The global landscape of chronic hepatitis B (CHB) has evolved significantly over the past few decades. With the advent of potent nucleos(t)ide analogues (NAs), achieving viral suppression has become possible for most patients, which has dramatically reduced the complications associated with active viral replication [
1]. However, despite this therapeutic success, CHB patients continue to face liver-related complications and mortality, indicating that factors beyond viral replication play a significant role in disease progression. In recent years, metabolic comorbidities have emerged as important cofactors in CHB progression [
2]. The prevalence of metabolic syndrome components—obesity, hypertension, dyslipidemia, and diabetes mellitus—has risen dramatically worldwide, including among CHB patients [
3]. Understanding how these metabolic factors interact with CHB in the era of effective antiviral therapy is crucial for optimizing patient care [
4].
The multinational study by Huang et al. provides valuable insights into this important clinical question. By analyzing data from 4,500 NA-treated CHB patients across 30 centers in seven countries, the authors have delivered robust evidence on the differential impact of various metabolic components on long-term outcomes [
5]. The study’s most important finding is that diabetes is consistently associated with adverse outcomes across all endpoints—cirrhosis, hepatocellular carcinoma (HCC), overall mortality, liver-related mortality, and non-liver-related death—with hazard ratios ranging from 2.0 to 3.8. This finding contrasts with other metabolic components, which showed less consistent or weaker associations with liver-specific outcomes. The message is clear: not all metabolic disturbances carry equal risk in CHB patients, and diabetes deserves special attention. These findings align with recent research demonstrating that diabetes acts as a multiplier of risk in chronic liver diseases. Mak et al. showed that not only diabetes diagnosis but also glycemic burden and glycemic control significantly impact adverse hepatic outcomes in CHB patients [
6]. At the molecular level, diabetes may contribute to adverse outcomes through mechanisms like hyperglycemia and hyperinsulinemia that accelerate fibrosis progression and carcinogenesis, potentially synergizing with HBV-induced oncogenic pathways [
7].
While diabetes and hepatic steatosis often coexist, they seem to have different effects on liver outcomes in CHB patients. Diabetes primarily contributes to metabolic dysfunction through systemic insulin resistance and hyperglycemia, resulting in a pro-inflammatory state that accelerates liver injury. Patients with diabetes exhibit a higher incidence of abnormal hepatic function, which includes conditions like hepatic steatosis, steatohepatitis, fibrosis, and cirrhosis [
8]. However, hepatic steatosis as an isolated finding represents fat accumulation in the liver that may not necessarily correlate with systemic metabolic dysfunction. The presence of steatosis alone, without metabolic dysfunction, may not have the same detrimental effects on liver-related outcomes in CHB patients [
9]. Similar observations have been reported in chronic hepatitis C, where a multicenter study demonstrated that diabetes mellitus significantly inhibited fibrosis regression following direct-acting antiviral therapy, while hepatic steatosis alone was not significantly associated with fibrosis regression [
10].
An intriguing aspect of Huang’s study is the relationship between hepatic steatosis and liver outcomes in CHB patients. The authors found that hepatic steatosis was associated with a lower risk of cirrhosis, HCC, and liver-related death. This finding suggests a complex interplay between fat accumulation and CHB progression [
5]. The authors carefully accounted for this potential confounder by matching for hepatic steatosis in their propensity score matching analysis. Furthermore, they performed sensitivity analyses excluding patients with hepatic steatosis and found consistent results regarding the negative impact of diabetes on long-term outcomes. This indicates that the effect of diabetes on adverse outcomes is likely independent of hepatic steatosis. These findings align with the recent studies that described distinct effects of hepatic steatosis and metabolic dysfunction on HCC risk in CHB, highlighting the importance of metabolic health beyond simple fat accumulation [
11,
12]. The observed protective effect of steatosis alone, in contrast to the detrimental effects of metabolic dysfunction (notably diabetes), constitutes a significant area for further research.
The clinical ramifications of these findings are substantial. They underscore the necessity of diabetes screening for all CHB patients, irrespective of cirrhosis status. Second, they propose that diabetes prevention and optimal glycemic control should be essential elements of CHB management. Third, they emphasize the necessity of a multidisciplinary approach to CHB care that integrates expertise from hepatology and endocrinology. Healthcare providers must implement routine screening for metabolic abnormalities in CHB patients to reduce adverse outcomes and tailor treatment plans accordingly [
13]. For patients with concurrent diabetes, regular surveillance for HCC is imperative due to the synergistic effect on HCC risk evidenced in the study by Huang et al. [
5].
Future research should investigate whether intensive diabetes management improves outcomes in CHB patients. Recent studies indicate that antidiabetic medications may have hepatoprotective effects; however, prospective interventional studies focused on CHB populations are necessary [
14]. Examining the molecular mechanisms through which diabetes hastens liver disease progression in CHB may reveal novel therapeutic targets. The interplay between viral factors and metabolic abnormalities establishes a complex pathophysiological milieu in which steatosis may influence immune responses and modify the progression of HBV infection [
15]. It is essential to enhance our comprehension of the biological mechanisms underlying the intricate interactions among HBV infection, hepatic steatosis, steatohepatitis, fibrosis, cirrhosis, and metabolic dysfunction, especially diabetes. Clarifying these relationships is crucial for precise risk stratification and the formulation of targeted interventions that tackle the fundamental causes of disease progression in CHB patients with concurrent metabolic disorders.
This study emphasizes that while controlling viral replication is essential, it is inadequate as we progress toward a more comprehensive approach to CHB management [
5]. The metabolic health of our patients, especially glycemic control, warrants equal consideration. By targeting both viral and metabolic factors, we may further improve long-term outcomes for patients with CHB in the era of effective antiviral therapy.
FOOTNOTES
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Authors’ contribution
All authors were responsible for the conceptualization, interpretation of data, drafting, and critical revision of the manuscript.
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Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
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Citations
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- Correspondence to editorial 2 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): e85. CrossRef
