Chronic liver disease (CLD) affects more than 800 million individuals worldwide and its associated complications, such as hepatocellular carcinoma (HCC), cause significant mortality, morbidity, and economic burden [
1]. Viral hepatitis, such as chronic hepatitis B and C, has been the leading etiology for CLD. However, along with the increase in metabolic abnormalities and effective interventions for the prevention and treatment of hepatitis B and C have led to changing CLD trends [
2,
3]. Recently, the impact of viral hepatitis for HCC development is expected to be attenuated by that of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease [
4,
5]. Especially, with the increasing prevalence, MASLD is a leading cause of HCC [
6,
7].
Current guidelines recommend HCC surveillance in patients with cirrhosis [
8-
10]. However, there is currently no consensus regarding HCC surveillance in non-cirrhotic patients with non-viral CLD, such as MASLD. The European Association for the Study of Liver Disease guidelines recommend considering HCC surveillance in MASLD patients with stage F3 fibrosis [
8], while the American Association for the Study of Liver Diseases guidelines do not [
9]. The American Gastroenterological Association recommends HCC surveillance in patients with MASLD positive for noninvasive markers suggestive of advanced fibrosis [
10]. Because HCC develops in a substantial proportion of over 20% of MASLD patients without cirrhosis in the real world [
11], it has implications for how physicians should prioritize HCC surveillance of patients with MASLD. However, there are few risk stratification models for HCC development to identify high-risk patients who require stringent HCC surveillance in these population. The practice guidelines recommend refer MASLD patients with high fibrosis-4 (FIB-4) levels to identify patients with at high risk [
8,
9,
12], but it may be insufficient for the risk stratification of HCC in MASLD having complex interactions of multiple metabolic risks along with fibrotic burden in the HCC development.
In the current issue of the
Clinical and Molecular Hepatology, Su et al. suggests clinical utility of the Steatosis-Associated Fibrosis Estimator (SAFE) score to predict HCC in MASLD and other CLD etiologies [
13]. In this study of 12,963 CLD patients [
13], the SAFE score stratifies the risk of HCC in CLD patients regardless of etiologies and a high SAFE score (≥100) is associated with a 7.54-fold increase of HCC risks compared with low-risk patients. Especially, 5-year predictive performance of the SAFE score for HCC development in MASLD was higher than 0.85, and the negative predictive value (NPV) of a SAFE score for HCC development in 5 years was very high of >99% to identify patients with low risk of HCC who may waive HCC surveillance [
13].
Although the SAFE score showed good performance in patients with MASLD, it may be insufficient to confirm the usefulness of the SAFE score in non-cirrhotic patients because this study included patients with all of fibrosis stages. The incidence of HCC in MASLD without cirrhosis is quite low. This study, which enrolled cirrhotic patients, also reported low cumulative incidences of HCC within 5 years: 0.3% in patients with non-alcoholic fatty liver disease and 0.6% in those with MASLD. However, as some patients with MASLD will eventually develop HCC, it is crucial to accurately identify high-risk patients. Given the inherently low incidence rate of HCC in population with MASLD, achieving a high positive predictive value can be challenging. Therefore, a more pragmatic approach may be to leverage a high NPV to effectively identify individuals at low risk of HCC who can be exempted from HCC surveillance, thereby optimizing risk stratification based on suggested HCC risk cutoffs of at least 0.2%/year in the guidelines [
8,
9]. In addition, considering that key variables in the SAFE score, such as diabetes and body mass index, are modifiable through lifestyle interventions, a patient’s HCC risk may fluctuate between high and low categories over time [
14,
15]. Therefore, rather than relying on a single-time assessment, periodic reassessments may be necessary to accurately capture dynamic risk changes.
Because HCC risk may not be uniform in patients with MASLD, risk prediction models considering multiple factors including fibrosis or metabolic risk factors are needed to identify individualized patients’ risk for HCC development. Further investigation in diverse population is required to provide adequate decision-making about risk stratifying patients at various risk of HCC.
FOOTNOTES
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Authors’ contribution
Study concept and design: Minjong Lee; Acquisition of data: Minjong Lee, Ho Soo Chun; Drafting of the manuscript: Minjong Lee, Ho Soo Chun; Critical revision of the manuscript for important intellectual content: Minjong Lee, Ho Soo Chun; All authors have read and approved the manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
negative predictive value
Steatosis-Associated Fibrosis Estimator
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