with undiagnosed MASLD, given that they got this referral from family members. Definitely, this is a pragmatic way for us to practice as a political provider.
Routine Risk Stratification Combining Blood Markers with Imaging Assessment
Hepatology Digest: The number of patients with metabolic-associated fatty liver disease (MAFLD) in Asia is increasing year by year, and there is an urgent need for more effective non-invasive diagnostic methods for clinical use. From a scientific research perspective, how do you view the opportunities and challenges of non-invasive diagnosis? What are the more promising research directions?
Daniel Q Huang: Non-invasive diagnosis of metabolic-associated fatty liver disease is a significant area with unmet needs. I believe that in the past year or two, both the AASLD and AGA have provided guidance on how to stratify these patients, especially those with metabolic risk factors.
I think in Asia, we do need to stratify by starting with four major markers and then proceeding to further imaging assessments. It is an area that still needs improvement as there are several flaws with the existing strategies, but the goal is to have routine stratification in the target population in the future.
Our group is researching strategies based on MRI. However, we are also concerned that this strategy may not be widely applicable to the general population. Therefore, I believe that other blood-based biomarkers are crucial and essential. This is an area where we hope to make more progress in the next year or two.
Yee Hui Yeo: I wholeheartedly agree with Professor Huang’s remarks. Additionally, in Asia, some biomarkers for MAFLD are not part of routine testing. Therefore, we need to consider strategies that are easier to implement and help improve accuracy, especially when dealing with the Asian population or Asian patients, given that many Asians have normal or low BMI and still develop fatty liver.
Furthermore, we need to consider the prevalence of NAFLD/MASLD in the context of various infection backgrounds. For example, the new AASLD fatty liver disease guidelines categorize all hepatitis virus infections in the MASLD definition. However, we do not know the interaction between viral hepatitis infections and metabolic syndrome in these patients with confirmed fatty liver through imaging. There are more potential research directions in the use of non-invasive testing for diagnosing NAFLD/MASLD in the future. We look forward to Professor Huang’s further discoveries in this regard.
<Hepatology Digest>: The number of patients with metabolic dysfunction-associated fatty liver disease in Asia is increasing year by year, and more effective noninvasive diagnostic methods are urgently needed for clinical use. From the perspective of scientific research, how do you see the opportunities and challenges of noninvasive diagnosis? More promising research directions?
Daniel Q Huang: That’s a great area of unmet need. I think, in the last 1 or 2 years, the AASLD and the AGA have provided guidance in terms of how we might risk stratify such patients, but especially those with metabolic risk factors.
I think in Asia, we do need to validate these pathways specifically by starting with big four and then stratifying further by last pathography. I think though this is an area that we still need improvement on, because there are many drawbacks of such approaches, there will be participant patients that are classified routinely. Those advanced versus might have a little bit for or vice versa. So, I think this is an area of unmet need.
Our group is working on MRI based strategies. But at the same time, we are also concerned that such strategies may not be widely available for the general population. So I think other blood based biomarkers are key and essential. And this is an area that we hope to have more results in the next 1 or 2 years.
Yee Hui Yeo: I really want to second what Doctor Huang just mentioned about the usability and some of the challenges that we have. Currently, some of the biomarkers of MAFLD are not routinely tested. So, we need to think about some of the more accessible strategies and also to help to increase the accuracy, especially when it comes to Asian audiences or Asian patients.
Then we need to think about the prevalence when, in the background, there are a lot of people with a concomitant variety of infections. In that case, for example, for the most recent AASLD guideline of steatotic liver disease, viral hepatitis infections are included in that definition. However, we do not clearly know what their roles are or the interplay between the virus infection and the existence of metabolic syndrome among all these patients with imaging-proven steatotic liver disease.
There is future potential for more research in terms of using the noninvasive test to diagnose MASLD. And we’re looking forward more work from Dr Huang really.
Diabetes Affects NAFLD/MASLD Progression, Blood Sugar Control is the Key Intervention
Hepatology Digest: What factors do you believe can predict the progression of metabolic-associated fatty liver disease (MAFLD)?
Daniel Q Huang: I believe one of the primary determinants of progression is the presence of type 2 diabetes (T2DM). In our recent work, we found that compared to those without T2DM, T2DM patients had a significantly faster rate of fibrosis progression. Furthermore, we also observed that individuals with higher levels of glycated hemoglobin (HbA1c) were significantly associated with a faster progression to liver cirrhosis compared to those with lower HbA1c levels. Therefore, while there are many determining factors for fibrosis progression, including genetics, HbA1c, and diabetes, overall, blood sugar control is undoubtedly a major area that needs attention.
Yee Hui Yeo: I completely agree. This is indeed an important study that uses serial biopsies to confirm the mechanisms of disease in the diabetic population and the presence of NAFLD/MASLD. In Asian patients, comorbidities such as metabolic syndrome, viral hepatitis infections, and alcohol use can exacerbate disease progression. Additionally, how we identify risk factors and dissect their role in disease progression is crucial. For example, we should pay more attention to modifiable risk factors such as HbA1c, metabolic syndrome, dietary management, and physical exercise.
Daniel Q Huang: We have so many modifiable risk factors, and one important determinant is actually taking action and waiting for change. I believe that for participants or patients, achieving weight loss doesn’t necessarily require reaching a 10% reduction in body weight because that may be unattainable for most patients. Even losing 1 to 2 kilograms can have a positive impact in the long run. Additionally, I think changing patients’ diets is also crucial, especially reducing the intake of high-sugar beverages and foods.
Yee Hui Yeo: Speaking of weight, there are several familiar medications used for weight control, such as semaglutide and other GLP-1 receptor agonists, which have significant potential for controlling NAFLD/MASLD, NASH/MASH.
Daniel Q Huang: I think it’s an exciting time. While these new drugs (such as GLP-1 receptor agonists) have not yet been approved for NASH treatment, we are seeing increasing evidence in patients with type 2 diabetes, obesity, and NASH that these new drugs may be useful for natural regression or reversal of advanced fibrosis.
Therefore, I’m really hopeful that as more trials are released, we will have more data showing that at least some of these drugs will be approved. I think at this point, it’s more about waiting and observing, but I’m hopeful for the near future.
Yee Hui Yeo: Indeed, these drugs have been used for the treatment of diabetes for a long time, and hopefully, they will receive FDA approval in the future.
Daniel Q Huang: NAFLD/MASLD is indeed a significant issue in Singapore, just like in other parts of Asia. In fact, over the past decade, we have seen a significant shift from hepatitis B to NAFLD/MASLD as a major concern. Our transplant clinics are now filled with NAFLD/MASLD-related HCC patients. I think we must address some major issues one by one. One of them is the overall lack of awareness among the Singaporean population about NAFLD/MASLD. Therefore, I believe that spreading relevant knowledge to the general public and healthcare providers is essential.
Furthermore, we need closer collaboration with other professionals, such as public health providers and endocrinologists, and conducting NAFLD/MASLD screening is an important step. The guidelines revised by AASLD and AGA provide excellent references for this, but we need to tailor various recommendations from AASLD or AGA into guidance suitable for the Southeast Asian population.
Yee Hui Yeo: I wholeheartedly agree with Professor Huang’s point, and interdisciplinary collaboration is crucial. This holds true in the United States as well. We still have many undiagnosed individuals, and some preliminary data show that many of those newly diagnosed with NAFLD/MASLD-related cirrhosis or NAFLD/MASLD-related HCC are already in the decompensated cirrhosis stage. Unlike patients with chronic hepatitis and alcohol-related liver disease, the public does not have a sufficient understanding of the harm of metabolic syndrome to the liver, so we must genuinely increase public awareness.
Turning Point in NAFLD/MASLD Prevention and Control, Urgent Need for Change
Hepatology Digest: Do you have any additional comments?
Daniel Q Huang: I completely agree with the important issue you’ve raised. I believe NAFLD/MASLD is a significant problem now. Moreover, I think this issue is faced by countries across Asia. Therefore, I believe that we indeed need to strengthen cooperation between nations and within individual countries to truly address this problem. I think we are at a turning point, and if we don’t use this time to effectively educate our people and formulate national strategies to deal with NAFLD/MASLD, we will face severe consequences in the future. Therefore, I consider this to be a very needed and urgent area.
Yee Hui Yeo: I completely agree. I hope that the predictive models we previously established for the disease’s prevalence in 2040 can be reversed/overturned due to effective control of NAFLD/MASLD.
Reference:
[1] Huang DQ, Ahlholm N, Luukkonen P, et al. Development and validation of the NAFLD familial risk score to detect advanced fibrosis: a prospective, multicenter study. AASLD 2023. Oral 236.
[2] Huang DQ, Wilson L, Amangurbanova M, et al. Liver stiffness progression in biopsy-proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study. AASLD 2023. Poster 2067-A.
[3] Tamaki N, Wakabayashi S, Kimura T, et al. Glycemic control target associated with a lower risk of liver-related and cardiovascular events in nonalcoholic fatty liver disease. AASLD 2023. Poster 2182-A.
Expert Profiles:
Daniel Q Huang Assistant Professor, National University Hospital, Singapore
Yee Hui Yeo Gastroenterology Fellow, Cedars-Sinai Medical Center, Los Angeles, USA
TAG：AASLD 2023, Interview, MASLD, NAFLD
