Hepatitis B virus (HBV) infection is a significant global public health issue. In 2019, chronic hepatitis B (CHB) affected about 296 million individuals worldwide, 820,000 of whom died from HBV-related diseases such as liver failure, cirrhosis, or hepatocellular carcinoma (HCC) (You et al., 2023). While long-term antiviral therapy with nucleos(t)ide analogues like entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide can reduce the risk of HCC occurrence in CHB patients, this treatment cannot completely eliminate the risk (Kim et al., 2022).

Non-alcoholic fatty liver disease (NAFLD) is another severe global health problem, with a worldwide prevalence of 29.8% and a prevalence in China of 29.2% (Le et al., 2019; Zhou et al., 2019). Because of the lack of a unified definition of NAFLD that incorporates key metabolic characteristics, Eslam et al. in 2020 proposed renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD), defining the condition as hepatic steatosis (HS) with obesity, diabetes mellitus (DM), or other metabolic abnormalities (Eslam et al., 2020a; Eslam et al., 2020b). In 2023, a joint proposal, following the Delphi consensus, was made to redefine NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD) and include patients with HS and at least one of five cardiometabolic risk factors (CMRFs) (Rinella et al., 2023). While some studies have identified a higher risk of HCC in CHB patients who also suffered from NAFLD (Chan et al., 2017; Kanwal et al., 2018), others have found that HS correlates with a decreased risk of HCC in CHB patients (Li et al., 2021; Mak et al., 2021). These conflicting findings suggest that NAFLD has a complex relationship with CHB, especially after being redefined as MASLD. Although the presence of HS may result in the suppression of HBV viral activity and a reduction in liver damage (Tourkochristou et al., 2022), CMRFs such as DM may increase the risk of HCC (Wang et al., 2012). These findings suggest that the individual components of MASLD may have opposing effects on the clinical manifestations of CHB. In the present study, we assessed the effect of MASLD on the risk of HCC in patients with CHB and compared the differences in the effects of MASLD and NAFLD on the risk of HCC in these patients. Inverse probability treatment weighting (IPTW) was used to adjust for potential confounding factors.

This retrospective study evaluated the effect of concurrent MASLD on the incidence of HCC in Chinese patients with CHB. As far as we know, this is the first study to report the correlation between MASLD and the risk of HCC in CHB patients. This study included 1,613 CHB patients, 29.9% of whom had MASLD. This prevalence rate aligns with the MASLD prevalence in the general population as reported in a previous study (Ciardullo et al., 2023). The incidence of CMRFs, including overweight, DM, hypertension, and dyslipidemia, was higher for patients in the MASLD group than the non-MASLD group. Correspondingly, patients in the MASLD group had a longer history of using statins, metformin, and ACEI/ARBs than those in the non-MASLD group. Interestingly, patients in the MASLD group had a lower baseline level of HBV DNA and a reduced likelihood of being HBeAg-positive. Several studies have shown a decrease in viral replication among CHB patients with HS (Wang et al., 2014; Ceylan et al., 2016), yet the underlying mechanisms remain obscure, suggesting a potential interplay between HBV and CMRFs during liver disease pathogenesis (Wang and Xie, 2022). Further study is needed to explore this relationship further.

Multivariable Cox analysis identified MASLD as an independent risk factor for developing HCC. CHB patients with MASLD had a 4-fold increased risk of HCC than those without. Even after adjusting for potential confounders using IPTW score matching, MASLD persistently emerged as an independent risk factor for HCC. Similarly, van Kleef et al. reported that CHB patients with MAFLD had a 2-fold higher risk of developing HCC (van Kleef et al., 2021). Another study using the South Korean National Health Insurance System database found that after adjusting for age, gender, cirrhosis, antiviral treatment, physical activity, smoking history, and alcohol consumption, the risk of developing HCC was 1.4-fold higher in CHB patients with MAFLD (Yun et al., 2022). After applying IPTW, there was a persistent association between the risk of developing HCC in CHB patients with MASLD regardless of whether they had advanced liver fibrosis. This suggests that MASLD may contribute to HCC progression independent of liver fibrosis. These findings indicate that patients with non-advanced liver fibrosis and MASLD should undergo increased HCC surveillance. Traditionally, advanced liver fibrosis has been considered a major HCC risk factor (Fujiwara et al., 2018). However, in the current study, it was excluded from the multivariate Cox model. The independent risk factors for HCC identified were age (≥40 years), MASLD, elevated AFP, and ALB levels. Advanced liver fibrosis was excluded even after mitigating potential confounding variables using IPTW. This may be attributed to the limitations of observational studies, including potential overlooked or unknown confounders that could bias the association between advanced liver fibrosis and HCC. However, the findings also suggest that advanced liver fibrosis may not be the only or leading cause of HCC. A broader spectrum of risk factors should be considered during HCC risk assessment and management, including age, MASLD, AFP, and ALB levels.

This study also discovered that the association between MASLD and HCC risk persisted in CHB patients regardless of whether they had received antiviral treatment for more than 6 months, both before and after adjustment with IPTW. The majority of patients in this study had undergone antiviral therapy for ≥6 months, primarily with entecavir or tenofovir disoproxil fumarate. Notably, patients in the MASLD group were more likely to have never received antiviral therapy or received therapy for <6 months than to have received therapy for ≥6 months, probably because this group had lower levels of HBV replication. While antiviral drugs can inhibit viral replication, averting liver disease progression and potentially offering long-term prevention against HCC (Gordon et al., 2014), the current study found that HCC risk remained high in MASLD patients who had received long-term treatment. This is particularly true for patients with HBV DNA levels ≥6 log₁₀ IU/mL or a positive HBeAg status, as these were identified as independent risk factors for HCC in CHB patients after adjusting for confounders with IPTW. Thus, in evaluating the risk of HCC in CHB patients who adhere to antiviral therapy, careful consideration should be given to MASLD.

Furthermore, we found that, compared to patients with CHB who had cryptogenic SLD, those with MASLD did not exhibit a significantly higher cumulative risk of developing HCC. Similarly, the cumulative risk of HCC in patients with cryptogenic SLD did not significantly differ from that of the patients without HS. This finding remained after IPTW with respect to the baseline characteristics of the patients. This suggests that the cumulative effect of multiple factors, including CMRFs and HS, mediate the effects of MASLD on the development of HCC in patients with CHB. However, the precise influence of each factor on the risk of HCC requires further investigation. Although the cumulative incidence of HCC was higher in patients with MASLD, those with overweight and those with ≥2, ≥3, or ≥4 CMRFs did not significantly influence the risk of HCC in the present sample of patients. Although overweight and CMRFs have been shown to be associated with a higher risk of HCC (Larsson and Wolk, 2007; Antwi et al., 2022), the present findings indicate that in patients with MASLD, the risk of developing HCC does not differ with varying levels of CMRFs. The findings also imply that in the presence of MASLD, the risk of HCC may also be higher in patients without overweight and in those with few CMRFs, which underscores the need for clinical vigilance.

To compare the risk of HCC in patients with CHB and either the newly named MASLD or the previously named NAFLD, we reclassified the patients according to whether they had NAFLD or not, to evaluate the effect of NAFLD on the development of HCC. The results showed that, both before and after adjustment using IPTW, the cumulative risk of HCC in the NAFLD group was significantly higher than that of the non-NAFLD group. However, after IPTW adjustment, the 3- and 5-year cumulative risks of HCC in the NAFLD group were 2.5% and 5.2%, respectively, which were lower than those in the MASLD group (4.3% and 7.5%). This suggests that the presence of MASLD, which includes a greater emphasis on metabolic parameters, is associated with a higher risk of HCC. This further underscores the importance of metabolic defects in the development of HCC.

The current study has some limitations. Its retrospective design prevented the collection of data on waist circumference, 2-h postprandial blood glucose, and glycated hemoglobin. The absence of this information could have led to an underdiagnosis of MASLD in certain patients and affected the study outcomes. Additionally, the evolving status of MASLD during the follow-up period could have changed the level of HCC risk in certain patients, a consideration not accounted for in the retrospective cohort. This limitation underscores the need for prospective studies to evaluate the correlation between MASLD and HCC risk in CHB patients while concurrently adjusting for the chronicity of MASLD. Finally, while the median follow-up duration was 5.02 years, this may not have been enough time to estimate the full impact of MASLD on HCC risk.

The present findings highlight the critical role of MASLD as an independent risk factor for HCC in patients with CHB. The findings were consistent when a number of subgroups were analyzed, including patients with and without advanced liver fibrosis and those undergoing antiviral therapy for <6 and ≥6 months. The higher risk of HCC in patients with CHB who have MASLD is driven by the cumulative effect of multiple factors, including CMRFs and HS. Furthermore, when compared to NAFLD, the classification MASLD places greater emphasis on metabolic factors and is associated with a higher risk of HCC. These findings suggest the importance of screening for steatosis, and especially MASLD, to reduce the risk of HCC in patients with CHB. Notably, even patients with MASLD who do not have overweight or have few CMRFs are at a high risk of HCC. Further investigations are needed to elucidate the mechanisms underlying the relationship between MASLD and HCC, which could inform the development of novel strategies for the prevention of HCC in this high-risk population.