Clinical characteristics and immunogenicity after Omicron breakthrough infection in patients with chronic hepatitis B infection: A longitudinal observational study.

The clinical and immunological features after breakthrough infection (BTI) during Omicron wave in patients with chronic hepatitis B virus infection (CHB) are still unclear. A total of 101 patients with CHB from our previous coronavirus disease 2019 (COVID-19) vaccination cohort (NCT05007665), were continued to be followed up at the Second Affiliated Hospital of Chongqing Medical University after BTI, while an additional 39 healthcare workers after BTI were recruited as healthy controls (HCs). Clinical data were collected using questionnaire survey and electronic medical record. Blood samples were used to determine the antibody responses, as well as B and T cell responses. After BTI, the clinical symptoms of COVID-19 were mild to moderate in patients with CHB, with a median duration of 5 days. Compared with HCs, patients with CHB were more susceptible to develop moderate COVID-19. The liver function was not significantly damaged, and HBV-DNA was not activated in patients with CHB after BTI. Patients with CHB could elicit robust antibody responses after BTI (NAbs 13.0-fold, BA.5 IgG: 24.2-fold, respectively), which was also significantly higher than that in every period after vaccination (all p < 0.001), and compared to that in HCs after BTI. The CD4+, cTfh, and CD8+ T cell responses were also augmented in patients with CHB after BTI, while exhibiting comparability to those observed in HCs. In patients with CHB after BTI, the immune imprint was observed in B cell responses, rather than in T cell responses. In conclusion, Omicron breakthrough infection induced mild to moderate COVID-19 symptoms in patients with CHB, without exacerbating the progress of liver diseases. Meanwhile, BTI demonstrated the ability to induce robust antibody and T cell responses in patients with CHB, which was comparable to those observed in HCs.

MTHFR and MTRR gene polymorphisms in patients with chronic hepatitis B virus infections in Zigong, Sichuan Province.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a severe disease affecting the physical and economic well-being of patients. The relationship between polymorphisms in the MTHFR gene and disease progression following HBV infection remains a controversial topic. AIM: To study MTHFR and MTRR gene polymorphisms in patients with chronic HBV infections in Zigong, Sichuan Province. SUBJECTS AND METHODS: One hundred and ninety-one patients with chronic HBV infections were divided into three groups: the chronic hepatitis B (CHB) group (n = 71), the hepatitis B-induced liver cirrhosis (LC) group (n = 56), and the hepatitis B-related primary liver cancer (PLC) group (n = 64). The gene polymorphisms were detected using the PCR-melt curve method and analysed. RESULTS: The distributions of MTHFR C677T (CC: 41.2% vs. 41.8%; CT: 50% vs. 45.5%; TT: 8.8% vs. 12.7%; p = 0.714), MTHFR A1298C (AA: 70.6% vs. 72.7%; AC: 26.5% vs. 25.5%; CC: 2.9% vs. 1.8%; p = 1.000), and MTRR A66G (AA: 58.1% vs. 65.5%; AG: 39.0% vs. 29.1%; 2.9% vs. 5.5%; p = 0.353) genetic polymorphisms did not vary between male and female patients from Zigong. In addition, there were no differences in the distributions of MTHFR C677T (CC: 43.4% vs. 38.8%; CT: 49.1% vs. 48.2%; TT: 7.5% vs. 12.9%; p = 0.444), MTHFR A1298C (AA: 76.4% vs. 64.7%; AC: 20.8% vs. 32.9%; CC: 2.8% vs. 2.4%; p = 0.155), and MTRR A66G (AA: 62.3% vs. 57.6%; AG: 34.0% vs. 38.8%; 3.8% vs. 3.5%; p = 0.353) genetic polymorphisms between the patients <60 and >60 years of age. The distributions of MTHFR C677T (CHB vs. LC, p = 0.888; CHB vs. PLC, p = 0.661; PLC vs. LC, p = 0.926), MTHFR A1298C (CHB vs. LC, p = 0.12; CHB vs. PLC, p = 0.263; PLC vs. LC, p = 0.550), and MTRR A66G (CHB vs. LC, p = 0.955; CHB vs. PLC, p = 0.645; PLC vs. LC, p = 0.355) gene polymorphisms were comparable between the CHB, LC, and PLC groups. CONCLUSION: The distributions of MTHFR and MRRR genetic polymorphisms in the population with HBV infections in Zigong, Sichuan Province did not differ in age and sex. The MTHFR and MRRR genetic polymorphisms were comparable between the CHB, LC, and PLC groups.

[Research progress on the role of hepatitis B virus DNA integration in chronic hepatitis B].

Chronic hepatitis B virus (HBV) infection will greatly contribute to raising the occurrence probability of cirrhosis and hepatocellular carcinoma in patients. Although existing antiviral treatment regimens have a certain effect on delaying disease progression and improving prognosis, it is still not effective in attaining functional cures. Hepatitis B virus DNA integration may be one of the reasons for this phenomenon. Therefore, this paper reviews the possible mechanisms of HBV DNA integration in maintaining chronic inflammation of the liver, evading existing antiviral treatment methods, and inducing hepatocellular carcinoma so as to further deepen the understanding of the role of HBV DNA integration in the occurrence and development of chronic hepatitis B, providing ideas and references for formulating better treatment strategies.

Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region.

GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants. In this analysis, the plasma pharmacokinetics (PK) of GSK3389404 were characterized and compared in patients with CHB across the Asia-Pacific region (N = 64), including mainland China (n = 16), Hong Kong (n = 8), Japan (n = 21), South Korea (n = 12), Singapore (n = 4), and the Philippines (n = 3), from a phase 2a, multicenter, randomized, double-blind, placebo-controlled study (NCT03020745). Hepatitis B(e) antigen-positive and -negative patients (on or not on stable nucleos[t]ide regimens) received single (30 mg or 120 mg) or multiple (30 mg, 60 mg, or 120 mg weekly or 120 mg biweekly) subcutaneous GSK3389404 injections. The plasma concentrations were measured on day 1 in all cohorts as well as on days 29 and 57 in the multiple-dose cohorts. The GSK3389404 plasma PK were similar to those reported in a previous study in non-Asian healthy participants with a median time to peak concentration (tmax) of 1 to 4 h postdose, a mean half-life of 3 to 5 h across cohorts, and no accumulation following repeat dosing. The GSK3389404 plasma tmax and half-life values were dose-independent. The increase in the plasma peak concentration (Cmax) and the area under the concentration versus time curve (AUC) was dose-proportional from 60 to 120 mg and greater than dose-proportional from 30 to 60 or 120 mg. The GSK3389404 plasma concentration versus time profiles, half-life, tmax, Cmax, and AUC values were all comparable across the Asia-Pacific populations. Given the similarity of the PK among ASOs, this analysis suggests that the PK from any Asia-Pacific population may be used to guide ASO dose selection in the Asia-Pacific region.

Challenges of hepatitis B treatment in rural Sub-Saharan Africa: Treatment initiation and outcomes from a public hospital-based clinic in Kono, Sierra Leone.

Despite a high prevalence, there are few successful models for de-centralizing diagnosis and treatment of chronic hepatitis B virus (HBV) infection among rural communities in Sub-Saharan Africa. We report baseline characteristics and 1 year retention outcomes for patients enrolled in a HBV clinic integrated within chronic disease services in a rural district hospital in Sierra Leone. We conducted a retrospective cohort study of patients with HBV infection enrolled between 30 April 2019 and 30 April 2021. Patients were eligible for 1 year follow-up if enrolled before 28 February 2020. Treatment eligibility at baseline was defined as cirrhosis (diagnosed by clinical criteria of decompensated cirrhosis, ultrasonographic findings or aspartate-aminotransferase-to-platelet ratio >2) or co-infection with HIV or HCV. Retention in care was defined as a documented follow-up visit at least 1 year after enrolment. We enrolled 623 individuals in care, median age of 30 years (IQR 23-40). Of 617 patients with available data, 97 (15.7%) had cirrhosis. Treatment was indicated among 113 (18.3%) patients and initiated among 74 (65.5%). Of 39 patients eligible for 1 year follow-up on treatment at baseline, 20 (51.3%) were retained at 1 year, among whom 12 (60.0%) had documented viral suppression. Among the 232 patients not initiated on treatment eligible for 1 year follow-up, 75 (32.3%) were retained at 1 year. Although further interventions are required to improve outcomes, our findings demonstrated feasibility of retention and treatment of patients with HBV infection in a rural district in Sub-Saharan Africa, when integrated with other chronic disease services.

IL-21 collaborates with anti-TIGIT to restore NK cell function in chronic HBV infection.

Available therapies for chronic hepatitis B virus (HBV) infection are not satisfying, and interleukin-21 (IL-21) and checkpoint inhibitors are potential therapeutic options. However, the mechanism underlying IL-21 and checkpoint inhibitors in treating chronic HBV infection is unclear. To explore whether IL-21 and checkpoint inhibitors promote HBV clearance by modulating the function of natural killer (NK) cells, we measured the phenotypes and functions of NK cells in chronic HBV-infected patients and healthy controls on mRNA and protein levels. We found that chronic HBV infection disturbed the transcriptome of NK cells, including decreased expression of KLRK1, TIGIT, GZMA, PRF1, and increased expression of CD69. We also observed altered phenotypes and functions of NK cells in chronic HBV-infected patients, characterized by decreased NKG2D expression, increased TIGIT expression and impaired interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) production. Furthermore, these alterations cannot be restored by telbivudine treatment but can be partially restored by IL-21 and anti-TIGIT stimulation. IL-21 upregulated the expression of activating receptor CD16, CD69, and NKG2D on NK cells, enhanced IFN-γ production, cytolysis, and proliferation of NK cells, while anti-TIGIT promoted IFN-γ production in CD56dim subset exclusively in chronic HBV infected patients. Additionally, IL-21 was indispensable for anti-TIGIT in HBsAg clearance in mice bearing HBV. It enhanced IFN-γ production in splenic NK cells rather than intrahepatic NK cells, indicating a brand-new mechanism of IL-21 in HBV clearance when combined with anti-TIGIT. Overall, our findings contribute to the design of immunotherapy through enhancing the antiviral efficacy of NK cells in chronic HBV infection.

Humoral responses after primary and booster SARS-CoV-2 inactivated vaccination in patients with chronic hepatitis B virus infection: A longitudinal observational study.

Given the pandemic of severe acute respiratory syndrome coronavirus 2 Omicron variants, booster vaccination (BV) using inactivated virus vaccines (the third dose) has been implemented in China. However, the immune responses after BV, especially those against Omicron, in patients with chronic hepatitis B virus (HBV) infection (CHB) are unclear. In this prospective longitudinal study, 114 patients with CHB and 68 healthy controls (HCs) were recruited after receiving inactivated vaccination. The anti-receptor-binding domain (RBD) immunoglobulin G (IgG), neutralizing antibodies (NAbs), neutralization against Omicron (BA2.12.1, BA.4/5), and specific B/T cells were evaluated. In patients, anti-RBD IgG was elevated significantly after BV; the titers were as high as those in HCs. Similar results were obtained for the NAbs. However, compared with that against wild type (WT), the neutralization against Omicron was compromised after BV. The frequency of RBD+ atypical memory B cells increased, but spike-specific cluster of differentiation 4+ /8+ T cells remained unchanged after BV. Moreover, no serious adverse events or HBV reactivation were observed after BV. These results suggest that BV significantly enhanced antibody responses against WT; however, it resulted in compromised antibody responses against Omicron in patients with CHB. Hence, new all-in-one vaccines and optimal vaccination strategies should be studied promptly.

Associations of Wnt5a expression with liver injury in chronic hepatitis B virus infection.

BACKGROUND: Aberrant Wnt5a expression contributes to immunity, inflammation and tissue damage. However, it remains unknown whether Wnt5a is associated with liver injury in chronic hepatitis B virus (HBV) infection. We aimed to explore the potential role of Wnt5a expression in liver injury caused by chronic HBV infection. METHODS: Wnt5a mRNA levels in peripheral blood mononuclear cells (PBMCs) were analyzed in 31 acute-on-chronic hepatitis B liver failure (ACHBLF) patients, 82 chronic hepatitis B (CHB) patients, and 20 healthy controls using quantitative real-time polymerase chain reaction. Intrahepatic Wnt5a protein expression from 32 chronic HBV infection patients and 6 normal controls was evaluated by immunohistochemical staining. RESULTS: Wnt5a mRNA expression was increased in CHB patients and ACHBLF patients compared to healthy controls and correlated positively with liver injury markers. Additionally, there was a significant correlation between Wnt5a mRNA expression and HBV DNA load in all patients and CHB patients but not in ACHBLF patients. Furthermore, intrahepatic Wnt5a protein expression was elevated in chronic HBV infection patients compared to that in normal controls. Moreover, chronic HBV infection patients with higher hepatic inflammatory grades had increased intrahepatic Wnt5a protein expression compared with lower hepatic inflammatory grades. In addition, the cut-off value of 12.59 for Wnt5a mRNA level was a strong indicator in predicting ACHBLF in CHB patients. CONCLUSIONS: We found that Wnt5a expression was associated with liver injury in chronic HBV infection patients. Wnt5a might be involved in exacerbation of chronic HBV infection.

Interleukin-21 modulates balance between regulatory T cells and T-helper 17 cells in chronic hepatitis B virus infection.

BACKGROUND: Chronic HBV infection is always accompanied by differences in the balance between regulatory T cells (Tregs) and T-helper 17 (Th17) cells in infection phases. IL-21 plays an important role in the progression of chronic HBV infection. Thus, the aim of our study was to investigate the role of the regulatory function of IL-21 in maintaining the balance between Tregs and Th17 cells in chronic HBV infection. METHODS: Twenty-five chronic HBV-infected patients in the immune-tolerant (IT) phase and 23 chronic hepatitis B (CHB) patients were recruited in this study. Cytokines production was measured by ELISA. The mRNA expression levels were determined by qPCR. CD4+T cells were stimulated with or without IL-21. Tregs and Th17 cells were measured by flow cytometry. pSTAT3 and STAT3 expression was assessed by Western blotting. RESULTS: The concentration of IL-21 in the serum of CHB were significantly higher than that in the serum from IT patients, and IL-21 and IL-21R levels in the PBMCs from CHB were higher than those from IT patients. IL-21 promoted Th17 cells differentiation and function but inhibited Treg cells differentiation and function by activating STAT3 signaling pathways, upregulating RORγt expression, downregulating Foxp3 expression, by increasing IL-17and IL-22 secretion, and decreasing TGF-ß secretion in chronic HBV infection. The proportion of Tregs and TGF-ß concentrations in CHB was significantly lower than that in IT patients. Furthermore, the percentage of Th17 cells and the IL-17 concentration in CHB was markedly higher than that in IT patients, causing a reduction in the Tregs/Th17 ratio in CHB patients. CONCLUSIONS: Our results suggest that IL-21 may contribute to inflammation in chronic HBV infection by modulating the balance between Treg and Th17 cells.

Prevalence of Latent Tuberculosis Infection Among Persons with Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Tuberculosis (TB) and chronic hepatitis B virus infection (HBV) can be prevented through latent tuberculosis infection (LTBI) treatment and HBV vaccination, respectively. Prevalence of LTBI and HBV are six- and ninefold higher among non-US-born compared to US-born persons, respectively. Few studies have described the prevalence of LTBI-HBV co-infection. AIMS: In this study, we estimated LTBI prevalence among persons with chronic HBV. METHODS: We conducted a systematic review and meta-analysis using PubMed from inception through September 1, 2019, and identified and reviewed studies that provided data regarding LTBI prevalence among adults with chronic HBV. Pooled LTBI prevalence among adults with HBV was calculated using a random-effects meta-analysis model. RESULTS: A total of 1,205 articles were identified by systematic review of the published literature. Six studies were included in the meta-analysis; five studies were conducted in North America, and one was in China. LTBI prevalence among adults with chronic HBV was estimated to be 34.25% (95% confidence interval: 17.88-50.62%). CONCLUSION: LTBI prevalence among adults with chronic HBV was two times higher than the LTBI prevalence among all non-US-born persons. The high LTBI prevalence and increased risk of hepatotoxicity with TB medications among persons with chronic HBV may warrant consideration of routine screening for HBV among persons who are tested for LTBI. Reducing morbidity and mortality associated with TB and chronic HBV may require healthcare systems and public health to ensure that persons at risk of both infections are screened and treated for LTBI and chronic HBV.

Liver Fibrosis in the Natural Course of Chronic Hepatitis B Viral Infection: A Systematic Review with Meta-Analysis.

BACKGROUND: Quantitative data are limited on the natural course of liver fibrosis in patients with chronic HBV infection (CHB). AIMS: To estimate the prevalence of fibrosis status including non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis throughout the natural course of CHB. METHODS: We searched Cochrane library, EMBASE, PubMed, SCOPUS, Web of Science, and ScienceDirect from January 1993 to November 2019 for studies with histologic data on liver fibrosis in CHB natural course. CHB course was defined based on current criteria for identifying infection phases as recommended by international clinical practice guidelines, including the HBeAg-positive immune-tolerant, HBeAg-positive immune-active, HBeAg-negative immune-inactive, HBeAg-negative immune-reactive, and HBsAg-negative phases. Pooled prevalence rate of fibrosis status at each phase was obtained from random-effect meta-analyses. RESULTS: Thirty-three studies with 9,377 adult participants (23.8-49.0 age years; 45.5-88.6% males) were eligible and finally included. The estimated prevalence of non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis was, for HBeAg-positive immune-tolerant phase: 31.2% (95%CI 15.6-46.7), 16.9% (95%CI 7.8-26.1), 5.4% (95%CI 0.0-11.2), and 0.0% (95%CI 0.0-1.5); HBeAg-positive immune-active phase: 6.9% (95%CI 3.6-10.2), 50.6% (95%CI 39.2-61.9), 32.1% (95%CI 24.2-40.0), and 12.8% (95%CI 8.6-17.0); HBeAg-negative immune-inactive phase: 32.4% (95%CI 0.0-100.0), 24.8% (95%CI 4.5-45.1), 3.0% (95%CI 0.0-8.3), and 0.0% (95%CI 0.0-1.0); and HBeAg-negative immune-reactive phase: 6.3% (95%CI 3.5-9.2), 50.3% (95%CI 38.9-61.7), 30.3% (95%CI 20.9-39.6), and 10.0% (95%CI 6.6-13.5), respectively. There was only one study for HBsAg-negative phase, thus not allowing further meta-analyses. CONCLUSIONS: Fibrosis risk persists through CHB natural course. These data can support risk estimation in clinical practice and provide reference for noninvasive investigation.

Hepatic steatosis and development of type 2 diabetes: Impact of chronic hepatitis B and viral specific factors.

BACKGROUND: Chronic hepatitis B (CHB) was associated with a lower prevalence of nonalcoholic fatty liver disease (NAFLD). The impact of CHB on the link between NAFLD and type 2 diabetes (T2D) and related virological implications remain unclear. METHODS: We recruited 2255 middle-to older-aged individuals who were examined serially for hepatic steatosis by ultrasonography and blood biochemistry as part of a population-based hepatocellular-carcinoma cohort study. In CHB patients, hepatitis B surface antigen (HBsAg) seroclearance and variation in viral load trajectory were also evaluated. RESULTS: During the average follow-up of 6 years, 168 participants developed T2D. CHB, as compared with uninfected subjects, was associated with lower risks for both new development and persistence of hepatic steatosis. Furthermore, the risk of steatosis decreased with higher levels of past viral load trajectories (p for trend = 0.0002). However, concomitant steatosis at baseline in CHB patients was still significantly associated with a 1.98-fold increased risk for T2D after multivariate adjustment including age, impaired fasting glucose, cirrhosis, and time-varying body mass index, although CHB reduced the propensity of hepatic steatosis to develop diabetes, especially for patients with high levels of past viral-load trajectory. In CHB, the functional cure of HBV infection, as indicated by HBsAg seroclearance, was associated with a 1.41-fold (95% CI 1.12-1.79) increased risk of steatosis. In addition, the increased risk for progressive impairment of glucose metabolism due to steatosis was especially prominent after HBsAg seroclearance. CONCLUSION: The data showed that HBV interferes with fatty liver disease and modulates its related T2D risk, offering additional insight into the interplay between NAFLD and CHB.

Depression Is Associated with Downregulation of IPS-1 in Chronic HBV-Infected Patients in a Sex-Dependent Manner.

BACKGROUND: Depression and anxiety can modulate immune-related molecule expressions. The chronic HBV-infected (CHB) patients suffer from inappropriate immune responses. Additionally, psychological disorders are prevalent among the patients. Thus, depression and anxiety may alter immune-related molecule expression. This study aimed to examine IPS-1 and RIP1 mRNA levels in CHB patients suffering from various degrees of anxiety and depression. METHODS: Sixty patients with CHB participated in this research and completed standard questionnaires to evaluate depression and anxiety. The expression levels of IPS-1 and RIP1 were examined using real-time PCR techniques. RESULTS: The result revealed that although the expression of IPS-1 and RIP1 did not change in the CHB patients with various ranges of depression and anxiety, IPS-1 was significantly decreased in the male CHB patients who suffered from mild, moderate, and severe depression when compared to the patients with no depression. CONCLUSION: So, it was hypothesized that depression may be associated with alteration in the expression of IPS-1 in a sex-dependent manner. In other words, it appears that the male CHB patients are at risk of depression-related alteration in immune-related gene expression.

Tri-typing of hepatitis B-related acute-on-chronic liver failure defined by the World Gastroenterology Organization.

BACKGROUND AND AIM: Tri-typing of acute-on-chronic liver failure (ACLF), as proposed by the World Gastroenterology Organization (WGO), has not been validated in patients infected with hepatitis B virus (HBV). We aim to compare the three types of ACLF patients in clinic characteristics. METHODS: Hospitalized ACLF patients with chronic hepatitis B from five hepatology centers were retrospectively selected and grouped according to the WGO classification. For each group, we investigated laboratory tests, precipitating events, organ failure, and clinical outcome. RESULTS: Compared with type-B (n = 262, compensated cirrhosis) and type-C (n = 129, decompensated cirrhosis) ACLF, type-A patients (n = 195, non-cirrhosis) were associated with a younger age, the highest platelet counts, the highest aminotransferase levels, and the most active HBV replications. HBV reactivation were more predominant in type-A, while bacterial infections in type-B and type-C ACLF cases. Liver failure (97.4%) and coagulation failure (86.7%) were most common in type-A compared with type-B or type-C ACLF patients. Kidney failure was predominantly identified in type-C subjects (41.9%) and was highest (23/38, 60.5%) in grade 1 ACLF patients. Furthermore, type-C ACLF showed the highest 28-day (65.2%) and 90-day (75.3%) mortalities, compared with type-A (48.7% and 54.4%, respectively) and type-B (48.4% and 62.8%, respectively) ACLF cases. Compared with type-A (11.7%) ACLF patients, the increased mortality from 28 to 90 days was higher in type-B (31.6%) and type-C (37.5%). CONCLUSION: Tri-typing of HBV-related ACLF in accordance with the WGO definition was able to distinguish clinical characteristics, including precipitating events, organ failure, and short-term prognosis in ACLF patients.

Effects of chronic HBV infection on lipid metabolism in non-alcoholic fatty liver disease: A lipidomic analysis.

INTRODUCTION AND OBJECTIVES: Chronic hepatitis B virus (HBV) infection exerts an impact on lipid metabolism, but its interaction with dysmetabolism-based non-alcoholic fatty liver disease (NAFLD) remains uncertain. The purpose of the study was to investigate the effects of HBV infection on lipid metabolism, hepatic steatosis and related impairments of NAFLD patients. METHODS: Biopsy-proven Chinese NAFLD patients with (NAFLD-HBV group, n = 21) or without chronic HBV infection (NAFLD group, n = 41) were enrolled in the case-control study. Their serum lipidomics was subjected to individual investigation by ultra-performance liquid chromatography-tandem mass spectrometry. Steatosis, activity, and fibrosis (SAF) scoring revealed the NAFLD-specific pathological characteristics. RESULTS: Chronic HBV infection was associated with global alteration of serum lipidomics in NAFLD patients. Upregulation of phosphatidylcholine (PCs), choline plasmalogen (PC-Os) and downregulation of free fatty acids (FFAs), lysophosphatidylcholine (LPCs) dominated the HBV-related lipidomic characteristics. Compared to those of NAFLD group, the levels of serum hepatoxic lipids (FFA16:0, FFA16: 1, FFA18:1, FFA18:2) were significantly lowered in the NAFLD-HBV group. These low-level FFAs demonstrated correlation to statistical improvements in aspartate aminotransferase activity (FFA16:0, r = 0.33; FFA16:1, r = 0.37; FFA18:1, r = 0.32; FFA18:2, r = 0.42), hepatocyte steatosis (FFA16: 1, r = 0.39; FFA18:1, r = 0.39; FFA18:2, r = 0.32), and ballooning (FFA16:0, r = 0.30; FFA16:1, r = 0.45; FFA18:1, r = 0.36; FFA18:2, r = 0.30) (all P < 0.05). CONCLUSION: Chronic HBV infection may impact on the serum lipidomics and steatosis-related pathological characteristics of NAFLD.

Primary Hepatic Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in a Patient with Chronic Hepatitis B Virus Infection: Case Report and Summary of the Literature.

BACKGROUND: The incidence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is low, at 7-8% of all non-Hodgkin lymphoma cases. The most common site of MALT lymphoma occurrence is the stomach. Primary hepatic extranodal marginal zone lymphoma of MALT is classified as a type of non-gastric MALT lymphoma and is considered extremely rare, with no consensus on imaging study findings or treatment due to a limited number of reports. We herein describe a rare case of primary hepatic extranodal marginal zone lymphoma of MALT with underlying hepatitis B infection (HBV) and present useful diagnostic findings of various imaging modalities, including contrast-enhanced ultrasonography (CEUS) with Sonazoid. CASE PRESENTATION: A 66-year-old woman was diagnosed as being a non-active carrier of HBV at 51 years of age at the time of total hysterectomy and bilateral adnexectomy for uterine cervical cancer. She was admitted to our hospital following the incidental detection of two focal liver lesions on computed tomography. The lesions were considered malignant based on clinical and other radiologic imaging findings. Her CEUS results of hypo-enhancement in the portal and late phases were consistent with those of previously reported cases of hepatic extranodal marginal zone lymphoma of MALT, and histological liver biopsy findings were compatible with the diagnosis. CONCLUSIONS: Primary hepatic extranodal marginal zone lymphoma of MALT is a rare condition that can appear in HBV carriers. Characteristic CEUS findings may help in disease diagnosis. Clinicians should bear primary hepatic extranodal marginal zone lymphoma of MALT in mind when encountering patients with focal liver lesions which exhibit image findings different from those of typical hepatocellular carcinoma.

Association of LIN28B polymorphisms with chronic hepatitis B virus infection.

BACKGROUND: LIN28B is involved in multiple cellular developmental processes, tissue inflammatory response and tumourigenesis. The association of LIN28B polymorphisms with hepatitis B virus (HBV) infection remains unknown. METHODS: This study investigated the association of LIN28B rs314277, rs314280, rs369065 and rs7759938 polymorphisms in patients with chronic HBV infection, a major cause of liver disease including hepatocellular carcinoma (HCC). A total of 781 individuals including 515 cases of chronic HBV infection (91 asymptomatic carrier status, 128 chronic hepatitis, 127 cirrhosis and 169 HCC), 97 HBV infection resolvers and 169 healthy controls were investigated. RESULTS: LIN28 rs314280 genotypes GA + AA were higher in resolver and controls than patients (P = 0.011). Patients had significantly lower rs314280 allele A than resolvers (P = 0.031, OR 0.689, 95%CI 0.491-0.969) or controls (P = 0.034, OR 0.741, 95%CI 0.561-0.978). In dominant model, patients had significantly lower rs314280 genotypes AA+GA than controls (P = 0.008, OR 0.623, 95%CI 0.439-0.884). LIN28 rs7759938 genotypes TC + CC were higher in resolvers and controls than patients (P = 0.015). Patients had significantly lower rs7759938 allele C than resolvers (P = 0.048, OR 0.708, 95%CI 0.503-0.999). In dominant model, patients had significantly lower rs7759938 genotypes TC + CC than controls (P = 0.010, OR 0.632, 95%CI 0.445-0.897). Chronic hepatitis patients had lower frequency of rs369065 genotype TC than asymptomatic carriers, cirrhosis and HCC (P = 0.019). CONCLUSIONS: These results suggest that LIN28 rs314280 and rs7759938 may be related to the susceptibility of chronic HBV infection. Further studies are warranted to examine the association of LIN28B polymorphisms with HBV-related diseases, especially HCC.

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis.

BACKGROUND: T cell dysfunction occurs in many diseases, especially in chronic virus infection and cancers. However, up to now, little is known on the distinctions in T cell exhaustion between cancer and chronic virus infection. The objective of this study is to explore the transcriptional similarities and differences in exhausted CD8 +T cell between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). METHODS: RNA sequencing was performed to compare the transcriptome of CD8 +T cells isolated from healthy donors' blood, tumour tissues of patients with HCC and chronic HBV infected HCC patients' paracancerous tissues. DESeq2 algorithm was used to determine differentially expressed genes. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted for in-depth analysis of these differentially expressed genes. RESULTS: A total number of 2109 and 2203 genes were differentially expressed in patients with chronic HBV infection and HCC, respectively. Comparing these two groups of differentially deregulated genes, we found that nearly half of them were shared, and these shared genes were further classified into several functional categories, such as metabolic process, binding and intracellular organelle. KEGG analysis revealed that these shared deregulated genes were involved in many important pathways such as Parkinson's disease, oxidative phosphorylation and messenger RNA surveillance. Interestingly, we reported that chronic HBV infection specific deregulated genes were mainly enriched in graft versus host disease, allograft rejection, phenylalanine, tyrosine and tryptophan biosynthesis pathways. Whereas, HCC-specific deregulated genes were highly enriched in oxidative phosphorylation, thyroid cancer and endometrial cancer pathways. CONCLUSION: Our study demonstrated that T cell dysfunction associated with HCC and chronic HBV infection shares high similarities, however, each possesses its own features in terms of specific genes and signalling pathways. Uncovering the differences of T cells dysfunction would facilitate our understanding the diseases pathogenesis and developing innovative therapies in the future.

NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection.

BACKGROUND & AIMS: Phenotypic and functional natural killer (NK)-cell alterations are well described in chronic hepatitis B virus (cHBV) infection. However, it is largely unknown whether these alterations result from general effects on the overall NK-cell population or the emergence of distinct NK-cell subsets. Human cytomegalovirus (HCMV) is common in cHBV and is associated with the emergence of memory-like NK cells. We aimed to assess the impact of these cells on cHBV infection. METHODS: To assess the impact of memory-like NK cells on phenotypic and functional alterations in cHBV infection, we performed in-depth analyses of circulating NK cells in 52 patients with cHBV, 45 with chronic hepatitis C virus infection and 50 healthy donors, with respect to their HCMV serostatus. RESULTS: In patients with cHBV/HCMV+, FcεRIγ- memory-like NK cells were present in higher frequencies and with higher prevalence than in healthy donors with HCMV+. This pronounced HCMV-associated memory-like NK-cell expansion could be identified as key determinant of the NK-cell response in cHBV infection. Furthermore, we observed that memory-like NK cells consist of epigenetically distinct subsets and exhibit key metabolic characteristics of long-living cells. Despite ongoing chronic infection, the phenotype of memory-like NK cells was conserved in patients with cHBV/HCMV+. Functional characteristics of memory-like NK cells also remained largely unaffected by cHBV infection with the exception of an increased degranulation capacity in response to CD16 stimulation that was, however, detectable in both memory-like and conventional NK cells. CONCLUSIONS: The emergence of HCMV-associated memory-like NK cells shapes the overall NK-cell response in cHBV infection and contributes to a general shift towards CD16-mediated effector functions. Therefore, HCMV coinfection needs to be considered in the design of immunotherapeutic approaches that target NK cells in cHBV. LAY SUMMARY: In chronic hepatitis B virus infection, natural killer (NK)-cell phenotype and function is altered. In this study, we demonstrate that these changes are linked to the emergence of a distinct NK-cell subset, namely memory-like NK cells. The emergence of these memory-like NK cells is associated with coinfection of human cytomegalovirus that affects the majority of patients with chronic hepatitis B.

Evaluation of early myocardial dysfunction with strain echocardiography in chronic hepatitis B patients.

INTRODUCTION: It is well known that chronic hepatitis B virus infection (CHBV) can be associated with cirrhosis and hepatocellular carcinoma but it can also be associated with extra-hepatic effects, of which cardiac manifestations are the one of the least known. There is a limited amount of data about myocardial dysfunction in CHBV and insufficient data of strain echocardiography in CHBV. The aim of this study was to detect early myocardial dysfunction in CHBV using strain echocardiography. METHOD: This prospective study included 40 CHBV patients without anti-viral treatment, 40 CHBV patients under anti-viral treatment, and 40 healthy volunteers as control group from 2017 October to 2018 May. The patients in all groups were aged 30-60 years, with no co-morbid diseases. Any patients with pathologies that would cause myocardial dysfunction were excluded from the study. All patients were evaluated with transthoracic two-dimensional (2D), tissue Doppler, and strain echocardiography. RESULTS: The mean age and gender distribution were similar in all groups (P = 0.677). A statistically significant difference was determined between the groups in respect of the global circumferential strain and global longitudinal strain values (P < 0.01). The difference in the mean lateral s' was of statistical significance between the CHBV patients and the control group (P = 0.035). No statistically significant difference was determined in respect of the other echocardiographic parameters. CONCLUSION: As it is a chronic necro-inflammatory period, chronic HBV can affect myocardial functions. Traditional echocardiographic parameters may not be useful in the detection of early myocardial dysfunction. The results of this study showed that strain echocardiography may be more valuable in early myocardial dysfunction rather than routine 2D echocardiography in CHBV patients.