Introduction
Hepatitis B virus (HBV) infection is a global public health concern, affecting approximately 300 million people and resulting in over 300,000 deaths every year due to cirrhosis, liver failure, or hepatocellular carcinoma.1,2 Antiviral treatment with nucleoside analogues can effectively inhibit HBV replication and delay disease progression.3,4 Several pivotal registration studies have shown that after five years of antiviral treatment with entecavir or tenofovir, 94%–99% of patients achieved undetectable HBV DNA and 80%–87% of patients achieved normalization of alanine aminotransferase (ALT),5-7 with approximately 13%–20% of patients still showing elevated ALT even after long-term viral suppression.8 Our previous study also reported that 34.8% of patients with chronic hepatitis B (CHB) had complete viral suppression and increased ALT during a follow-up of 18.36 months.9 Multiple studies have reported that elevated ALT during antiviral therapy is associated with an increased risk of liver events, cirrhosis, and hepatocellular cancer in patients with CHB.10-13 Moreover, an increase in ALT inhibits the accurate assessment of the disease stage and progression of CHB.14 However, the reason and mechanism underlying elevated ALT in patients with CHB after viral suppression have not been fully explored.
Various studies have explored the reasons for elevated ALT during antiviral therapy. An intermittent increase in ALT during antiviral therapy is generally considered an immune response to HBV infection, indicating changes in CHB disease activity.15Additionally, persistent ALT elevation is typically associated with metabolic syndrome and liver steatosis.16-18 However, the persistent elevation of ALT in patients with CHB cannot be explained completely by these factors. Numerous studies have recently found that metabolites play a critical role in the development of liver inflammation.19 For example, 3,4-dihydroxyphenylpropionic acid, a metabolite of gut microbiota, can suppress macrophage activation and improve hepatic ischemia/reperfusion injury via inhibiting histone deacetylase activity.20Additionally, the endogenous metabolite phosphonic acid can alleviate acetaminophen-induced liver injury by inducing the release of interleukin (IL-6) from adipose tissue.21 A recent study showed that 2-oleoylglycerol produced by triacylglycerol metabolism promotes western diet-induced liver inflammation and fibrosis in mice through activating macrophages and hepatic stellate cells.22 Overall, these findings imply that metabolites possibly play a role in ALT elevation in patients with CHB. Furthermore, alterations in circulating metabolites are associated with disease activity and progression in patients with CHB.23-25 A study with 10 years follow-up found that dysregulation of methionine and branched-chain amino acid-related metabolites were associated with progression of CHB.23In addition, lipid and bile acid-related metabolites are associated with liver inflammation and fibrosis in patients with CHB. However, the association between elevated ALT and circulating metabolites in patients with CHB remains unclear.
In this study, we investigated the association between the levels of circulating metabolites and the risk of persistently elevated ALT (PeALT) in patients with CHB with complete viral suppression. Additionally, the potential role of differential metabolites in liver injury was primarily explored using animal models. Our aim was to provide novel insights into the mechanism and potential predictive biomarkers of PeALT in patients with CHB after complete HBV inhibition.