Epidemiology, natural history, and management of patients with CHB concurrent with MASLD

Chronic hepatitis B (CHB) has long been a principal etiology that contributes to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Meanwhile, the global prevalence of non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), is rapidly increasing. In Asia, an area endemic to hepatitis B virus (HBV), the prevalence of NAFLD has reached 29.62%,¹ rendering a heavier health burden. The coexistence of CHB and MASLD is becoming increasingly common, and the relationship within the 2 diseases is complex. Of note, different terms have been used to describe fatty liver in previous studies, including hepatic steatosis (HS), NAFLD, or MASLD. These discrepancies arise from changes in nomenclature (Table 1) and variations in diagnostic methods in population-based studies. In this review, we discuss issues regarding epidemiology, natural history, and potential strategies for managing patients with CHB with MASLD, and previous concepts were retained, adhering to original articles.

TABLE 1.

Different concepts of fatty liver

Concept	Description/definitions
Hepatic steatosis/fatty liver	Fat accumulation in the liver
NAFLD	The presence of hepatic steatosis is detected by imaging or histology without secondary causes of hepatic fat accumulation.
NASH	The presence of ≥ 5% hepatic steatosis and inflammation with hepatocyte injury, with or without any fibrosis.
MASLD	The presence of hepatic steatosis concurrent with at least 1 cardiometablic risk factor and no other discernible cause.

Abbreviation: MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

PREVALENCE AND RISK FACTORS OF PATIENTS WITH CHB WITH MASLD

The significant overlap between CHB and HS has been well-documented. A meta-analysis reported that 32.83% of patients with CHB worldwide were affected by HS, with a prevalence of 30.98% from 1997 to 2007, increasing to 35.92% from 2008 to 2016.² A recent study focusing on the Asia CHB population found that the overall proportion of HS was 36.5%, with the highest proportion of 47.9% in Malaysia and the lowest proportion of 32.4% in Turkey.³

In the CHB population, various demographic, metabolic, and viral characteristics pose different risks of HS. Previous studies proved that male gender, body mass index, waist circumference, diabetes, metabolic syndrome, and dysregulated lipid metabolism were significantly associated with HS among patients with CHB.^2,3 A negative relationship has been observed between HS and HBeAg positive status as well as HBV DNA levels.^2,3 These findings suggest that metabolic factors, rather than viral factors, played a more prominent role in the development of MASLD among the CHB population.

THE UNCERTAINTY OF NATURAL HISTORY IN PATIENTS WITH CHB WITH MASLD

CHB and MASLD are vital contributors to the development of fibrosis, cirrhosis, and HCC. However, there is considerable inconsistency in the association between the coexistence of CHB and MASLD and the development of liver-related adverse outcomes (Table 2). Several factors potentially contribute to the conflicting results. First, the status of antiviral therapy for patients with CHB is a crucial factor. In treatment-naïve patients with CHB, the coexistence of HS was recognized as a significant factor associated with hepatic fibrosis progression, with a controlled attenuation parameter ≥ 280 dB/m identified as the only independent indicator linked with fibrosis progression.⁴ However, another retrospective cohort study showed that in patients with CHB who received antiviral therapy, the presence of fatty liver was an independent and strong variable associated with a diminished risk of cirrhosis and HCC after propensity score matching, whereas this finding was not observed in untreated patients with CHB.⁵ It was supposed that the viral activity was less active, and the HBV viral load was lower in patients with CHB who received antiviral therapy. In this population, the viral factor may not be the primary driver in the development of liver-related outcomes.

TABLE 2.

The association between the CHB population with or without FL and liver-related outcomes in population-based studies

Year	Author (Ref)	Study type	Country/area	Population	Antiviral therapy status	Overall sample size	Diagnostic method of FL	Main outcomes
2020	Mak et al4	Prospective	Hong Kong	Patients with CHB with HS	Treatment-naïve	330	CAP	HS was associated with fibrosis progression (OR: 2.379, p = 0.01), but a higher fold of HBsAg seroclearance (HR: 3.246, p = 0.013).
2020	Li et al5	Retrospective	United States, Taiwan	Patients with CHB with or without FL	35.13% and 31.79% in non-FL and FL group received antiviral therapy, respectivelya	2158a	Imaging (ultrasonography or CT)	Compared with patients with CHB without FL, those with FL had a lower cumulative 10-year incidence of cirrhosis (10.52% vs 15.47%, p = 0.0001), HCC (4.51% vs 6.48%, p = 0.06), and a higher rate of HBsAg seroclearance (16.19% vs 5.92%, p = 0.05).
2022	Huang et al6	Retrospective, cross-sectional	Mainland China	Patients with CHB with or without NAFLD/NASH	Treatment-naïve	1081	Liver biopsy	NASH was an independent predictor of significant fibrosis (OR, 2.53, p < 0.001) and severe fibrosis (OR, 1.83, p = 0.023), whereas the presence and degree of HS were not associated with the fibrosis stage (p > 0.05).
2021	Khalili et al7	Prospective	North America	Positive HBsAg adults with or without FL	Not on HBV therapy during study enrollment	421	Liver biopsy	Steatohepatitis was associated with a 1.50-fold and 2.89-fold risk of Ishak fibrosis score and advanced fibrosis, respectively, compared to patients with HS alone.
2021	Kim et al8	Longitudinal	Korea	Patients with CHB	14% of patients with normal ALT received antiviral therapyc	48,335	Fatty liver index	Patients with CHB with G1 and G2b FL had 1.48- and 1.96-fold increased risk of HCC, respectively, compared to patients without FL (p for trend < 0.001).
2021	Mak et al9	Prospective	Hong Kong	Patients with CHB with or without HS	57.1% of patients received antiviral therapy	2403	Transient elastography and CAP	Cumulative 48-month probability of HCC was 2.88%, 1.56%, and 0.71%, respectively for patients without steatosis, with mild-to-moderate steatosis, and severe steatosis (log rank: p = 0.01).
2023	Huang et al10	Retrospective	Taiwan	Patients with CHB with or without MASLD	Treatment-naïve	4084	Ultrasonography	The overall HBsAg seroclearance rates in the CHB-MASLD and CHB no-MASLD group were 17.6% and 9.8%, respectively. MASLD was an independent factor associated with HBsAg seroconversion (adjusted HR: 1.37, p = 0.049).

^aThe cohorts were matched after propensity score matching.

^bG1 and G2 were defined as 30 ≤ fatty liver index <6 0 and fatty liver index > 60, respectively.

^cThe upper limit of normal for ALT was defined as 40 IU/L for both males and females.

Abbreviations: ALT. alanine transaminase; CAP, controlled attenuation parameter; CHB, chronic hepatitis B; FL, fatty liver; HBV, hepatitis B virus; OR, odds ratio; HR, hazard ratio; HCC, hepatocellular carcinoma; HS, hepatic steatosis; MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Secondly, the heterogenous impact of MASLD on liver injury may be attributed to the different severity of fatty liver disease. A cross-sectional study from China, enrolling 1081 patients with CHB who were treatment-naïve, found that patients with concurrent non-alcoholic steatohepatitis (NASH) had 74.2% of significant fibrosis or severe fibrosis, significantly higher than the percentage of 38.8% in patients with CHB and nonalcoholic fatty liver.⁶ In a North American cohort of 420 patients who were HBsAg-positive, steatohepatitis was associated with a 1.50-fold and 2.89-fold risk of Ishak fibrosis score and advanced fibrosis, respectively, compared to patients with HS alone.⁷ These studies indicated that steatohepatitis rather than HS is a more important risk factor for the development of fibrosis.

Moreover, the content of HS influences the incident risk of liver-related adverse outcomes. A cohort study from Hong Kong showed that reduced controlled attenuation parameter was an independent risk factor for HCC incidence, with a 10 dB/m lower controlled attenuation parameter increasing the risk of HCC by 6%.⁹ Similarly, a meta-analysis of individual participants conducted by Lee SW et al¹¹ demonstrated that patients with NASH within low liver fat content group exhibited the highest incidence rate of decompensation and HCC compared to patients with NASH within the higher liver fat group. Low liver fat content was proved to be associated with the highest indication for the composite outcome of decompensation, HCC, and all-cause mortality.¹¹ The transition from simple HS to burnt-out NASH appeared to elevate the likelihood of liver-related events. One plausible explanation was that patients with lower fat content experienced more severe deterioration in liver structure, potentially leading to poorer outcomes.

What cannot be ignored is that the different detective methods of fatty liver can impact the accuracy of diagnosis and the evaluation of disease severity. Many studies used imaging techniques like ultrasonography to assess HS. The inevitability of inter-observer and intra-observer variability introduced bias. Furthermore, liver biopsy is the gold standard of diagnosis, but its invasive nature has limited its application in research. Consequently, the disease severity has variations in patients who received liver biopsy and those who did not. A recent individual patient meta-analysis proved that the overall incidence of HCC in patients with CHB and fatty liver was 5.2 per 1000 person-years, significantly lower than the incidence of 7.7 per 1,000 person-years in the group with CHB and no fatty liver.¹² While in the subgroup with fatty liver proven by liver biopsy, the pooled incidence of HCC was significantly higher in CHB-fatty liver patients compared to patients with CHB and no fatty liver.¹² It was assumed that patients selected for liver biopsy are usually considered to have a higher perceived risk for adverse outcomes. The results acquired from the liver biopsy cohort require careful interpretation.

Despite the uncertain impact of MASLD on fibrosis, cirrhosis, and HCC, evidence has shown that MASLD promotes HBsAg clearance. Huang SC et al¹⁰ consecutively enrolled 4084 patients with CHB, of whom 21.7% combined with MASLD. The authors showed that the corresponding 1-, 3-, and 5-year cumulative incidences of HBsAg seroclearance were 2.3%, 8.1%, and 12.0%, respectively, in the CHB-MASLD group, which were higher than the corresponding incidences of 1.2%, 3.7%, and 6.9% in the group with CHB and no MASLD. Further, compared to CHB patients with MASLD and 1-2 metabolic criteria, CHB patients with MASLD and ≥ 3 metabolic criteria had the highest HBsAg seroclearance rate.¹⁰ Under the proposed criteria of MASLD, HS was identified as one of the most significant factors in HBsAg loss.¹⁰ HBsAg seroclearance is an important marker for the functional cure of HBV infection. Several hypotheses have been proposed to elucidate the connection between fatty liver and HBsAg seroclearance. Metabolic factors in fatty liver, such as alterations in gluconeogenesis, may enhance antiviral responses through the activation of innate immunity. Additionally, fatty liver could potentially augment apoptosis in HBV-infected cells, thereby facilitating the clearance of HBsAg. However, the intricate mechanism beneath the 2 conditions remains to be explored.

THE MANAGEMENT IN PATIENTS WITH CHB WITH MASLD

The impact of MASLD on the responsiveness to antiviral therapy among individuals with CHB and MASLD remains uncertain. A previous retrospective study enrolling 555 patients with CHB who received oral antiviral therapy found no significant difference in the rates of complete viral suppression and biochemical response between the CHB-NAFLD group and the CHB no-NAFLD group during a 60-month follow up.¹³ NAFLD was not recognized as an independent factor affecting complete viral suppression and/or biochemical response outcomes.¹³ Nevertheless, a meta-analysis comprising 98 studies with 48,472 patients showed that patients with CHB with HS had a lower rate of virological response and alanine aminotransferase normalization compared to those with simple HBV-infected patients after 48 weeks of antiviral therapy.¹⁴

Currently, a lack of treatment options presents challenges in effectively managing patients with CHB concurrent with MASLD. While the impact of MASLD on liver-related outcomes is still inconclusive. The presence of metabolic components in the MASLD criteria, such as diabetes mellitus, undoubtedly increases the risk of cardiovascular disease and all-cause mortality. Therefore, it is crucial to implement appropriate interventions for patients with CHB with MASLD. Weight loss is the cornerstone of MASLD. Adopting a modified lifestyle that includes a balanced diet and regular exercise has shown positive effects in the alleviation of MASLD. Benefits were also observed in patients with CHB who modified their lifestyle.¹⁵ Nevertheless, the precise advantages of an improved lifestyle in patients with CHB with MASLD remain uncertain. Some medications, such as glucagon-like peptide 1 agonists and analogs of FGF-19, have demonstrated promising results in NASH resolution in clinical trials. Further studies are required to determine their efficacy in the CHB-MASLD population. In the context of CHB and MASLD, a multidisciplinary team is essential for controlling the viral load and managing metabolic risk factors. This approach not only aims to prevent the development of liver-related adverse events but also to reduce the incidence of cardiovascular disease and all-cause mortality.