CHB is a dynamic liver disease characterized by hepatic necroinflammation that is influenced by host and virological factors. Elucidation of the host inflammatory-immune response involved in CHB pathogenesis provides new perspectives for the identification of biomarkers and therapeutic targets. RAGE functions as a crucial transducer in the inflammatory immune response by interacting with its ligand and activating downstream cascades. sRAGE, a circulating soluble isoform of RAGE, has recently gained interest due to its potential to ameliorate inflammation by competing with cell surface RAGE for ligand binding under pathological conditions. sRAGE can be detected in human serum and has been implicated in liver diseases, including nonalcoholic fatty liver disease (NAFLD), autoimmune hepatitis and HCC. Nevertheless, its natural behavior and relationship with disease progression as well as its clinical predictive values in CHB development remain elusive. Here, we assessed the serum levels of sRAGE and its association with hepatic necroinflammation parameters during the dynamic course of CHB, aiming to determine its potential clinical significance for clinical judgment and surveillance of CHB.
The presence of HBV replication is closely associated with persistent hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation, liver cirrhosis or HCC. Generally, the HBV life cycle is heavily dependent upon and regulated by multiple host functions including intrinsic host innate defensive factors and gene products that provide functions necessary for the virus to complete its life cycle. The present study demonstrated that there was no significant difference among CHB patients with different viral loads, which was confirmed in the three subgroups with high viral loads HBeAg(-) IR phase, HBeAg(+) IT phase and HBeAg(+) IA phase. These findings indicate that sRAGE may not be a factor of the host innate defense system that participates in HBV replication, consistent with a previous report showing that serum sRAGE levels were linked to the chronic inflammation in lung disease rather than pathogen infection.
The present study demonstrated that CHB patients in a well-defined cohort exhibited reduced sRAGE levels, implying that sRAGE may exert opposite functions in regulating CHB pathogenesis. This finding supports those of previous studies showing low sRAGE levels in other inflammatory-immune disorders[25–27]. It has been reported that sRAGE is mainly generated from the proteolytic cleavage of membrane RAGE by metalloproteases such as MMP9 and ADAM1[8, 28]. MMP9 and ADAM1 were also reported to be in turn regulated by RAGE expression. Based on the current finding of reduced levels of RAGE and sRAGE in CHB patients, we cannot exclude the possibility that decreased levels of RAGE along with possible reduced levels of metalloproteases together contributed to the reduced circulatory sRAGE levels.
The assessment of sRAGE levels in the CHB subgroups revealed that the HBeAg(-) IR and HBeAg(+) IA phases exhibited lower sRAGE levels than the HBeAg(-) IC and HBeAg(+) IA phases, respectively, suggesting an inverse correlation between sRAGE and hepatic necroinflammation. Since active hepatic necroinflammation in CHB patients represents one of the important risk factors for developing liver fibrosis and even HCC, an evaluation of necroinflammation severity as well as its early control is imperative to determine the need for surveillance and treatment in patients with CHB. Here, patients with moderate-to-severe necroinflammation (G ≥ 2) had lower sRAGE levels than those with no or minimal hepatic necroinflammation (G0-1). Serum sRAGE levels were inversely correlated with ALT levels, a classic indicator of hepatic necroinflammation and prior CHB treatment. Similar results were also observed in the HBeAg (-) IR and HBeAg (+) IA phases, which exhibited hepatic necroinflammation. These observations suggest that reduced sRAGE levels may be identical to elevated ALT, reflecting inflammatory activity. Furthermore, RAGE expression in biopsy specimens from CHB patients was reduced along with hepatic necroinflammation grades. While RAGE binds to its ligands, leading to the activation of downstream cascades, and maintains persistent inflammation. With the inconsistence of reduced RAGE but its supporting role in inflammation, we hepothesize that persistent inflammation elicited by RAGE-ligand systems may be mainly dependent on RAGE’s ligands, but this hypothesis stll needs to be clarified in future research.
Many investigators have been trying to develop noninvasive tests for predicting liver inflammation. To date, ALT remains widely used as a routine indicator for hepatic necroinflammation or therapeutic judgment for antiviral therapy. Nonetheless, growing evidence has revealed that ALT alone is not as good as as an indicator as the grade of hepatic necroinflammation. One statistical study in China revealed that nearly half of CHB patients with ALT < 2 ULN showed moderate-to-severe necroinflammation (G ≥ 2) . Another biopsy report in the USA similarly showed that one-third of CHB patients with normal ALT levels showed severe inflammation. Therefore, CHB patients may exhibit normal ALT levels, leading to an inaccurate assessment of disease severity or even misdiagnosis. The present data revealed that combination of sRAGE and ALT value was superior to ALT, sRAGE or sRAGE/ALT alone for predicting hepatic necroinflammation. Therefore, sRAGE combining with ALT is necessary and may be used for patients who lack clear-cut indications for treatment. We also found that sRAGE has predictive power for CHB patients (G ≥ 2) with normal and minimally elevated ALT levels. This finding is meaningful that a CHB patient with a low serum sRAGE level may have significant hepatic necroinflammation even with a normal or minimally elevated ALT. However, further work on larger samples should be performed to substantiate the findings.
Nonetheless, several limitations to the present study exist. First, we did not assess the specificity of serum sRAGE in CHB compared to those with other liver disease entities such as chronic hepatitis C, nonalcoholic fatty liver disease and alcoholic liver disease using the same set of analyses. Second, we investigated the sRAGE levels during the chronic phase of HBV infection, and it is insufficient to elucidate dynamic changes of sRAGE during the different phase of HBV infection from acute hepatitis, CHB, hepatic fibrosis, and HBLC to HCC. Last, the detailed molecular mechanism regarding underlying the role of sRAGE in RAGE signaling activation in CHB pathogenesis and whether sRAGE can serve as a therapeutic target still need further clarification.