The global frequency of OHCV infection varies widely, ranging from 3.3 to 57% among individuals with unexplained abnormalities in liver function tests [
4,
25]. Our previous study found a 53.84% occurrence of OHCV infection among individuals with chronic liver disease of unknown origin [
23]. In HCV infection, releasing IL-17 and IL-22 by CD4 + T cells contributes to the immune regulatory mechanisms [
26]. Until now, little is known about how IL-17 and IL-22 function in OHCV infection. Our findings show that individuals with chronic HCV infection have higher IL-17 levels than those with OHCV and healthy individuals. Balanescu et al. also found similar results, showing elevated serum IL-17 levels in patients with chronic HCV infections [
27]. Additionally, a study has demonstrated that CHC patients have higher proportions of circulating and liver-infiltrating Th17 cells than healthy people and that liver inflammation was connected with both measures of Th17 cell presence [
28]. According to this study, there was no statistically significant difference in IL-22 levels across the research groups. Additionally, a prior study discovered that patients with chronic hepatitis C had no significant difference in blood IL-22 levels between the HCV hepatitis and normal control groups [
29]. In this study, the CHC group exhibited higher levels of necro-inflammatory grades (A2-A3) and fibrosis/cirrhosis (F2-F4) compared to the OHCV cases. This is consistent with previous research showing that OHCV infection tends to have milder effects compared to chronic hepatitis C [
8,
9]. Higher levels of IL-17 in individuals with chronic HCV versus those with OHCV may contribute to increased liver inflammation and fibrosis/cirrhosis in chronic HCV cases. Other studies have supported this finding, showing a connection between elevated levels of circulating Th17-positive cells and HCV-specific Th17 cells, as well as IL-17 cells in the liver, and the severity of liver inflammation in chronic HCV patients. These studies have also demonstrated a significant correlation between the fibrosis stages in chronic hepatitis and the quantity of IL-17 + neutrophils and overall IL-17 production in liver tissue [
29,
30]. Additionally, Rios et al. discovered that the only lymphocyte subset associated with advanced fibrosis was Th17 [
31]. The proposed mechanism for IL-17 to induce fibrogenesis is by enhancing the transformation of hepatic stellate cells into myofibroblasts and promoting the epithelial-mesenchymal transition of the hepatocytes. This results in the production of extracellular matrix, alterations in the microstructure and microcirculation of the liver, and eventually, the progression of fibrosis [
32]. However, Sousa et al. challenged this knowledge by presenting evidence that IL-17 levels were elevated in healthy individuals compared to those with chronic HCV. They proposed that in cases of CHC, IL-17 may play a role in managing liver damage and fighting off infection [
33]. Our explanation is supported by the findings of Bălănescu et al., who revealed that specific HCV-Th17 cells are involved in hepatic inflammation and are associated with the severity of fibrosis and the regulation of immune responses [
27]. This study found that, while there is no statistically significant difference in IL-22 levels between occult HCV and chronic HCV, IL-22 levels are higher in occult HCV. This may help explain the mild histological pattern seen in occult HCV. Research has shown that IL-22 can restrict apoptosis and increase proliferation, suggesting it may directly protect against hepatic injury [
34]. Dambacher and colleagues supported our findings by showing that individuals with viral hepatitis did not have significantly different IL-22 serum levels compared to healthy individuals [
29].
Our study found no link between blood cytokine levels and fibrosis stages in either patient group. However, individuals in the occult group with high inflammatory activity (A2-A3) had significantly higher blood levels of IL-17 compared to those with low activity (A0-A1).
Our analysis found no significant difference in IL-17 or IL-22 levels and hepatic inflammation in chronic HCV infection. However, the occult group with high inflammatory activity had significantly higher blood levels of IL-17 compared to those with low activity. This difference between OHCV and chronic HCV may be because we only examined both cytokines in the peripheral compartment. Additionally, this non-significant value may account for the discrepancy, as it is understood that IL-22, hepatic stellate cells, and Th17 cells create a positive feedback loop that may lead to increased liver inflammation in infected patients [
35]. Furthermore, this contradictory finding can be explained by several factors. Firstly, occult HCV refers to the presence of HCV RNA in the blood, but there is no detectable HCV antibody. This condition is often asymptomatic and may not have significant liver inflammation.
Conversely, CHC refers to persistent infection with HCV, resulting in chronic liver inflammation. The IL-17 cytokine plays a crucial role in inflammation and immune response. It has been shown to promote inflammation in various conditions, including liver disease. However, its exact role in HCV infection is not fully understood. While IL-17 levels were higher in OHCV, the severity of liver inflammation was milder, suggesting that IL-17 may not significantly drive the progression of liver inflammation in OHCV [
36]. Another potential explanation for the contradictory finding is the study’s small sample size. OHCV is a rare condition, and the sample size may have limited the ability to assess the association between IL-17 levels and liver inflammation accurately. More extensive studies with more participants are needed to explore further the relationship between IL-17 and liver histology in OHCV.
Our study was limited because we could not directly follow up on treating these patients with direct-acting antivirals, and there is a lack of comparison with liver cirrhosis in the study. However, this was not the focus of our study.