RESUMO
Background: Hepatitis B virus (HBV) is a global health problem endemic in Sub-Saharan Africa, with 65% of global cases occurring in the WHO Western Pacific and African regions. HBV is a known primary cause of kidney disease that progresses throughout the illness. Early detection of kidney disease and antiviral initiation can slow its progression. Our study aimed to identify the prevalence of kidney disease and associated factors in adults with chronic HBV. Methods: We conducted a cross-sectional study from November 2023 to December 2024 in Mbarara, Uganda, recruiting adults with chronic hepatitis B. Data collected: socio-demographics, comorbidities, coinfections, and hepatitis B-related data. Spot urine and blood were collected for dipstick, urine neutrophil gelatinase-associated lipocalin (NGAL), and creatinine with estimated glomerular filtration rate (eGFR). We defined kidney disease as the presence of (1) urine NGAL >132 ng/mL, (2) eGFR <60 mL/min/1.73 m2, or (3) eGFR between 60 and <90 mL/min/1.73 m2 with proteinuria or hematuria. We utilized logistic regression to determine factors associated with kidney disease. Results: We enrolled 157 participants with a mean age of 35.8 (standard deviation, ±12.5) years, and 50% (79/156) were males. Overall kidney disease prevalence was 27% (43/157; 95% confidence interval (CI): 20.6-35.1%). Prevalence based on urine NGAL was 17.2% (27/157; 95% CI: 11.6-24.0), eGFR <60 mL/min/1.73 m2 was 5.7% (9/157; 95% CI: 2.7-10.6), and eGFR between 60 and <90 mL/min/1.73 m2 with either proteinuria or hematuria was 9.6% (15/157; 95% CI: 5.4-15.3). Being female was associated with higher odds of kidney disease (adjusted odds ratio, 2.49; 95% CI: 1.16-5.36; P = 0.019). Conclusion: Nearly one-third of adults with chronic Hepatitis B in Uganda had kidney disease, with NGAL increasing the detection by 12% over creatinine and urine dipstick alone. We recommend frequent monitoring of kidney function in adults with chronic HBV.
RESUMO
OBJECTIVE: To investigate the incidence of colorectal polyps in patients with chronic hepatitis B (CHB) complicated by non - alcoholic fatty liver disease (NAFLD) and its risk factors. METHODS: A total of 505 patients who underwent electronic colonoscopy at The Tianjin Second People's Hospital from October 2018 to November 2023 and met the inclusion criteria were selected as the research subjects. They were divided into the CHB group, the NAFLD group, and the CHB + NAFLD group. Chi-square test, analysis of variance, and Kruskal Wallis rank sum test were used to compare the characteristics of the three groups of patients. Univariate and multivariate logistic regression were used to evaluate the risk factors for colorectal polyps in patients in the CHB + NAFLD group. RESULTS: (1) The detection rate of polyps in the NAFLD group was 73.9%, in the CHB + NAFLD group was 64.2%, and in the CHB group was 48.4%, with a statistically significant difference (P < 0.05). (2) There were statistically significant differences among the three groups in terms of sex, BMI, CAP, history of hypertension, ALT, GGT, ALB, FPG, TG, TC, TBA, UA, HDL, LDL, WBC, RBC, HGB, PLT, PT, and CA19-9(P < 0.05). (3) The CHB + NAFLD group mainly had multiple polyps (58.8%), most of the polyps were small, with polyps ≤ 0.5 cm accounting for 68.7%, and the proportion of polyps located in the distal colon was 40.5%. (4) In the comparison of inflammatory polyps among groups, detection rate of the NAFLD group was 9.8%, the CHB + NAFLD group was 5.3%, and the CHB group was 1.1%, with a statistically significant difference (P < 0.05).(5)Age(OR = 1.047,95%CI:1.016 ~ 1.080),diabetes(OR = 3.732,95%CI:1.044 ~ 13.335),WBC(OR = 1.272,95%CI:1.043 ~ 1.552) were independently associated with colorectal polyps development in the CHB + NAFLD group. CONCLUSION: More than half of the patients with CHB complicated by NAFLD can be detected with colorectal polyps. Age, diabetes, WBC were independently associated with colorectal polyps development in this group of people. Colonoscopy screening should be actively carried out for CHB patients complicated by NAFLD.
RESUMO
Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) remains a major global health challenge due to late diagnosis and high tumor heterogeneity. Cytokines, as key mediators of the tumor microenvironment, contribute to immune evasion and tumor progression in HBV-HCC. However, their prognostic significance remains unclear. Bulk RNA sequencing revealed differentially expressed cytokine genes in HBV-HCC. A cytokine-based gene signature was created using the LASSO model, and Single-cell RNA sequencing analyzed gene expression at the cellular level. Serum and in vitro assays confirmed the key cytokine's role in tumor progression. Ten cytokine genes were differentially expressed in HBV-HCC, and six (CCL19, CCL20, CXCL2, GHR, IL1RAP, and LIFR) were selected to construct the LASSO-based risk model. This six-cytokine signature stratified patients into high- and low-risk groups with significantly different overall survival (P < 0.0001), achieving an area under the curve (AUC) exceeding 0.7 for 3-year survival in both training and validation cohorts. scRNA-seq revealed distinct cellular expression patterns of these cytokines, providing insights into their roles in tumor heterogeneity. High-risk patients exhibited enriched cell proliferation pathways and pronounced immunosuppression, whereas low-risk patients were associated with metabolic pathways. Drug sensitivity analysis identified 61 differentially responsive antitumor agents between risk groups. Notably, serum GHR levels increased during fibrosis but declined significantly in HBV-HCC. Functional assays demonstrated that GHR overexpression suppressed proliferation, migration, and invasion while promoting apoptosis. Our study integrates bulk and single-cell transcriptomics with functional validation, unveiling cytokine-driven mechanisms in HBV-HCC. The cytokine-based prognostic model holds promise for risk stratification, immunomodulation, and personalized therapy, offering new avenues for improving HBV-HCC management.
RESUMO
BACKGROUND: Hepatocellular carcinoma, typically linked to chronic hepatitis B or C, usually presents with liver-related symptoms, mainly jaundice, abdominal pain, and weight loss, and rarely spreads beyond the liver. Bone metastases and their complications are uncommon and seldom the initial sign. CASE PRESENTATION: We report the case of a North African (Tunisian) man in his 70s with undiagnosed chronic hepatitis B who presented with back pain and was subsequently diagnosed with multifocal hepatocellular carcinoma. His clinical course was complicated by acute paraplegia due to spinal cord compression caused by vertebral metastases. CONCLUSION: This case highlights the variability in hepatocellular carcinoma presentations and underscores the need for heightened clinical vigilance in patients presenting with unexplained bone or neurological symptoms, even in the absence of overt hepatic signs. Skeletal metastases are rare in this tumor compared with other cancers. The diagnosis can be even more challenging when bone metastases are the predominant initial manifestation, particularly when neurological complications emerge early in the course of disease.
RESUMO
Hepatocellular carcinoma (HCC) was characterized by a highly complex genome, with structural variations (SVs) playing a significant role in its development. In this study, we employed Oxford Nanopore Technology long-read sequencing in paired tumor and adjacent normal liver tissues from 74 Chinese HCC patients to thoroughly characterize the landscape of somatic SVs. Our analysis revealed that somatic SVs were more prevalent in hepatitis B virus (HBV)-related HCC, with chromosome 1 emerging as a major hotspot, and several members of the chromosome 1 open reading frame (C1orf) family genes expression level exhibited significant age-related difference. Notably, HBV-related HCC cases exhibited a higher frequency of deletions, particularly among younger ones (≤ 35 years old). In addition, we observed an increased burden of HBV integration events in younger ones. Remarkably, the divergent-paired related homeobox (DPRX) loci was identified as a novel gene for HBV integration in younger patients. Together, these findings delineated the somatic SV landscape in HCC and underscored age-associated HBV-related genomic alterations as key pathological features of hepatocarcinogenesis.
RESUMO
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) poses significant health challenges globally, particularly in regions with considerable HBV prevalence such as Egypt. Despite immunisation programmes, HBV remains a leading cause of liver cancer in Egypt, often diagnosed at advanced stages, complicating management and worsening prognosis. This retrospective multicentre study included 365 Egyptian patients diagnosed with HBV-related HCC between February 2007 and July 2023 from six tertiary care centres across Egypt. Clinical, laboratory, tumour characteristics, treatment outcomes and overall survival were collected and analysed. Diagnosis was confirmed according to international guidelines using triphasic CT or dynamic MRI. Treatment responses were assessed using modified RECIST criteria, and survival was analysed using Kaplan-Meier curves. Patients had a median age of 59 years, predominantly male (76.4%), and most (98.4%) presented with cirrhosis at diagnosis. The majority were not receiving antiviral treatment (76.71%) at presentation. Intermediate and advanced BCLC stages (B-D) comprised over 75% of cases. Trans-arterial chemoembolization was the primary treatment modality (34.5%), followed by sorafenib (24.1%) and best supportive care (28.8%). Median overall survival was 13.1 months. Independent factors associated with mortality included high ALBI score, positive HBV DNA at diagnosis, and advanced Child-Pugh classification. In conclusion: this study underscores the advanced stage at which HBV-related HCC is typically diagnosed in Egypt and the resulting poor survival outcomes. Strengthening early detection through surveillance programmes, increasing antiviral therapy coverage and adherence to treatment protocols are critical strategies to enhance patient prognosis.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Hepatite B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Egito/epidemiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Idoso , Adulto , Resultado do Tratamento , Antivirais/uso terapêutico , Hepatite B/complicações , Hepatite B Crônica/complicações , Quimioembolização Terapêutica , Análise de SobrevidaRESUMO
This study aims to analyze the predictive value of preoperative hepatitis B surface antigen (HBsAg) level in terms of recurrence after radical resection in treatment-naïve patients with hepatitis B virus (HBV)-related primary hepatocellular carcinoma (HCC) who have not received antiviral therapy. This study performed a retrospective analysis of the clinical data of 301 patients with or without high HbsAg levels who underwent partial hepatectomy for HCC. The primary end point of this study was relapse-free survival (RFS). After a follow-up period of 25.9â ±â 16.3 months, recurrence was observed in 227 (75.4%) patients with HCC. Among all the patients, RFS was better for those with low serum level of HbsAg, and RFS was better for those who received postoperative antiviral therapy. And RFS was similar for patients who did not receive antiviral treatment no matter HbsAg level. High preoperative serum level of HBsAg was associated with poor RFS of HBV-related HCC. This finding suggest HBsAg as a predictor of short-term prognosis, as well as an indicator for follow-up in postoperative HBV-related HCC patients. In addition, postoperative antiviral therapy may improve prognosis of patients with HBV-associated HCC, with more significant benefits observed in patients with low preoperative serum HBsAg levels.
Assuntos
Carcinoma Hepatocelular , Antígenos de Superfície da Hepatite B , Hepatite B , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/sangue , Antígenos de Superfície da Hepatite B/sangue , Estudos Retrospectivos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Hepatectomia , Antivirais/uso terapêutico , Idoso , Adulto , Período Pré-Operatório , Prognóstico , Hepatite B/complicações , Vírus da Hepatite B , Valor Preditivo dos TestesRESUMO
Domestic cat hepatitis B virus (DCHBV), shares similarities with human hepatitis B virus (HBV) which is associated with liver disease. We report the first case of cholangiocarcinoma in a 17-year-old spayed female cat infected with DCHBV and positive for feline immunodeficiency virus. The patient presented with vomiting, anorexia, and an elevated globulin level. Ultrasonography revealed multiple hypoechoic hepatic lesions, and histopathology confirmed cholangiocarcinoma. The tumor exhibited CK7 positivity and HepPar-1 negativity, confirming biliary origin. Quantitative PCR detected DCHBV in the spleen and ascitic fluid, while immunohistochemistry and RNA in situ hybridization revealed viral antigen and mRNA in both tumor and non-tumor liver. The presence of a viral antigen and mRNA in neoplastic tissue suggests a potential role for DCHBV in hepatobiliary carcinogenesis.
RESUMO
Background: Hepatitis B virus-related chronic liver disease (HBV-CLD), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) patients' tongue coating microbiota dysbiosis has not yet been clearly defined. Objectives: We aimed to reveal shifts in the bacterial composition of tongue coating microbiota during the progression of HBV-CLD in three different phases. Design: We examined tongue coating microbiota of 16 healthy individuals and 81 patients with HBV-CLD, including 25 with CHB, 27 with LC, and 29 with HCC, using 16S rRNA gene sequencing technique. Results: The bacterial richness in tongue coating was higher in patients with HBV-CLD (all P < 0.05) than in healthy controls. A clear clustering pattern between patients with HBV-CLD and healthy controls is shown using beta diversity analysis (all p < 0.05). Linear discriminant analysis revealed multiple taxa that varied significantly in abundance between healthy controls and patients with HBV-CLD; Firmicutes were higher in patients with LC and HCC, whereas CHB patients had higher levels of Bacteroidetes. PICRUSt2 analysis of the sequencing data revealed changes in microbial activity with disease development. Conclusions: Our investigation revealed tongue coating microbiota dysbiosis in patients with HBV-CLD, which may offer unique diagnostic possibilities and provide microbial biomarkers for monitoring disease progression.
RESUMO
The development of therapeutic strategies capable of achieving functional cure remains an unmet need in chronic hepatitis B management. Class A capsid assembly modulators (CAM-As) emerge as a promising treatment option. CAM-As not only directly disrupt the normal assembly of capsids, but some of which have also been reported to activate the innate immune response in animal models with unclear mechanisms. GLS4 is one of CAM-As with great potential. In this study, we investigate its capacity to activate immune response both in vitro and in vivo, as well as the underlying mechanisms involved. GLS4 activates the RIG-I-mediated interferon signaling pathway in both HBV-expressing hepatocellular carcinoma cell lines and HBV carrier mouse models, as indicated by RNA-seq. Besides, combination treatment with GLS4 and ritonavir elevates the frequencies of both peripheral blood IFNγ + NK cells and liver-resident IFNγ + CD8+ T cells in the pAAV/HBV1.2 hydrodynamic injection (HDI) model. In conclusion, our study reveals a previously unknown mechanism by which GLS4 activates the interferon signaling pathway in HBV-expressing hepatocytes. Furthermore, GLS4 partially restores innate and adaptive immunity in vivo. This signifies a potentially effective strategy for achieving a functional cure for HBV infection.
Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Hepatite B , Interferons , Transdução de Sinais , Animais , Transdução de Sinais/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Camundongos , Humanos , Modelos Animais de Doenças , Interferons/metabolismo , Interferons/imunologia , Imunidade Inata/efeitos dos fármacos , Hepatócitos/virologia , Hepatócitos/imunologia , Hepatócitos/efeitos dos fármacos , Hepatite B/imunologia , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Células Matadoras Naturais/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Imunidade AdaptativaRESUMO
Infection with HBV and its satellite virus HDV remain a significant global health issue due to their involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin's lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HBV in BNHL development, although mechanistic insight is lacking and the role of HDV infection in this process is unknown. To help elucidate viral drivers of B cell transformation, we performed RNA-sequencing on peripheral B cells from patients with HBV mono-infection, HBV/HDV co-infection, HBV/HDV-associated BNHL, BNHL without viral infection, and healthy donors. In this way, we sought to identify unique and shared transcriptional profiles associated with viral infection and transformation. Our data suggest dysregulated epigenetic and miRNA-mediated regulatory gene expression may be a potential common pathway for lymphomagenesis among viral- and non-viral-associated lymphoma. We also observed wide-spread upregulation of snoRNAs in B cells from virally infected patients, supporting a role for these non-coding RNAs in viral infection and, potentially, viral-associated lymphomagenesis. These results have identified novel areas for future functional studies on the effect of HBV and HDV infection on B cell activity and present additional therapeutic strategies that may benefit both viral- and non-viral associated BNHL.
RESUMO
Hepatitis B virus (HBV) remains a major cause of chronic liver diseases, especially in the Asia-Pacific region. In recent decades, coinfection with hepatitis C virus (HCV) and coexistence with metabolic dysfunction-associated steatotic liver disease (MASLD) have emerged as significant clinical concerns among HBV-infected subjects. Although global HBV vaccination programs and curative therapies for HCV have led to a marked decline in HBV/HCV coinfection, MASLD is rapidly becoming the predominant comorbidity due to the global surge in metabolic risk factors. HBV/HCV coinfection typically results in more severe liver damage, with unique challenges in antiviral treatment and risk of HBV reactivation post-HCV clearance. In contrast, HBV/MASLD overlap demonstrates complex metabolic-viral interactions that may influence viral replication, hepatitis B surface antigen seroclearance, fibrosis progression, and risk of hepatocellular carcinoma. This review critically compares the epidemiology, clinical outcomes, and management strategies of HBV patients with concurrent HCV or MASLD, while addressing current research gaps and proposing directions for future investigations.
RESUMO
OBJECTIVES: To establish a metabolic burden-based clinical-radiological model for predicting postoperative recurrence in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) at Barcelona Clinic Liver Cancer (BCLC) stages 0-A. MATERIALS AND METHODS: This retrospective multi-center study included HBV-related HCC (BCLC 0-A) undergoing curative surgery. Metabolic burden was defined as the cumulative number of metabolic abnormalities. Trend test assessed dose-dependent relationship. Predictors were identified via univariate and multivariate Cox regression analyses, and a nomogram was developed. The model underwent internal validation (5-fold, 100 times cross) and external validation. Performance was evaluated using C-index, calibration curves, and decision curve analysis. RESULTS: The internal and external cohorts consisted of 363 patients (55.9 ± 10.7 years, 295 males) and 74 patients (55.5 ± 10.2 years, 55 males). Recurrence risk increased by 1.53 times (p = 0.049) and 1.64 times (p = 0.018) for patients with 2 and 3-4 metabolic abnormalities (ptrend = 0.022). Independent predictors included tumor burden score > 2.4 (HR = 2.40, p = 0.003), metabolic abnormalities ≥ 2 (HR = 1.49, p = 0.023), aspartate transaminase/alanine transaminase ratio > 1 (HR = 1.51, p = 0.012), albumin-bilirubin grade 2 (HR = 1.70, p = 0.020), arterial rim enhancement (HR = 1.87, p = 0.002) and mosaic appearance (HR = 1.55, p = 0.033). C-indices for predicting 2- and 5-year recurrence were 0.728 (95% CI: 0.726-0.729) and 0.674 (95% CI: 0.673-0.675) in training sets, 0.716 (95% CI: 0.711-0.720) and 0.657 (95% CI: 0.653-0.660) in internal validation sets, and 0.710 (95% CI: 0.602-0.855) and 0.683 (95% CI: 0.594-0.798) in external cohort. The model showed higher predictive efficacy (p < 0.001 for all) and better clinical net benefit compared to BCLC and CNLC staging systems in the very early/early-stage of HCCs. CONCLUSION: The metabolic burden-based clinical-radiological model effectively predicts postoperative recurrence in HBV-related HCC. CRITICAL RELEVANCE STATEMENT: Patients with HBV-related HCC who have two or more coexisting metabolic abnormalities may have a higher risk of postoperative recurrence. The metabolic burden-based clinical-radiological model is valuable in predicting postoperative recurrence KEY POINTS: Metabolic abnormalities were dose-dependently related to the risk of postoperative recurrence. The clinical-radiological model showed well-predictive efficacy in validation cohorts. The clinical-radiological model displayed higher efficacy compared to existing staging systems for the very early/early-stage of HCCs.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown. METHODS: We compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes. RESULTS: C. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1+ macrophages, exhausted CD8+ T cells and COL1A1+ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2+ liver vascular endothelial cells, respectively. CONCLUSION: These findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.
Assuntos
Carcinoma Hepatocelular , Clonorquíase , Clonorchis sinensis , Hepatite B , Neoplasias Hepáticas , Análise de Célula Única , Transcriptoma , Humanos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/parasitologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/parasitologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Vírus da Hepatite B , Análise de Célula Única/métodos , Prognóstico , Masculino , Hepatite B/complicações , Hepatite B/virologia , Feminino , Clonorquíase/complicações , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Perfilamento da Expressão Gênica , Biomarcadores TumoraisRESUMO
BACKGROUND: Hepatitis B virus (HBV) is clinically associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), while cellular communication in the tumour microenvironment (TME) is recognized as a critical driver of tumour progression. Nevertheless, whether HBV infection mediates DLBCL cell-immune cell crosstalk remains undefined, with the precise mechanisms and associated key molecules remaining elusive. METHODS: SsGSEA, Cox regression (univariate/multivariate), WGCNA, and Kaplan-Meier analyses identified prognostic immune subsets and miRNAs in HBV+ DLBCL. Dual luciferase assay, qRT-PCR, western blot, ChIP, Co-IP, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and murine models were employed together to evaluate CD4+ T cell dysfunction in vitro and in vivo. ScRNA-seq analyses encompassed clustering, pseudotemporal trajectory, and ligand-receptor networks to decode TME dynamics. RESULTS: TME profiling identified diminished CD4⺠T cell infiltration as an independent predictor of poor survival in HBV⺠DLBCL. Mechanistically, HBx-mediated down-regulation of miR-19a-3p activated the BAMBI/Wnt signalling pathway, thereby enhancing TGF-ß1 secretion and suppressing the anti-tumour activity of CD4+ T cells. Single-cell analysis revealed that BAMBIhigh DLBCL cells engage CD4+ T cells via TGFB1-TGFBR2 pair, with TGFBR2 enriched in exhausted subsets of CD4+ T cells and shaping their dysfunctional fate. Therapeutic restoration of miR-19a-3p or blockade of TGF-ß reinforced the CD4⺠T cell anti-tumour activity and restrained the progression of HBx-overexpressing DLBCL in vivo. CONCLUSIONS: HBx promoted TGF-ß1 hypersecretion via miR-19a-3p repression-mediated Wnt/ß-catenin activation, directly driving CD4+ T cell depletion and functional exhaustion in DLBCL. Our work provided important insights into the immune determinants of poor prognosis in HBV+ DLBCL, highlighting the pivotal role of CD4+ T cell dysfunction in driving disease progression and adverse clinical outcomes. HIGHLIGHTS: Reduced CD4+ T cell enrichment in the TME predicted poor survival in HBV+ DLBCL. Down-regulation of miR-19a-3p by HBx activated the BAMBI-mediated Wnt signalling, amplifying TGF-ß1 secretion to suppress anti-tumour activity of CD4⺠T cells. The TGF-B1/TGFBR2 pair mediated the HBV+ DLBCL-CD4+ T cell communication. Targeting TGF-ß or miR-19a-3p improved CD4+ T cell immunity to suppress HBV+ DLBCL progression.
Assuntos
Linfócitos T CD4-Positivos , Linfoma Difuso de Grandes Células B , MicroRNAs , Transativadores , Fator de Crescimento Transformador beta1 , Proteínas Virais Reguladoras e Acessórias , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Camundongos , Proteínas Virais Reguladoras e Acessórias/metabolismo , Transativadores/metabolismo , Transativadores/genética , Microambiente Tumoral/imunologia , Vírus da Hepatite B/patogenicidade , Masculino , Feminino , Hepatite BRESUMO
BACKGROUND & AIMS: The presence of metabolic comorbidities is associated with a higher risk of liver-related events in chronic hepatitis B (CHB) patients. However, the association between presence of metabolic comorbidities and the severity of biopsy-proven liver fibrosis is yet unknown. METHODS: Data from CHB patients from 2 tertiary clinics and 8 clinical trials was analyzed. We studied the association between presence of metabolic comorbidities with severity of liver fibrosis in untreated patients, and with fibrosis regression or progression in biopsies taken after initiation of antiviral therapy. RESULTS: We analyzed biopsies from 3179 untreated CHB patients. Median age was 37 years, 57.6% were hepatitis B e antigen positive, with median hepatitis B virus DNA of 7.30 logIU/mL. Overweight (29.4% vs 19.0%; P < .001), hypertension (40.7% vs 23.2%; P < .001), diabetes (42.2% vs 23.6%; P < .001), and dyslipidemia (42.9 vs 23.6%; P < .001) were associated with a higher risk of advanced fibrosis, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in multivariable analysis (1 comorbidity: adjusted odds ratio [aOR], 1.115; ≥2 comorbidities: aOR, 1.627; P = .006). Regression to nonadvanced fibrosis, after treatment initiation, was more often observed in patients without metabolic comorbidities (43.1%), compared with patients with 1 (31.6%) or ≥2 comorbidities (17.0%) (P = .005). Findings were consistent in multivariable analysis (1 comorbidity: aOR, 0.792; ≥2 comorbidities: aOR, 0.260; P = .025). The risk of progression to advanced fibrosis was highest in patients with ≥2 comorbidities (14.3% vs 4.6%; P = .001). CONCLUSIONS: Presence of metabolic comorbidities in untreated CHB patients is associated with more severe liver fibrosis and, after initiation of antiviral therapy, with less fibrosis regression and a higher risk of fibrosis progression.
Assuntos
Hepatite B Crônica , Cirrose Hepática , Humanos , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Masculino , Feminino , Adulto , Cirrose Hepática/patologia , Cirrose Hepática/epidemiologia , Pessoa de Meia-Idade , Comorbidade , Índice de Gravidade de Doença , Biópsia , Antivirais/uso terapêutico , Adulto Jovem , Progressão da DoençaRESUMO
BACKGROUND AND AIMS: HCC poses a significant global health burden, with HBV being the predominant etiology in China. However, current diagnostic markers lack the requisite sensitivity and specificity. This study aims to develop and validate serum N-glycomics-based models for the diagnosis and prognosis of HCC in patients with chronic hepatitis B-related cirrhosis. APPROACH AND RESULTS: This study enrolled a total of 397 patients with chronic hepatitis B-related cirrhosis and HCC for clinical management. N-glycomics profiling was conducted on all participants, and clinical data were collected. First, machine learning-based models, Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, were established for early screening and diagnosis of HCC using N-glycomics. The AUC values in the validation set were 0.967 (95% CI: 0.930-1.000) and 0.908 (0.840-0.976) for Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, respectively, outperforming AFP (0.687 [0.575-0.765]) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) (0.665 [0.507-0.823]). It also showed superiority in subgroup analysis and external validation. Calibration and decision curve analysis also showed good predictive performance. Additionally, we developed a prognostic model, the prog-G model, based on N-glycans to monitor recurrence in patients with HCC after curative treatment. During the follow-up period, it was observed that this model correlated with the clinical condition of the patients and could identify all recurrent HCC cases (n=12) prior to imaging findings, outperforming AFP (n=7) and PIVKA-II (n=9), while also detecting recurrent lesions earlier than imaging. CONCLUSIONS: N-glycomics models can effectively predict the occurrence and recurrence of HCC to improving the efficiency of clinical decision-making and promoting the precision treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Detecção Precoce de Câncer , Glicômica , Hepatite B Crônica , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/patologia , Hepatite B Crônica/complicações , Hepatite B Crônica/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Glicômica/métodos , Detecção Precoce de Câncer/métodos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/sangue , Adulto , Cirrose Hepática/virologia , Cirrose Hepática/sangue , Estudos de Coortes , Prognóstico , Biomarcadores Tumorais/sangue , Máquina de Vetores de Suporte , alfa-Fetoproteínas/análise , China/epidemiologia , Precursores de Proteínas , Protrombina , BiomarcadoresRESUMO
BACKGROUD: Hepatitis B virus (HBV) infection can cause cholesterol accumulation, induce endoplasmic reticulum stress (ERS) and enhance autophagy in hepatocytes. However, the mechanisms underlying these interactions remain unclear, as well as the potential benefit of cholesterol-lowering treatment in patients with chronic hepatitis B (CHB). Therefore, the effects of of cholesterol accumulation caused by HBV on ERS and autophagy were explored in this study, aiming to identify the key molecules mediating the crosstalk between ERS and endoplasmic reticulophagy (ER-phagy). METHODS: Bioinformatics, immunohistochemistry (IHC), proteomics, western blot, and transmission electron microscopy (TEM) were used to analyse clinical specimens, HBV transgenic animal and cell models. RESULTS: Analysis of Gene Expression Omnibus (GEO) database demonstrated that the transcription levels of LDLR, SREBF2/SREBP2, ATF6, MAP1LC3B/LC3B and SQSTM1/P62 in CHB tissues were higher than those in normal liver tissues. The IHC results showed that the expressions of LDLR, SREBP2, GRP78, ATF6, LC3B, P62 and FAM134B in CHB tissues were higher than those in normal liver tissues. The free cholesterol content, the expression of GRP78, ATF6, LC3B II, P62 and FAM134B were higher in the livers of HBV transgenic mice and HepG2.2.15 cells compared with their control groups. TEM showed endoplasmic reticulum (ER) expansion and degranulation, as well as ER-phagy, in the livers of HBV transgenic mice and HepG2.2.15 cells. Furthermore, melatonin administration, an ATF6 inhibitor, attenuated hepatic inflammation, alleviated ERS, downregulated ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells. Fatostatin administration, a cholesterol synthesis inhibitor, attenuated hepatic inflammation, decreased the free cholesterol content, alleviated ERS, downregulated GRP78 and ATF6 expression, and inhibited ER-phagy in HBV transgenic mice and HepG2.2.15 cells CONCLUSION: HBV infection leads to cholesterol accumulation in hepatocytes, which promotes ATF6-mediated ERS and FAM134B-mediated ER-phagy. Reducing intracellular cholesterol accumulation alleviates ATF6-mediated ERS, inhibits FAM134B-mediated ER-phagy, and attenuates hepatic inflammation. ATF6 may represent a promising therapeutic target for an adjuvant treatment of CHB. Our study provides experimental evidence for the use of statin as an adjuvant treatment of CHB.
Assuntos
Fator 6 Ativador da Transcrição , Autofagia , Colesterol , Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Vírus da Hepatite B , Hepatite B Crônica , Animais , Humanos , Fator 6 Ativador da Transcrição/metabolismo , Colesterol/metabolismo , Chaperona BiP do Retículo Endoplasmático , Vírus da Hepatite B/fisiologia , Camundongos , Células Hep G2 , Camundongos Transgênicos , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Masculino , Retículo Endoplasmático/metabolismoRESUMO
Chronic hepatitis B virus (HBV) infection remains a significant concern in public health, and if unmanaged, is associated with hepatocellular carcinoma and liver cirrhosis. Despite the availability of an effective vaccine, many individuals remain susceptible to infection in the US, especially individuals with experiences of homelessness and other commonly housing-unstable populations, such as veterans, formerly incarcerated individuals and intravenous drug users (IDU). At various low-income housing sites in Texas, a team of Community Health Workers (CHWs) offered residents and visitors no-cost HBV testing and vaccination. In total, 524 individuals received the first dose of the two-dose or three-dose HBV vaccine and 305 (58.21%) completed their vaccination series. A multivariable logistic regression was performed to determine associations between completion of vaccination series and demographic factors. Older age was shown to be predictive of completion of the HBV vaccination series, while other demographic factors such as gender, race and ethnicity were not associated with series completion. Receiving the two-dose compared to the three-dose vaccine and the year the vaccine series was initiated were also associated with vaccine uptake. Kaplan-Meir survival analysis showed that the difference in completion rates by age was most pronounced among those receiving the three-dose vaccine. Additionally, our low-barrier, CHW-based strategy for HBV vaccination resulted in a relatively high vaccine series completion rate (almost 60% of those who initiated a series), as compared to similar programs serving at-risk populations in a non-healthcare-based setting. This analysis highlights the need for low-barrier and convenience-based HBV vaccination programs to reduce viral hepatitis B susceptibility in at-risk US populations.