Cytokine Signature behind Occult Hepatitis B Virus Infection

Background Hepatitis B virus (HBV) infection is a serious public health threat and one of the leading causes of acute, chronic and occult hepatitis (OBI). Standard diagnostics that detect HBsAg are insufficient for identifying OBI, defined by the presence of hepatic DNA in the absence of detectable serum HBsAg. Accumulating evidence indicate that the inadequate immune responses are responsible for HBV persistency. Cytokines are known to be important chemical mediators that regulate the differentiation, proliferation and function of immune cells. The goal of this study is to investigate the cytokine signature in OBI patients. Methods The study initially enrolled 6,773 healthy volunteers, after excluding individuals under 18 years of age, hepatitis B marker testing revealed 57 cases of OBI. As controls, 37 healthy donors with the absence of viral hepatitis markers, HIV, and somatic diseases were selected from the same initial cohort. Immune mediators (cytokines, chemokines, and growth factors) in blood plasma were measured with the MAGPIX multiplex analysis. Results We found high levels of IFNα, IFNγ, IL-1α, IL-2, IL-10, IL-15, IL-17A, IL-22, CXCL9/MIG and growth factors (EGF, FLT-3L, TGFα, G-CSF, M-CSF, VEGF) in OBI patients. Based on anti-HBsAg IgG positivity, patients with OBI were separated into two groups; seropositive cohort demonstrated an increase in CCL22/MDC. ROC analysis indicates that M-CSF, FLT-3L, G-CSF, EGF, and TGFα possess high diagnostic potential as biomarkers for OBI. Based on the results of decision tree, we established that combined detection of M-CSF and FLT-3L is more valuable in terms OBI diagnostic. Conclusions OBI is characterized by a dominant anti-inflammatory and pro-fibrotic background, mediated by cytokines such as IL-10 and TGF-α, which facilitates viral persistence and promotes liver fibrosis despite the concurrent elevation of some pro-inflammatory signals. The activation of growth factors like TGF-α and EGF drives aberrant tissue repair, resulting in incomplete regeneration and scarring. The roles of FLT-3L and IL-22 appear dual, mediating hepatoprotection while simultaneously contributing to fibrotic progression. ROC and decision tree analysis indicates that several cytokines possess high diagnostic potential as biomarkers for OBI.