Mechanisms of hepatocellular carcinoma and cirrhosis development in concurrent steatotic liver disease and chronic hepatitis B

Article information

Clin Mol Hepatol. 2025;31(Suppl):S182-S195

Publication date (electronic) : 2024 November 21

doi : https://doi.org/10.3350/cmh.2024.0837

Saisai Zhang ¹, Lung-Yi Mak ¹^,², Man-Fung Yuen ¹^,², Wai-Kay Seto^,¹^,²^,³

¹Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong

²State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong

³Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

Corresponding author : Wai-Kay Seto Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong Tel: 852 22556979, Fax: 852 28725828, E-mail: wkseto@hku.hk

Editor: Byoung Kuk Jang, Keimyung University, Korea

Received 2024 September 25; Revised 2024 November 13; Accepted 2024 November 16.

Abstract

Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in hepatitis B virus (HBV)-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and hepatocellular carcinoma (HCC). This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.

Keywords: Hepatitis B virus; Fatty liver; Cirrhosis; Hepatocellular carcinoma; Non-alcoholic fatty liver disease

INTRODUCTION

Chronic hepatitis B and steatotic liver disease

Chronic hepatitis B (CHB) infection is a major health burden affecting approximately 296 million people and is a prominent contributor to cirrhosis and liver cancer worldwide. Ongoing liver inflammation and fibrogenesis in CHB infection contribute to liver fibrosis and cirrhosis, with 25–40% of HBV carriers progressing to hepatocellular carcinoma (HCC) [1]. The WHO 2024 global hepatitis report [2] showed a decline in incidence but an increase in mortality due to hepatitis B. In 2022, approximately 1.10 million people died due to hepatitis B. Approximately 25% of untreated CHB patients will die from complications related to cirrhosis and/or HCC, with the rate rising to 50% in men [1]. Recent Global Burden of Disease studies reported that the burden of liver cancer is predicted to rise, and it is always a threat to mortality both in the past and in the next 20 years [3].

It has been reported that the prevalence of hepatic steatosis is lower in hepatitis B surface antigen (HBsAg)-positive patients than that in HBsAg-negative patients [4]. Approximately one-third of CHB patients have concurrent steatosis [5]. This co-occurrence is expected to rise due to the global increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) [6], including in areas where CHB infection is common [7]. According to a recent meta-analysis of 98 studies with 48,472 CHB patients, the global prevalence of MASLD was about 34.93% [8]. The impact of hepatic steatosis on CHB-related disease progression remains debatable. One independent risk factor for the development of cirrhosis [9] and HCC [10] in patients with CHB is hepatic steatosis. This review explores the potential mechanisms underlying the progression to advanced liver disease, such as cirrhosis and HCC, in patients with concomitant CHB and steatotic liver disease (SLD).

STEATOSIS AND HBV ACTIVITY: AN INVERSE CORRELATION

There is no evidence that HBV infection itself directly confers excessive risk of steatosis. Nonetheless, increased hepatic steatosis was associated with reduced HBV DNA production and an increased likelihood of HBsAg seroclearance. The lower serum levels of HBV DNA, decreased hepatitis B e antigen (HBeAg) positivity and higher HBsAg seroclearance rate were observed in CHB-SLD patients. Moreover, the positivity of intrahepatic hepatitis B core antigen (HBcAg) and HBsAg was lower in treatment-naïve CHB-SLD patients [11]. A recent meta-analysis further demonstrated a negative correlation between HBV viral activity and hepatic steatosis [5]. Approximately 30% of CHB patients had hepatic steatosis, which was negatively associated with serum HBeAg and HBV DNA [5].

The quantitative demonstration of the inverse relationship between HBV viremia and hepatic steatosis was shown in treatment-naïve CHB patients. Individuals with hepatic steatosis, quantified by controlled attenuation parameter (CAP) measurements [12], exhibited a lower HBV viral load in a dose-dependent manner, demonstrating an independent negative correlation with hepatic steatosis and serum HBV DNA levels. Routine bedside quantification assessment of hepatic steatosis can also provide prognostic value in virologically quiescent CHB patients since fibrosis progression remains a risk for those patients with persistent severe steatosis [13].

Mechanisms of interaction between CHB and steatosis

Mechanistic role of hepatic steatosis in CHB

There have been several studies describing potential mechanistic pathways of steatosis impacting CHB (Fig. 1). Toll-like receptor 4 (TLR4) is a vital cell surface receptor essential for initiating innate immune responses, and its specific ligand inhibits HBV replication in vivo [14]. Saturated fatty acids have been shown to suppress HBV replication in CHB patients with concomitant MASLD by activating the TLR4 signalling pathway [15]. Another potential pathway is via the suppression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which can inhibit HBV replication. PGC-1α is a transcription factor crucial for gluconeogenesis, but its expression is diminished in MASLD. Consequently, the metabolic changes triggered by MASLD hinder HBV replication by downregulating PGC-1α expression [16]. Elevated levels of the death receptor-Fas on hepatocytes could trigger steatosis-induced apoptosis, potentially causing the loss of HBsAg and contributing to viral clearance [17]. Besides, reducing the level of adiponectin has been shown to inhibit HBV replication. It has been demonstrated in the in vitro study that adiponectin can enhance viral replication. However, the use of small interfering RNAs targeting adiponectin can prevent this enhancement [18], as supported by a prospective study indicating a correlation between elevated adiponectin levels and increased HBV viral load [19]. Furthermore, steatosis in hepatocytes inhibits the secretion of HBV DNA and HBsAg by activating endoplasmic reticulum (ER) stress [20].

Figure 1.

Mechanisms of interaction between hepatitis B and steatosis. The interaction between CHB and liver steatosis involves complex mechanisms. Liver steatosis can inhibit HBV replication through several pathways, including the induction of endoplasmic reticulum (ER) stress, activation of Toll-like receptor 4 (TLR4), and suppression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, increased apoptosis of hepatocytes via the Fas receptor and the suppression of adiponectin, which can enhance HBV replication, contribute to reduced HBV activity in the presence of steatosis. Conversely, HBV itself can promote liver steatosis through the action of the HBx protein, which induces lipid accumulation in liver cells and also inhibits apoptosis. Additionally, HBV interferes with bile acid uptake via sodium taurocholate co-transporting polypeptide (NTCP), further contributing to steatosis. CHB, chronic hepatitis B; HBV, hepatitis B virus; HBx, HBV X; HBc, HBV core. Created with BioRender.com.

Mechanistic role of the HBV genome in hepatic steatosis

The presence of the HBV X (HBx) gene is a risk factor for steatosis in CHB patients and HBx overexpression leads to lipid accumulation. HBx modulates hepatic lipid metabolism by influencing the lipogenesis via traperoxisome proliferator-activated receptor gamma and sterol regulatory element-binding protein 1 [21]. It has been demonstrated that HBx upregulates the expression of fatty acid-binding protein 1, leading to intrahepatic lipid accumulation and facilitating the progression of steatosis in HBV-infected cells [22].

Other HBV genomes may also play a role in steatosis. During chronic infection, the HBV core (HBc) gene may protect infected hepatocytes from Fas-induced apoptosis via increasing antiapoptotic receptor form and decreasing the levels of the proapoptotic Fas form [23]. Moreover, the pre-S1 domain of the HBV envelope binds to sodium taurocholate co-transporting polypeptide (NTCP), the hepatic bile acid transporter [24], reducing its ability to transport bile acid into hepatocytes, which results in elevated bile acid production, cholesterol supply, and hepatic steatosis [25].

MECHANISMS OF MASLD-ASSOCIATED HCC AND CIRRHOSIS DEVELOPMENT

MASLD is initiated by the accumulation of fat in the liver, driven by insulin resistance, with inflammation as a critical hallmark that accelerates disease progression [26]. When fatty acid disposal through beta-oxidation or triglyceride formation is overwhelmed, excess fatty acids contribute to the formation of lipotoxic species, leading to ER stress and inflammasome activation. These mechanisms collectively result in inflammation, hepatocellular injury, stellate cell activation, and progressive accumulation of extracellular matrix, culminating in fibrosis, cirrhosis, and HCC [27,28].

MASLD is a multifactorial disease also influenced by a combination of host genetics, epigenetics, gut microbiota, and microbial metabolites. These factors do not act independently; rather, they interact and influence one another throughout the development and progression of MASLD. Imbalance in microbial metabolites, such as branched-chain amino acids, bile acids, short-chain fatty acids, trimethylamine and endogenous ethanol, has a strong link with development of MASLD and HCC [29-31]. In addition to these metabolites, bacterial antigens such as lipopolysaccharide (LPS) [32,33], peptidoglycan [29], flagellin [34,35], and polysaccharide A [36], as well as bacterial DNA in the liver have a close relationship with MASLD disease progression [37]. These factors together lead to intrahepatic lipid accumulation, persistent inflammation, and progression to MASLD-related HCC.

Due to improvements in surveillance strategies for viral hepatitis, the rising prevalence of obesity and metabolic syndrome has positioned MASLD as a dominant driver of HCC in numerous instances [38]. Although approximately half of HCC patients have MASLD, only 12% of HCC cases occur in individuals with MASLD as the sole liver disease [39]. Nevertheless, MASLD frequently serves as a cofactor in individuals with other liver disease etiologies, highlighting its broad role in the pathogenesis of HCC.

MECHANISMS OF HBV-ASSOCIATED HCC AND CIRRHOSIS DEVELOPMENT

Since HBV does not directly cause cellular damage, it is hypothesized that host immune responses targeting virus-infected hepatocytes are pivotal in liver cell damage. Prolonged liver inflammation and insufficient immune-mediated viral clearance are critical contributors to the advancement to cirrhosis and liver cancer.

Roles of HBV genome integration

One of the main causes of HBV-related HCC is the integration of the HBV genome into the genome of host hepatocytes. According to whole-genome sequencing, it was present in 80–90% of cases of HCC and in ~30% of non-HCC adjacent liver tissue, with this integration appearing before the occurrence of HCC [40]. It is worth noting that about 70% of Asian patients with HCC and occult HBV infection (OBI) have HBV DNA integration primarily affecting the HBx and preS/S domains [41]. In HCC patients with OBI, the HBV DNA integration correlates with alterations in telomerase reverse transcriptase gene activation, p53 gene mutations, tumor suppressor genes, and genomic instability [42,43].

Roles of HBV-encoded proteins

HBsAg, HBeAg, DNA polymerase, and the HBx protein are synthesized from mRNA transcripts originating from covalently closed circular DNA (cccDNA) and/or integration into the host genome from HBV DNA. It has been documented that the IL-6-STAT3 pathway, which is activated by HBsAg, increases the malignant potential of HBV-related HCC [44]. On the other hand, HBeAg has been linked to the host’s immune response and cytokine production, thereby contributing to HBV-related HCC [45]. Studies indicate that liver-specific transgenic mice expressing the reverse transcriptase domain of HBV polymerase have a tendency to develop early cirrhosis with concurrent steatosis, with approximately 10% eventually advancing to HCC [46]. Additionally, numerous studies highlighted the involvement of the HBx protein in hepatocarcinogenesis [21,47-49]. Several transcription factors can be activated by HBx, such as STAT3, NF-κβ, PI3K/AKT, leading to hepatocyte inflammation, proliferation, and apoptosis, ultimately contributing to the development of HCC [50,51]. Moreover, C-terminal truncated HBx protein plays an oncogenic role by affecting glycolysis, cell cycle, and mTORC1 signalling pathways in HCC [52].

Roles of Inflammation

CHB triggers immune dysregulation through multiple mechanisms that contribute to HCC development [53,54]. Immune cells such as CD4+ T cells, natural killer cells, natural killer T cells, monocytes/macrophages, and hepatic stellate cells (HSCs) drive inflammation, promoting HCC progression [55]. Notably, two distinct subsets of CD8+ T cells are present in the liver: intrahepatic HBV-specific CD8+ T cells, which are associated with HBV control and viral clearance, and bystander CD8+ T cells, which are not HBV-specific but contribute to inflammation and hepatotoxicity [56,57]. On the other hand, immunosuppressive cells, including regulatory T cells, myeloid-derived suppressor cells, and Kupffer cells, potentially act as negative regulators on HCC by releasing IL-10 and TGF-β, potentially acting as negative regulators of HCC [58,59]. The persistent immune-mediated liver damage in CHB often leads to cirrhosis, which is a key precursor to HCC.

The involvement of epigenetic mechanisms

A crucial role of epigenetic mechanisms has been reported in HBV-associated HCC. MicroRNAs (miRNAs), in terms of noncoding RNAs, modulate their target genes post-transcriptionally. HBV encourages the development of HCC by activating multiple signalling pathways through various miRNAs. Certain miRNAs that participate in the TLR signalling pathways play a crucial role in the innate immune response to HBV infection [60]. HBV may affect the expression of miRNAs and inflammatory cytokines. Additionally, HBV can induce changes in DNA methylation [61] as well as post-translational modifications of histones [62], resulting in epigenetic alterations that are essential in the progression of HBV-related HCC.

Roles of gut microbiome

The gut microbiome mediates immune responses to HBV. In adult mice, the maturation of the gut microbiota stimulates liver immunity, leading to rapid HBV clearance. Conversely, when the gut microbiota is sterilized with antibiotics, this rapid clearance is prevented [63]. Patients with HBV-related HCC and non-viral HCC exhibit varying levels of bacteria associated with distinct functions or biological pathways [64]. Moreover, dysbiosis and impaired intestinal permeability cause increased hepatic exposure to and microbiota-associated molecular patterns (MAMPs). Bacterial MAMPs, such as TLR4 agonist LPS and TLR2 agonist lipoteichoic acid, stimulate hepatic HSCs activation and fibrosis, as well as macrophages, inducing inflammatory responses that promote the development of HCC [65].

MECHANISMS OF HCC AND CIRRHOSIS DEVELOPMENT IN CONCURRENT SLD AND CHB

The increased risks of HCC and cirrhosis in SLD-CHB patients

The relationship between concurrent SLD and CHB in the development of cirrhosis and HCC is complex and not fully understood. Although both SLD and CHB are well-established risk factors for HCC, whether their co-occurrence leads to a higher risk of disease progression than CHB alone remains inconclusive. More recent studies have shown the increased risks of HCC and cirrhosis in SLD-CHB patients (Table 1). Several studies with conflicting results [66,67] possibly due to the heterogeneity of the study populations. Patients with CHB who meet the criteria for liver biopsy tend to have more severe disease, representing a minority within the broad spectrum of CHB and SLD, which may contribute to the diverse outcomes observed [68,69].

Table 1.

The increased risks of disease progression in CHB patients with concurrent steatotic liver disease

Severe steatosis, in contrast to mild/moderate steatosis, was linked to a higher proportion of severe fibrosis in patients with CHB (23.2% and 12.6%, respectively, P=0.005) [12]. A study also showed that co-existing SLD in patients with CHB leads to a higher likelihood of a functional cure from HBV but worsening liver fibrosis [13]. Severe steatosis, quantified by CAP measurements, is associated with severe fibrosis in both treatment-naïve and treated CHB patients [70]. Based on a meta-analysis that included 34 studies with a total of 68,268 CHB patients, positive associations were found between hepatic steatosis and cirrhosis (odds ratio [OR] 1.52) and HBsAg seroclearance (OR 2.22) [71]. Notably, hepatic steatosis was linked to higher odds of HCC (OR 1.59), while there was no significant correlation among patients receiving nucleos(t)ide analogues (OR 1.05). Co-existing steatohepatitis with CHB leads to more advanced fibrosis and poorer liver-related outcomes or death, compared to CHB alone [72]. MASLD is an independent risk factor for developing HCC in CHB patients [73,74]. A research study utilizing data from the South Korean National Health Insurance System database discovered that, even after accounting for factors such as age, sex, antiviral treatment, alcohol consumption and cirrhosis, CHB patients with MASLD had a 1.4 times higher risk of HCC development [75].

Furthermore, in the majority of analyses, hepatic steatosis and other systemic metabolic dysfunctions have not been distinguished, thus highlighting the combined impact of these two distinct factors on CHB patients. Different combinations of hepatic steatosis and metabolic factors are associated with varying levels of cirrhosis risk. Hepatic steatosis alone was associated with a lower risk of cirrhosis (adjusted hazard ratio [aHR] 0.57 within 5 years); however, when hepatic steatosis occurred in individuals meeting the diagnostic criteria for MASLD, the risk of cirrhosis was higher [76]. Moreover, hepatic steatosis and metabolic dysfunction had distinct impacts on HCC: steatosis protected HCC (aHR 0.45), while an increasing burden of metabolic dysfunction elevated the risk (aHR 1.40 per additional dysfunction) [77].

HBsAg seroclearance

Functional cure of CHB, i.e., HBsAg seroclearance, only occurs in a small percentage of patients. Nonetheless, its chances are increased with the concomitant presence of steatosis [13,66,71,78], and may also explain why the inverse relationship between steatosis and the progression to cirrhosis and HCC was demonstrated in certain studies [79]. The exact mechanism behind the association between HBsAg seroclearance and hepatic steatosis is still unknown. One hypothesis is that the accumulation of fat in hepatocytes may alter the distribution of HBsAg within the cytoplasm, an increase in the death receptor-Fas may lead to steatosis-induced apoptosis of hepatocytes, which in turn could result in loss of HBsAg. The disruption of immune homeostasis, which is characteristic of both CHB and SLD, plays a crucial role in liver disease progression to HCC [80]. While HBV is typically not viewed as a cytopathic virus per se, hepatocellular damage can be induced by triggering immune responses within the HBV-infected hepatocytes [17,81]. The clearance of HBsAg is linked to a significant decrease in the likelihood of cirrhotic complications and HCC [82]. It remains to be investigated through further studies the extent to which the risk of such liver-related outcomes persists following HBsAg clearance in patients with hepatic steatosis. Metabolic determinants may play a role; suboptimal glycemic control has been demonstrated as a risk factor for HCC after HBsAg seroclearance [83].

Possible mechanisms of CHB-SLD interplay leading to disease progression

Several proposed mechanisms suggest that the presence of SLD promotes CHB-related disease progression. Fat deposition, lipotoxicity, low-grade inflammatory responses and oxidative stress in SLD may create a pro-fibrotic as well as a pro-carcinogenic environment, accelerating the progression of CHB-related cirrhosis and HCC [84-88]. CHB may influence metabolic changes, contributing to the development of SLD, while HBV-induced inflammatory responses and molecular pathways could exacerbate hepatic steatosis. Interestingly, CHB has been associated with a decreased risk of hyperlipidemia and a lower prevalence of steatosis, potentially due to elevated serum adiponectin levels [89], while HBV infection might also induce hepatic lipid accumulation via HBx overexpression and genetic susceptibility to steatosis in CHB patients.

Several underlying mechanisms are outlined (Fig. 2), even if the precise mechanisms of SLD in CHB-related disease progression are yet unknown: (1) DNA methylation: Loss of global DNA methylation, a common epigenetic modification, can lead to chromosomal abnormalities and disease progression [90]. Patients with concurrent SLD and CHB exhibit lower global DNA methylation levels compared to those with SLD alone, correlating with fibrosis and cirrhosis [91]. (2) Alterations of immune microenvironment: Immune homeostasis imbalance in CHB and SLD, characterized by disrupted immune cell function due to dysregulated lipid metabolism or HBV-mediated immunosuppression, can impair anti-tumor immunity and promote liver cancer progression [80,81,92]. (3) Genetic susceptibility: Genetic factors, such as single-nucleotide polymorphisms in PNPLA3 and TM6SF2 [93,94], are associated with steatosis and inflammation in CHB patients [95], suggesting a genetic predisposition to steatosis in this population. (4) Direct oncogenic mechanisms: Genomic instability due to HBV DNA integration into the host genome can increase oncogenic potential [40]. HBV-encoded proteins (e.g., HBx, HBc) contribute to cellular heterogeneity and tumorigenesis through various mechanisms, including stabilizing oncoproteins, inducing ER stress, and causing DNA damage [96,97]. Excessive lipid accumulation exacerbates these processes, further promoting liver cancer development [98].

Figure 2.

Potential mechanisms of interaction between steatosis and CHB in the development of cirrhosis and HCC. HBV-infected hepatocytes are believed to mediate liver cell injury and, with long-term chronic liver inflammation and ineffective immune-mediated viral clearance, lead to activation and proliferation of hepatic stellate cells. Fat deposition and oxidative stress may create a pro-fibrotic and procarcinogenic environment within the liver. In addition, abnormal lipid metabolism, gene susceptibility, and lower levels of global DNA methylation in patients with concurrent NAFLD and CHB could both accelerate the development of cirrhosis and HCC. CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NTCP, sodium taurocholate co-transporting polypeptide; ROS, reactive oxygen species; pgRNA, pregenomic RNA; cccDNA, covalently closed circular DNA; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; MAMPs, metabolites and microbiota-associated molecular patterns; LPS, lipopolysaccharide; ER, endoplasmic reticulum; TLR4, toll-like receptor 4; HCSs, hepatic stellate cells. Created with BioRender.com.

It is crucial to highlight that there are currently no robust in vitro or in vivo models specifically designed to study the interplay between steatosis and HBV. This limitation is partly due to the fact that existing HBV mouse models do not fully replicate the complete life cycle of HBV, particularly the formation of cccDNA [99]. While human liver chimeric mice and chimpanzees can exhibit a disease spectrum similar to that of humans, ethical concerns, high costs, and technical challenges associated with setting up these models make their practical application in this field unfeasible [100]. As a result, all available evidence provides only a partial understanding of the complex underlying mechanisms of the interplay between steatosis and CHB, especially regarding the pathogenesis of HCC and cirrhosis.

UNANSWERED QUESTIONS AND FUTURE DIRECTIONS

The interplay between CHB and concurrent steatotic liver diseases presents significant challenges in managing liver disease progression. While hepatic steatosis may offer some protective effects against HBV replication, the long-term risks of cirrhosis and HCC in patients with both CHB and SLD require further investigation. Since the updated WHO guidelines [101] expand eligibility for treatment if there is the presence of MASLD, understanding the mechanisms underlying CHB and SLD interactions is crucial for developing targeted therapies and improving patient outcomes.

The potential suppression of viral activity by concurrent steatosis raises important questions. Specifically, whether simple steatosis (without other systemic metabolic dysfunction) is tolerable or even beneficial in certain populations, such as CHB patients, warrants more clinical studies. Additionally, the impact of therapeutic agents for MASLD on the disease course and prognosis of CHB remains unclear due to their exclusion from clinical trials. Future real-world studies and post-marketing clinical trial data are needed to address this gap.

Antiviral treatment with nucleos(t)ide analogues has been connected to fibrosis regression, but hepatic steatosis and metabolic syndrome are linked to fibrosis progression [102]. It has been documented [103] that the association between HBV DNA levels and HCC risk follows a nonlinear parabolic pattern, with the highest risk observed at moderate serum HBV DNA levels in treatment-naïve CHB patients. Persistent HBV DNA levels within a range of 4–8 log10 IU/mL in HBeAg-positive patients continue to drive clonal hepatocyte expansion, which accumulates hepatocyte damage and increases HCC risk. This risk is elevated in cases of long-term inflammation and ineffective immune clearance, contributing significantly to cirrhosis and HCC development. When immune control of HBV is achieved, HBeAg seroclearance may occur, and serum HBV DNA levels typically drop below 4 log10 IU/mL (inactive hepatitis phase), thus reducing HCC risk substantially. Patients who achieve HBsAg seroclearance show a time-dependent decline in liver stiffness over a decade [104]. Despite MASLD being associated with a lower HBV viral load and increased rates of HBsAg clearance, the combined effects of CHB and MASLD may synergistically accelerate liver disease progression, leading to hepatocyte injury, inflammation, fibrosis, and HCC. These findings underscore the importance of prioritizing antiviral treatment for chronic viral hepatitis before addressing MASLD [105]. Early initiation and proactive antiviral therapy may yield different outcomes for CHB patients with hepatic steatosis. A strong correlation between severe steatosis and advanced fibrosis has been reported in both treatment-naïve and treated CHB patients [70]. However, this association is less pronounced in those receiving early, potent antiviral therapy [106]. Long-term antiviral therapy, such as the use of nucleos(t)ide analogues, effectively suppresses HBV replication and slows fibrosis progression, including in patients with coexisting hepatic steatosis [107]. Further in vitro or in vivo research is essential to clarify the complex interactions between HBV and SLD in disease progression, determine the most effective therapeutic strategies, and ultimately improve long-term outcomes for affected patients.

CONCLUSION

The interplay between CHB and concurrent SLD presents a complex and evolving challenge. This review highlights the intricate balance between the potential protective effects of steatosis against HBV replication and the increased risks of cirrhosis and HCC in patients with co-existing conditions. While hepatic steatosis may be associated with lower HBV viral load and a higher rate of HBsAg seroclearance, the synergistic effects of HBV and SLD may accelerate liver disease progression, underscoring the need for careful clinical management. Current evidence suggests that antiviral therapy with nucleos(t)ide analogues is crucial for reducing fibrosis and improving liver stiffness in CHB patients. However, the role of hepatic steatosis in modifying the course of HBV-related liver disease, particularly in terms of fibrosis progression and cancer risk, requires further investigation. The potential impact of emerging treatments for MASLD on HBV-related outcomes is another area that warrants more focused research.

Notes

Authors’ contribution

S Zhang: Conceptualization, literature review, writing and original draft preparation; LY Mak: Review, critical revision; MF Yuen: Review, critical revision, final approval of published version; WK Seto: Review, critical revision, final approval of published version.

Conflicts of Interest

MF Yuen is an advisory board member and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals; and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation and Sysmex Corporation. WK Seto received speaker’s fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and research fund from Gilead Sciences. The remaining authors have no conflicts to disclose.

Abbreviations

aHR

adjusted hazard ratio

CAP

controlled attenuation parameter

cccDNA

covalently closed circular DNA

CHB

chronic hepatitis B

endoplasmic reticulum

HBc

HBV core

HBcAg

hepatitis B core antigen

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HBx

HBV X

HCC

hepatocellular carcinoma

HSCs

hepatic stellate cells

LPS

lipopolysaccharide

MAMPs

microbiota-associated molecular patterns

MASLD

metabolic dysfunction-associated steatotic liver disease

miRNAs

microRNAs

NTCP

sodium taurocholate cotransporting polypeptide

OBI

occult HBV infection

odds ratio

PGC-1α

proliferator-activated receptor gamma coactivator 1-alpha

SLD

steatotic liver disease

TLR

toll-like receptor

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Study	SLD diagnosis	Viral suppression	Disease progression
Study	SLD diagnosis	Viral suppression	Cirrhosis	HCC
Aggravation
1,202 CHB patients in a 1:1 ratio with or without steatosis [12]	VCTE	Lower median serum HBV DNA levels	Severe steatosis was associated with an increased percentage of severe fibrosis in both treatment-naïve and treated patients.	/
330 treatment-naïve patients with CHB [13]	VCTE	HBsAg seroclearance	Persistent severe hepatic steatosis was independently associated with fibrosis progression (OR 2.379).	/
606 patients with CHB [70]	VCTE	/	Severe steatosis was associated with severe fibrosis in treatment-naïve patients (OR 3.60) and treated patients (OR 1.95 for ≥3 years of treatment, 2.28 for ≥5 years of treatment, and 2.79 for ≥7 years of treatment).	/
A meta-analysis of 34 studies with 68,268 CHB patients [71]	VCTE/biopsy-proven steatosis	HBsAg seroclearance (OR, 2.22)	Steatosis was associated with the development of cirrhosis (OR 1.52).	Hepatic steatosis was associated with higher odds of HCC (OR 1.59)
A multicenter study of 1,089 CHB patients [72]	Biopsy data	/	/	Patients with concomitant steatohepatitis and CHB had more advanced fibrosis and shorter time to develop liver-related outcomes or death compared to patients with CHB alone.
197,346 CHB participants from National Health Insurance System database in South Korea [75]	MASLD criteria	/	/	The risk of developing HCC was 1.4-fold higher in CHB patients with MASLD
11,502 CHB patients [76]	MASLD criteria	Lower HBV DNA levels	Hepatic steatosis occurred in individuals meeting the diagnostic criteria for MASLD, the risk of cirrhosis was higher	/
10,546 treatment-naïve CHB patients [77]	MASLD criteria	Fewer HBeAg positivity, lower HBV DNA levels	/	Hepatic steatosis with an increasing burden of metabolic dysfunction elevated the risk of HCC (aHR 1.40 per additional dysfunction).