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.