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The New England Journal of Medicine Jul 2023
Review
Topics: Humans; Hepatitis Delta Virus; Hepatitis D; Hepatitis B Surface Antigens; Hepatitis B virus
PubMed: 37407002
DOI: 10.1056/NEJMra2212151 -
International Journal of Molecular... Nov 2023Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it... (Review)
Review
Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it is not restricted to them and can also involve smaller vessels. The clinical presentation is heterogeneous and characterized by a significant number of patients exhibiting general symptoms, including asthenia, fever, and unintended weight loss. Although PAN can involve virtually any organ, it preferentially affects the skin, nervous system, and the gastrointestinal tract. Orchitis is a rare but specific manifestation of PAN. The absence of granulomas, glomerulonephritis, and anti-neutrophil cytoplasmic antibodies serves to distinguish PAN from other types of vasculitis. Major complications consist of hemorrhagic and thrombotic events occurring in mesenteric, cardiac, cerebral, and renal systems. Historically, PAN was frequently linked to hepatitis B virus (HBV) infection, but this association has dramatically changed in recent years due to declining HBV prevalence. Current epidemiological research often identifies a connection between PAN and genetic syndromes as well as neoplasia. This article provides a comprehensive review of PAN, specifically focusing on the progression of its clinical manifestations over time.
Topics: Male; Humans; Polyarteritis Nodosa; Vasculitis; Hepatitis B; Hepatitis B virus; Gastrointestinal Tract
PubMed: 38068989
DOI: 10.3390/ijms242316668 -
Digestive Diseases and Sciences Aug 2023Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease.... (Review)
Review
Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.
Topics: Coinfection; Humans; Hepatitis Delta Virus; Hepatitis D; Superinfection; Hepatitis B virus
PubMed: 37338616
DOI: 10.1007/s10620-023-07960-y -
Hepatology (Baltimore, Md.) Jan 2024Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer....
BACKGROUND AND AIMS
Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer. Interferon-alpha (IFN-α) therapy is a conventional immunotherapy that has been widely used in CHB treatment and achieved promising therapeutic outcomes by activating viral sensors and interferon-stimulated genes (ISGs) suppressed by HBV. However, the longitudinal landscape of immune cells of CHB patients and the effect of IFN-α on the immune system are not fully understood.
APPROACH AND RESULTS
Here, we applied single-cell RNA sequencing (scRNA-seq) to delineate the transcriptomic landscape of peripheral immune cells in CHB patients before and after PegIFN-α therapy. Notably, we identified three CHB-specific cell subsets, pro-inflammatory (Pro-infla) CD14+ monocytes, Pro-infla CD16+ monocytes and IFNG+ CX3CR1- NK cells, which highly expressed proinflammatory genes and positively correlated with HBsAg. Furthermore, PegIFN-α treatment attenuated percentages of hyperactivated monocytes, increased ratios of long-lived naive/memory T cells and enhanced effector T cell cytotoxicity. Finally, PegIFN-α treatment switched the transcriptional profiles of entire immune cells from TNF-driven to IFN-α-driven pattern and enhanced innate antiviral response, including virus sensing and antigen presentation.
CONCLUSIONS
Collectively, our study expands the understanding of the pathological characteristics of CHB and the immunoregulatory roles of PegIFN-α, which provides a new powerful reference for the clinical diagnosis and treatment of CHB.
Topics: Humans; Hepatitis B, Chronic; Antiviral Agents; Interferon-alpha; Transcriptome; Sequence Analysis, RNA; Hepatitis B virus; Hepatitis B Surface Antigens; Hepatitis B e Antigens; DNA, Viral
PubMed: 37368993
DOI: 10.1097/HEP.0000000000000524 -
Hepatology (Baltimore, Md.) Oct 2023The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH)...
BACKGROUND AND AIMS
The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis.
APPROACH AND RESULTS
A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve.IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data.
CONCLUSIONS
Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Case-Control Studies; Hepatitis B virus; Liver Neoplasms; Tumor Microenvironment
PubMed: 37114494
DOI: 10.1097/HEP.0000000000000427 -
Signal Transduction and Targeted Therapy Sep 2023The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) serves not only as a bicistronic message RNA to translate core protein (Cp) and DNA polymerase (Pol), but also as...
The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) serves not only as a bicistronic message RNA to translate core protein (Cp) and DNA polymerase (Pol), but also as the template for reverse transcriptional replication of viral DNA upon packaging into nucleocapsid. Although it is well known that pgRNA translates much more Cp than Pol, the molecular mechanism underlying the regulation of Cp and Pol translation efficiency from pgRNA remains elusive. In this study, we systematically profiled HBV nucleocapsid- and pgRNA-associated cellular proteins by proteomic analysis and identified TIA-1-related protein (TIAR) as a novel cellular protein that binds pgRNA and promotes HBV DNA replication. Interestingly, loss- and gain-of-function genetic analyses showed that manipulation of TIAR expression did not alter the levels of HBV transcripts nor the secretion of HBsAg and HBeAg in human hepatoma cells supporting HBV replication. However, Ribo-seq and PRM-based mass spectrometry analyses demonstrated that TIAR increased the translation of Pol but decreased the translation of Cp from pgRNA. RNA immunoprecipitation (RIP) and pulldown assays further revealed that TIAR directly binds pgRNA at the 5' stem-loop (ε). Moreover, HBV replication or Cp expression induced the increased expression and redistribution of TIAR from the nucleus to the cytoplasm of hepatocytes. Our results thus imply that TIAR is a novel cellular factor that regulates HBV replication by binding to the 5' ε structure of pgRNA to tip the balance of Cp and Pol translation. Through induction of TIAR translocation from the nucleus to the cytoplasm, Cp indirectly regulates the Pol translation and balances Cp and Pol expression levels in infected hepatocytes to ensure efficient viral replication.
Topics: Humans; Cytoplasm; Hepatitis B virus; Proteomics; RNA
PubMed: 37699883
DOI: 10.1038/s41392-023-01573-7 -
Journal of Translational Medicine Jun 2023Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation...
BACKGROUND
Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation and metabolic disorders contribute to the progression of ACLF, but the crosstalk between immunity and metabolism during ACLF is less understood. This study aims to depict the immune microenvironment in the liver during ACLF, and explore the role of lipid metabolic disorder on immunity.
METHODS
Single-cell RNA-sequencing (scRNA-seq) was performed using the liver non-parenchymal cells (NPCs) and peripheral blood mononuclear cells (PBMCs) from healthy controls, cirrhosis patients and ACLF patients. A series of inflammation-related cytokines and chemokines were detected using liver and plasma samples. The lipid metabolomics targeted free fatty acids (FFAs) in the liver was also detected.
RESULTS
The scRNA-seq analysis of liver NPCs showed a significant increase of monocytes/macrophages (Mono/Mac) infiltration in ACLF livers, whereas the resident Kupffer cells (KCs) were exhausted. A characterized TREM2 Mono/Mac subpopulation was identified in ACLF, and showed immunosuppressive function. Combined with the scRNA-seq data from PBMCs, the pseudotime analysis revealed that the TREM2 Mono/Mac were differentiated from the peripheral monocytes and correlated with lipid metabolism-related genes including APOE, APOC1, FABP5 and TREM2. The targeted lipid metabolomics proved the accumulation of unsaturated FFAs associated with α-linolenic acid (α-LA) and α-LA metabolism and beta oxidation of very long chain fatty acids in the ACLF livers, indicating that unsaturated FFAs might promote the differentiation of TREM2 Mono/Mac during ACLF.
CONCLUSIONS
The reprogramming of macrophages was found in the liver during ACLF. The immunosuppressive TREM2 macrophages were enriched in the ACLF liver and contributed to the immunosuppressive hepatic microenvironment. The accumulation of unsaturated FFAs in the ACLF liver promoted the reprogramming of the macrophages. It might be a potential target to improve the immune deficiency of ACLF patients through regulating lipid metabolism.
Topics: Humans; Lipid Metabolism; Acute-On-Chronic Liver Failure; Hepatitis B virus; Leukocytes, Mononuclear; Macrophages; Fatty Acid-Binding Proteins
PubMed: 37380987
DOI: 10.1186/s12967-023-04294-1 -
Journal of Hepatology Feb 2024Hepatitis delta virus (HDV) is a satellite RNA virus that requires the hepatitis B virus (HBV) for assembly and propagation. Individuals infected with HDV progress to... (Review)
Review
BACKGROUND & AIMS
Hepatitis delta virus (HDV) is a satellite RNA virus that requires the hepatitis B virus (HBV) for assembly and propagation. Individuals infected with HDV progress to advanced liver disease faster than HBV-monoinfected individuals. Recent studies have estimated the global prevalence of anti-HDV antibodies among the HBV-infected population to be 5-15%. This study aimed to better understand HDV prevalence at the population level in 25 countries/territories.
METHODS
We conducted a literature review to determine the prevalence of anti-HDV and HDV RNA in hepatitis B surface antigen (HBsAg)-positive individuals in 25 countries/territories. Virtual meetings were held with experts from each setting to discuss the findings and collect unpublished data. Data were weighted for patient segments and regional heterogeneity to estimate the prevalence in the HBV-infected population. The findings were then combined with The Polaris Observatory HBV data to estimate the anti-HDV and HDV RNA prevalence in each country/territory at the population level.
RESULTS
After adjusting for geographical distribution, disease stage and special populations, the anti-HDV prevalence among the HBsAg+ population changed from the literature estimate in 19 countries. The highest anti-HDV prevalence was 60.1% in Mongolia. Once adjusted for the size of the HBsAg+ population and HDV RNA positivity rate, China had the highest absolute number of HDV RNA+ cases.
CONCLUSIONS
We found substantially lower HDV prevalence than previously reported, as prior meta-analyses primarily focused on studies conducted in groups/regions that have a higher probability of HBV infection: tertiary care centers, specific risk groups or geographical regions. There is large uncertainty in HDV prevalence estimates. The implementation of reflex testing would improve estimates, while also allowing earlier linkage to care for HDV RNA+ individuals. The logistical and economic burden of reflex testing on the health system would be limited, as only HBsAg+ cases would be screened.
IMPACT AND IMPLICATIONS
There is a great deal of uncertainty surrounding the prevalence of hepatitis delta virus among people living with hepatitis B virus at the population level. In this study, we aimed to better understand the burden in 25 countries and territories, to refine techniques that can be used in future analyses. We found a lower prevalence in the majority of places studied than had been previously reported. These data can help inform policy makers on the need to screen people living with hepatitis B virus to find those coinfected with hepatitis delta virus and at high risk of progression, while also highlighting the pitfalls that other researchers have often fallen into.
Topics: Humans; Hepatitis B Surface Antigens; Hepatitis Delta Virus; Prevalence; Hepatitis B; Hepatitis B virus; RNA; Coinfection
PubMed: 38030035
DOI: 10.1016/j.jhep.2023.10.043 -
Zeitschrift Fur Gastroenterologie Dec 2023
Topics: Humans; Hepatitis B virus; Hepatitis D, Chronic; Gastroenterology; Hepatitis B; Hepatitis D; Metabolic Diseases; Antiviral Agents
PubMed: 38081179
DOI: 10.1055/a-2181-3046 -
Zeitschrift Fur Gastroenterologie Dec 2023
Topics: Humans; Hepatitis B virus; Hepatitis D, Chronic; Gastroenterology; Hepatitis B; Hepatitis D; Metabolic Diseases; Antiviral Agents
PubMed: 38081177
DOI: 10.1055/a-2181-3162