In the era of effective antiviral therapy for chronic hepatitis B (CHB), the attention of hepatologists has gradually shifted from viral suppression alone to a broader picture of comorbidities and long-term outcomes. In a recent issue, the multinational cohort study by Huang et al. provided compelling evidence that metabolic comorbidities, particularly diabetes mellitus (DM), may serve as a significant determinant of prognosis in CHB patients with long-term nucleos(t)ide analogue treatment [
1]. By including over 4,500 CHB patients from the REAL-B consortium, the authors found that among various metabolic dysfunctions, DM emerged as the single most predictive factor, independently associated with the development of cirrhosis, hepatocellular carcinoma (HCC), and both liver-related and all-cause mortality. These findings not only align with the growing body of literature underscoring the adverse impact of metabolic dysfunctions on liver disease progression but also reinforce the urgent need for integrated care models to address control of both virological and cardiometabolic risk factors in CHB populations.
The pronounced prognostic value of DM in this study echoes prior lines of evidence demonstrating that glycemic abnormalities play a crucial role in shaping outcomes among treatment-naïve CHB patients. Beyond serving as a comorbidity, DM exerts a multifaceted impact on liver health [
2], accelerating fibrosis progression [
3,
4], increasing the risk of HCC [
4,
5], and elevating both liver-specific and extrahepatic mortality in CHB patients [
6]. Poor glycemic control was independently associated with worse hepatic outcomes [
4], reinforcing the notion that metabolic health not only significantly influences the natural history of CHB, but also in patients receiving effective antiviral therapy.
Given the accumulating evidence, routine surveillance for metabolic dysfunctions should be an integral component of CHB management. At a minimum, clinical protocols should include regular monitoring of glycemic and lipid profiles, blood pressure, and body mass index, along with timely interventions such as lifestyle modifications, pharmacological therapy, and multidisciplinary consultations [
7]. The mere presence or count of metabolic abnormalities may no longer suffice for accurate prognostication; instead, the type and severity of dysfunction, especially the presence of DM, should be prioritized in risk-stratification frameworks. This paradigm shift will be essential in redefining long-term management goals for patients with CHB in the antiviral era.
One of the intriguing findings in the study is the observation that hepatic steatosis alone may confer a protective effect against adverse outcomes. This counterintuitive association, manifested as reduced risks of cirrhosis, HCC, and liver-related mortality, aligns with earlier findings from our and other groups’ cohort studies, challenging the traditional viewpoint that all forms of steatosis are inherently deleterious for CHB patients [
3,
5,
6,
8-
12].
Several hypotheses have been proposed to explain this paradox. Clinical data indicated that steatotic liver disease (SLD) was inversely correlated with viral replication [
13], which may facilitate the functional cure of CHB [
14,
15]. Preliminary experimental data suggested that hepatic fat accumulation may suppress hepatitis B virus (HBV) replication through mechanisms such as endoplasmic reticulum stress [
16]. However, the mechanism(s) remain incompletely understood, and the net impact of steatosis may vary depending on the metabolic context in which it occurs. Previous studies highlighted the presence or absence of systemic metabolic dysfunctions significantly modified the prognostic relevance of steatosis. Thus, lumping hepatic steatosis together with cardiometabolic risk factors under umbrella terms like metabolic dysfunction-associated steatotic liver disease (MASLD) may obscure their distinct biological behaviors. Future investigations should disentangle the individual contributions of hepatic steatosis and systemic metabolic dysfunctions in CHB [
17]. A more granular stratification—distinguishing “simple” steatosis from MASLD—may enable better risk prediction, deepen mechanistic understanding, and ultimately guide more tailored management strategies in the CHB population.
The study by Huang et al. [
1] serves as a timely and important reminder that viral suppression alone is not sufficient to ensure optimal long-term outcomes in patients with CHB. As standard of care continues to evolve in the antiviral era, it is imperative that we should broaden our clinical focus to include the metabolic landscape of each patient. DM stands out as a modifiable determinant of prognosis that warrants routine screening and proactive management. Meanwhile, the complex and sometimes paradoxical role of SLD in CHB further underscores the need of precise phenotyping [
18].
Looking ahead, the future of CHB management lies in integrated, multidisciplinary care that unites hepatology with metabolic medicine, along with adequate patient education and system-level implementation strategies. Risk stratification tools should account not just for virological and hepatic parameters, but also for the type, severity, and control of metabolic dysfunctions. Meanwhile, research should continue to unravel the distinct mechanistic role of SLD and its interplay with HBV. Such efforts would be instrumental in moving us toward a truly personalized model of hepatology, addressing not only the virus, but also the broader host environment in which it resides.
FOOTNOTES
-
Authors’ contribution
SC Huang: drafting of the manuscript. JH Kao: critical revision for important intellectual content.
-
Acknowledgements
During the preparation of this work, the authors used Grammarly for English proofreading and editing. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
-
Conflicts of Interest
S.-C. H. was on speaker’s bureau for Gilead Sciences. J.-H. K. has served as a consultant for Abbvie, Abbott, Gilead Sciences, Roche, and Sysmex and on speaker’s bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Sysmex.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 1. Huang R, Jun DW, Toyoda H, Hsu YC, Trinh H, Nozaki A, et al. Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues. Clin Mol Hepatol 2025;31:1003-1017.
- 2. Huang SC, Kao JH. The interplay between chronic hepatitis B and diabetes mellitus: a narrative and concise review. Kaohsiung J Med Sci 2024;40:6-10.
- 3. Huang SC, Su TH, Tseng TC, Liao SH, Hsu SJ, Hong CM, et al. Pre-existing and new-onset metabolic dysfunctions increase cirrhosis and its complication risks in chronic hepatitis B. Am J Gastroenterol 2025;120:401-409.
- 4. Mak LY, Hui RW, Lee CH, Mao X, Cheung KS, Wong DK, et al. Glycemic burden and the risk of adverse hepatic outcomes in patients with chronic hepatitis B with type 2 diabetes. Hepatology 2023;77:606-618.
- 5. Huang SC, Su TH, Tseng TC, Chen CL, Hsu SJ, Liao SH, et al. Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B. Hepatol Int 2023;17:1139-1149.
- 6. Huang SC, Su TH, Tseng TC, Hsu SJ, Hong CM, Lan TY, et al. All-cause and cause-specific mortality in patients with chronic hepatitis B and concurrent steatotic liver disease. J Hepatol 2025;83:43-51.
- 7. Huang SC, Liu CJ. Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: challenges and perspectives. Clin Mol Hepatol 2023;29:320-331.
- 8. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Li B, et al. Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection. Hepatol Int 2021;15:901-911.
- 9. Oh JH, Lee HW, Sinn DH, Park JY, Kim BK, Kim SU, et al. Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. Hepatol Int 2021;15:892-900.
- 10. Li J, Yang HI, Yeh ML, Le MH, Le AK, Yeo YH, et al. Association between fatty liver and cirrhosis, hepatocellular carcinoma, and hepatitis B surface antigen seroclearance in chronic hepatitis B. J Infect Dis 2021;224:294-302.
- 11. Hsueh RC, Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, et al. Impact of PNPLA3 p.I148M and hepatic steatosis on long-term outcomes for hepatocellular carcinoma and HBsAg seroclearance in chronic hepatitis B. J Hepatocell Carcinoma 2022;9:301-313.
- 12. Wong YJ, Nguyen VH, Yang HI, Li J, Le MH, Wu WJ, et al. Impact of fatty liver on long-term outcomes in chronic hepatitis B: a systematic review and matched analysis of individual patient data meta-analysis. Clin Mol Hepatol 2023;29:705-720.
- 13. Hui RWH, Seto WK, Cheung KS, Mak LY, Liu KSH, Fung J, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study. J Viral Hepat 2018;25:97-104.
- 14. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Cheung KS, et al. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B. J Hepatol 2020;73:800-806.
- 15. Huang SC, Su TH, Tseng TC, Chen CL, Hsu SJ, Liu CH, et al. Metabolic dysfunction-associated steatotic liver disease facilitates hepatitis B surface antigen seroclearance and seroconversion. Clin Gastroenterol Hepatol 2024;22:581-590.e6.
- 16. Liu Q, Mu M, Chen H, Zhang G, Yang Y, Chu J, et al. Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress. Mol Cell Biochem 2022;477:2481-2491.
- 17. Huang SC, Su TH. Divergent roles of MASLD components in chronic hepatitis B: A double-edged sword. J Hepatol 2025;83:e34-e35.
- 18. Huang SC, Liu CJ, Kao JH. Impact of metabolic disorders on chronic hepatitis B. Clin Liver Dis (Hoboken) 2024;23:e0130.
Citations
Citations to this article as recorded by
- Advancing metabolic risk profiling in chronic hepatitis B: Reply to correspondence on “Metabolic health in antiviral era of chronic hepatitis B”
Shang-Chin Huang, Jia-Horng Kao
Clinical and Molecular Hepatology.2026; 32(1): e117. CrossRef - Correspondence to editorial 1 on “Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues”
Rui Huang, Mindie H. Nguyen
Clinical and Molecular Hepatology.2026; 32(1): e83. CrossRef
