Hepatitis B-related hepatocellular carcinoma and stress: untangling the host immune response from clinical outcomes

Chronic hepatitis B virus (HBV) infection is a major public health challenge on the global scale. Affecting hundreds of millions worldwide, HBV is a leading risk factor for hepatocellular carcinoma (HCC). Clinical outcomes from chronic HBV infection are varied and appear to be influenced by a complex and dysregulated host immune response. In turn, much attention has been given to the immunologic response to HBV in an effort to identify host factors that lead to the development of HCC. However, the role of nonimmunologic host factors, such as chronic stress, in HBV-related HCC is poorly defined. Indeed, a growing appreciation for the effects of stress on chronic liver diseases raises the question of its role in chronic HBV infection. In this light, the present review will untangle the roles of key host factors in HBV-related HCC with an emphasis on chronic stress as a viable contributor. First discussed is the interplay of stress, inflammation and chronic liver disease. The host immune response’s role as a driver of HBV-related HCC is then reviewed, allowing for a close exploration of the effects of stress on immune function in chronic hepatitis B and as a potential risk factor for HBV-related HCC.

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Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis

Bioscience Reports ◽

10.1042/bsr20190783 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 4

Author(s):

Han Shi ◽

Hongyan He ◽

Suvash Chandra Ojha ◽

Changfeng Sun ◽

Juan Fu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Meta Analysis ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv

Abstract Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07–1.29, PA=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09–1.76, PA=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (PA<0.01) and chronic hepatitis B (CHB)-related HCC (PA<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.

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Studies on Mutual Relationship between Anti-HBx and sFas, IL-10 or IL-12 in Sera of Cases with Chronic Hepatitis B Infection

Infection International ◽

10.1515/ii-2017-0075 ◽

2014 ◽

Vol 3 (2) ◽

pp. 49-53

Author(s):

Ai-kun Ding ◽

Li-wei Guo ◽

Yong-kong Wang ◽

Wei Liu ◽

Cheng Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Sandwich Elisa ◽

Hbv Infection ◽

Mutual Relationship ◽

Chronic Hbv Infection ◽

Chronic Hbv

Abstract Objective To study the mutual relationship between anti-HBx and IL-10, IL-12 or soluble Fas (sFas) in sera of patients with chronic HBV infection and to explore the importance of anti-HBx detection as well as its role in the development of chronic HBV infection. Methods Total of 90 cases with chronic HBV infection were randomly selected, including 10 of asymptomatic carriers (ASC), 28 of chronic hepatitis B (CHB), 26 of liver cirrhosis (LC) and 26 patients of hepatocellular carcinoma (HCC). Their clinical data and blood samples were collected, and serum was prepared and stored at -73℃. Anti-HBx was detected with an indirect ELISA established in our earlier research, and levels of IL-10, IL-12 and Fas were determined with commercial double-antibody sandwich ELISA kits. The mutual relationship between anti-HBx and IL-10, IL-12 or sFas in serum were analyzed with the software SPSS 20.0. Results All levels of IL-10, IL-12 and sFas in peripheral blood showed a rising trend with development of chronic HBV infection. The levels of IL-10 in ASC, CHB, LC and HCC groups were 13.93 ± 14.40 ng/L, 39.38 ± 20.77 ng/L, 69.06 ± 46.37 ng/L and 62.82 ± 23.42 ng/L, respectively, levels of IL-12 in the 4 groups were 15.64 ± 23.04 ng/L, 68.50 ± 23.14 ng/L, 76.83 ± 12.82 ng/L and 83.74 ± 24.88 ng/L, respectively, and levels of sFas were 58.17 ± 77.42 ng/L, 179.88 ± 104.36 ng/L, 249.22 ± 107.80 ng/L and 252.98 ± 87.65 ng/L, respectively. Twenty-seven out of 90 patients showed a positive result for anti-HBx detection, including 1 in ASC, 4 in CHB, 12 in LC and 10 in HCC group. The levels of IL-10, IL-12 and sFas were higher in anti-HBx positive group than in negative group. Statistical analysis demonstrated significant differences of IL-10 and IL-12 between the two groups (P < 0.05), but the differences of sFas had no statistical significance (P = 0.094). Conclusions Anti-HBx antibody is not protective, and is closely related to IL-10, IL-12 and sFas. It may be an important serum indicator for aggravation from chronic hepatitis B to liver cirrhosis or hepatocellular carcinoma in patients with chronic HBV infection.

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The Multiple Functions of B Cells in Chronic HBV Infection

Frontiers in Immunology ◽

10.3389/fimmu.2020.582292 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ying Cai ◽

Wenwei Yin

Keyword(s):

Immune Response ◽

Chronic Hepatitis ◽

B Cells ◽

Hepatitis B ◽

B Cell ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Multiple Functions ◽

Chronic Hbv ◽

B Cell Subsets

Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.

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Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma Development in Chronic HBV Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00474-10 ◽

2011 ◽

Vol 18 (6) ◽

pp. 914-921 ◽

Cited By ~ 33

Author(s):

Jong-Han Lee ◽

Kwang-Hyub Han ◽

Jae Myun Lee ◽

Jeon Han Park ◽

Hyon-Suk Kim

Keyword(s):

Hepatocellular Carcinoma ◽

Risk Factor ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Regulatory Pathways ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv ◽

The Impact

ABSTRACTThe hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131 (double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] = 1.101 to 12.768,P= 0.033) and 5.34-fold (95% CI = 1.65 to 17.309,P= 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-κB activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-κB activity. Other regulatory pathways seem to exist for NF-κB activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-κB activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.

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Recombinant hepatitis B core antigen carrying preS1 epitopes induce immune response against chronic HBV infection

Vaccine ◽

10.1016/j.vaccine.2003.07.014 ◽

2004 ◽

Vol 22 (3-4) ◽

pp. 439-446 ◽

Cited By ~ 31

Author(s):

Xinchun Chen ◽

Meizhong Li ◽

Xiaohua Le ◽

Weimin Ma ◽

Boping Zhou

Keyword(s):

Immune Response ◽

Hepatitis B ◽

Hbv Infection ◽

Core Antigen ◽

Recombinant Hepatitis ◽

Chronic Hbv Infection ◽

Chronic Hbv ◽

Hepatitis B Core Antigen

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Serum pentraxin 3 as a biomarker of hepatocellular carcinoma in chronic hepatitis B virus infection

Scientific Reports ◽

10.1038/s41598-020-77332-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Huan Deng ◽

Xiude Fan ◽

Xiaoyun Wang ◽

Lu Zeng ◽

Kun Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Early Stage ◽

Hbv Infection ◽

Healthy Controls ◽

Pentraxin 3 ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

AbstractBiomarkers for early diagnosis of hepatocellular carcinoma (HCC) are needed in chronic hepatitis B virus (HBV) infection, a leading cause of HCC. We evaluated whether measurement of serum pentraxin 3 (PTX3) could improve diagnosis of HCC in chronic HBV infection. Data from patients with HBV-related chronic hepatitis (n = 159), cirrhosis (n = 99) and HCC (n = 107), and healthy controls (n = 151) were analyzed. Serum PTX3 concentration was measured by immunoassay. Area under the receiver operating characteristic curve (AUC) was applied to assess diagnostic accuracy. PTX3 levels were significantly higher in HBV patients than in healthy controls (P < 0.001) and in HCC than in chronic hepatitis (P < 0.001) or cirrhosis patients (P < 0.001). PTX3 was an independent risk factor of HCC [odds ratio (OR) 1.617, P < 0.001] and could distinguish HCC in chronic HBV infection [cutoff 9.231 ng/mL, AUC 0.929 with 95% confidence interval (CI) of 0.898–0.953], including α-fetoprotein (AFP) negative [cutoff 8.985 ng/mL, AUC (95%CI) 0.947 (0.908–0.973)] and early-stage HCC [cutoff 9.359 ng/mL, AUC (95%CI) 0.920 (0.885–0.947)]. Combination of PTX3 with AFP improved the discrimination of early HCC from chronic HBV infection [AUC (95%CI) 0.948 (0.918–0.970)]. In short, PTX3 measurement could identify HCC, including AFP-negative and early-stage HCC, in chronic HBV infection.

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Hepatitis B vaccination status and vaccine immune response among children in rural Senegal

European Journal of Public Health ◽

10.1093/eurpub/ckz185.592 ◽

2019 ◽

Vol 29 (Supplement_4) ◽

Author(s):

L Perieres ◽

M Coste ◽

S Ndiour ◽

P Halfon ◽

C Sokhna ◽

...

Keyword(s):

Immune Response ◽

Hepatitis B ◽

Chronic Infection ◽

Vaccination Status ◽

Hbv Infection ◽

Hepatitis B Vaccination ◽

Chronic Hbv Infection ◽

Hbv Vaccination ◽

Chronic Hbv ◽

Vaccine Immunity

Abstract Background Hepatitis B vaccination during childhood is key to reduce the prevalence of Hepatitis B virus (HBV) infection. In Senegal, a highly endemic country, the three-dose hepatitis B vaccine and the birth dose vaccine were introduced in the Expanded Programme on Immunization (EPI) in 2004 and 2016 respectively. This study aimed to determine chronic HBV infection prevalence, hepatitis B vaccination status and vaccine immunity among children in Senegal. Methods A cross-sectional study including HBV screening was conducted at home among children aged 6 months to 15 years (i.e. born after the introduction of the HBV vaccine in the EPI) in the rural zone of Niakhar. Dried Blood Spot (DBS) samples were collected for the detection of HBsAg, anti-HBc Ab and anti-HBs Ab using chemoluminescence. Vaccination status was assessed using information on vaccination cards. Detectable vaccine immunity was defined with an adjusted DBS threshold of DOI≥0.36 IU/mL (corresponding to 10 IU/mL in venous blood sampling). Results Between October and December 2018, 455 children were enrolled. Preliminary results show that 7/455 (1.5%) had been in contact with HBV (positive anti-HBc Ab) and 5/455 (1.1%) had chronic HBV infection (positive HBsAg). Only 161/455 (35.4%) children had a vaccination card available. Among those, 150/161 (93.2%) received at least 3 doses of hepatitis B vaccine, of which 83/150 (55.3%) had detectable vaccine immunity. The proportion of children with detectable vaccine immunity was significantly higher in children <5 years than in children aged 5-9 and 10-15 (72.3% versus 47.3%, p = 0.006 and 72.3% versus 14.3%, p < 0.001). Conclusions Preliminary results suggest a low prevalence of HBV chronic infection among children born after the introduction of HBV vaccination in Senegal. However, detectable vaccine immunity rapidly decreases with age among vaccinated children, signalling a need for further studies on the immune response to HBV vaccination in this context. Key messages HBV chronic infection is low among children born after the introduction of HBV vaccination in Senegal. Further studies on the immune response to HBV vaccination in this context are needed.

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Soluble immune markers in the different phases of chronic hepatitis B virus infection

Scientific Reports ◽

10.1038/s41598-019-50729-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Steffen B. Wiegand ◽

Bastian Beggel ◽

Anika Wranke ◽

Elmira Aliabadi ◽

Jerzy Jaroszewicz ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbeag Seroconversion ◽

Hbv Infection ◽

Immune Markers ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

Abstract Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-β and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-β and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.

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Chronic hepatitis B virus infection and total and cause-specific mortality: a prospective cohort study of 0.5 million people

BMJ Open ◽

10.1136/bmjopen-2018-027696 ◽

2019 ◽

Vol 9 (4) ◽

pp. e027696 ◽

Cited By ~ 4

Author(s):

Jiahui Si ◽

Canqing Yu ◽

Yu Guo ◽

Zheng Bian ◽

Ruogu Meng ◽

...

Keyword(s):

Chronic Hepatitis ◽

Cohort Study ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Specific Mortality ◽

Chronic Hbv

ObjectivesChronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality.DesignPopulation-based prospective cohort study.SettingChina Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008.Participants475 801 participants 30–79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline.Primary and secondary outcome measuresTotal and cause-specific mortality.ResultsA total of 35 822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95% CI: 2.01 to 2.31) than in women (HR=1.74, 95% CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95% CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95% CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95% CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95% CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95% CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants.ConclusionsAmong Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.

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