Around 300 million people worldwide live with chronic hepatitis B (CHB). The primary goal of antiviral therapy is a functional cure, meaning the clearance of HBsAg and, in some cases, the development of protective antibodies (HBsAb). Studies have shown that prolonged use of nucleoside and nucleotide analogs (NUCs) following pegylated interferon (Peg-IFN) treatment significantly increases the likelihood of HBsAg loss.
Metabolic syndrome (MetS) combines abdominal obesity, insulin resistance, high blood pressure, and lipid metabolism disorders. MetS is linked to worse liver outcomes. Specifically, type 2 diabetes and hepatic steatosis increase the risk of cirrhosis and hepatocellular carcinoma, regardless of the underlying cause of liver disease.
Research indicates that MetS or type 2 diabetes delays the clearance of hepatitis B e antigen (HBeAg, a marker of active viral replication and high infectivity), even when viral load and antiviral therapy are taken into account. At the same time, fatty liver disease associated with metabolic dysfunction is linked to reduced viral activity and may improve treatment response in CHB patients. However, it also increases inflammation and fibrosis, raising the likelihood of severe complications, including liver cancer. In some patients, fatty liver disease is associated both with accelerated clearance of HBsAg — the primary marker of HBV infection — and with fibrosis progression.
It remains unclear how exactly metabolic syndrome affects HBsAg loss, particularly in HBeAg-negative patients with low HBsAg levels undergoing pegylated interferon (Peg-IFN) treatment. Another open question is how Peg-IFN therapy itself influences metabolic syndrome. Chinese researchers set out to clarify these relationships.
Study Design
The study included 758 CHB patients who had received NUC therapy for at least one year and had low HBsAg levels (<1500 IU/mL), HBeAg seroconversion, and undetectable viral DNA (<20 IU/mL). Patients with co-infections, autoimmune, metabolic, oncological, or other severe diseases were excluded from the study. Subsequent treatment involved Peg-IFN monotherapy or combination therapy at a dose of 180 µg weekly. The duration of treatment was not fixed: once HBsAg levels dropped below 0.05 IU/ml, patients received a consolidation course of Peg-IFN for 12–24 weeks. Patients were monitored every 12 weeks with clinical data collection and blood sampling for liver function, viral, and metabolic markers. Additionally, experiments using the HepG2.2.15 hepatoblastoma cell line were conducted to investigate the effects of IFN-α on lipid metabolism and the expression of viral proteins.
Metabolic Syndrome May Hinder HBsAg Clearance
Peg-IFN did not significantly affect blood glucose levels. However, the presence of diabetes and hyperglycemia reduced the probability of HBsAg clearance, aligning with data showing that metabolic syndrome and diabetes increase the risk of hepatocellular carcinoma and worsen liver disease outcomes. A possible mechanism involves hyperglycemia-induced activation of autophagy, which promotes HBV replication and impedes HBsAg clearance.
Peg-IFN Reduces HBsAg by Promoting Steatosis
Researchers found a correlation between liver steatosis, elevated lipid levels — particularly triglycerides — and the clearance of HBsAg.
Previous findings include:
- In some patients, steatosis was associated with accelerated clearance of HBsAg.
- HBsAg clearance was associated with a 1.41-fold increased risk of liver steatosis, and impaired glucose metabolism due to steatosis was particularly evident following HBsAg clearance.
- CHB patients are less likely to develop MetS and fatty liver disease.
- Liver steatosis suppresses HBV replication.
- Patients with steatosis were more likely to experience fibrosis progression, but HBsAg clearance rates were three times higher in untreated patients.
The present study demonstrated that Peg-IFN influences lipid metabolism by reducing appetite and body weight, decreasing cholesterol synthesis, and promoting the release of triglycerides in the liver. Triglycerides accumulate in hepatocytes as lipid droplets, leading to steatosis.
Moreover, IFN-α stimulates expression of ACSL1, an enzyme that promotes triglyceride synthesis, thereby inducing liver steatosis. Given that steatosis inhibits viral replication, IFN-α may reduce HBsAg levels indirectly through this mechanism. Data also suggested that higher blood lipid levels could improve response to Peg-IFN therapy.
Higher Uric Acid Levels May Contribute to HBsAg Loss
The researchers observed an inverse relationship between uric acid concentration and HBsAg levels, suggesting a role of purine metabolism in HBsAg synthesis and secretion. Previous studies have shown that uric acid can enhance immune responses by activating dendritic cells and T lymphocytes, which also facilitates the clearance of HBsAg.
Conclusion
Metabolic syndrome influences patient response to IFN-α therapy for CHB. However, prognosis may depend on multiple factors. Diabetes or impaired glucose tolerance lowers the likelihood of HBsAg loss, while higher blood lipid and uric acid levels may promote HBsAg clearance.
Triglyceride levels and liver steatosis increased after Peg-IFN therapy. IFN-α can induce steatosis and indirectly contribute to HBsAg loss by raising triglyceride levels through ACSL1-mediated triglyceride synthesis.
Further long-term studies are needed to determine whether functional cure of CHB is associated with increased risk of steatosis and diabetes.
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Reference
Interferon-α could induce liver steatosis to promote HBsAg loss by increasing triglyceride level
