Search Results (2,444)

Dysfunction-associated steatotic liver disease (MASLD) is a newly introduced term for the condition previously known as nonalcoholic fatty liver disease (NAFLD). MASLD affects 38% of the global population and is now diagnosed based on the presence of steatosis but also with cardiometabolic risk factors indicating metabolic dysfunction. Chronic hepatitis B (CHB), another significant public health issue, impacts over 296 million people worldwide, or approximately 3.2% of the global population. Studies have consistently reported a complex relationship between MASLD and CHB. Previous studies indicate that MASLD may protect against high viral loads, while other studies indicate that coexisting MASLD and CHB may lead to more advanced fibrosis and an elevated risk of HCC. Additionally, numerous studies highlight a strong association between CHB and metabolic syndrome components. This review article examines the relationship between CHB and MASLD, considering what has been previously published. Full article

Background/Objectives: The hepatitis A virus (HAV) infection continues to represent a considerable public health issue in Eastern Europe, particularly in Bulgaria, where incidence rates exceed the EU average. This study sought to investigate the epidemiological and clinical aspects of acute hepatitis A in Southern Bulgaria between 2015 and 2023 and to assess changes during the COVID-19 pandemic period. Methods: A retrospective descriptive-analytic study was conducted among 1810 hospitalized patients with confirmed acute HAV infection at a tertiary infectious diseases center from 2015 to 2023. Demographic, clinical, laboratory, and temporal data were analyzed, comparing the pre-pandemic period (2015–2019) with the pandemic phase (2020–2023). Results: Most hospitalized cases occurred during the pre-pandemic period (88.0%), with epidemic peaks observed in 2016–2017. Individuals under 18 years comprised 69.9% of cases, with a median age of 9 years and a slight male predominance of 54.9%. A notable seasonal pattern was identified, characterized by peaks in autumn and early winter. Patients hospitalized during the pandemic period were significantly older compared with the pre-pandemic period (median age 14 vs. 8 years, p < 0.001). Adults experienced significantly longer hospitalization and higher ALT, AST, total bilirubin, and direct bilirubin levels compared with pediatric patients (all p < 0.001). The median duration of hospitalization was 7 days (IQR 6–10). Two in-hospital deaths were recorded, corresponding to a case fatality rate of 0.11%. Conclusions: Hepatitis A in Southern Bulgaria mostly impacts children but exhibits changing epidemiological trends, underscoring the necessity for focused preventative methods, such as vaccination and enhanced surveillance. Full article

Background and Aims: Type 2 diabetes mellitus is a recognized risk factor for hepatocellular carcinoma (HCC), particularly in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), chronic viral hepatitis, advanced fibrosis, and cirrhosis. Beyond hyperglycemia and insulin resistance, diabetic hepatocarcinogenesis is shaped by metabolic inflammation, lipotoxicity, oxidative stress, fibrogenic remodeling, and the cirrhosis-dysplasia-HCC continuum. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may influence several hepatometabolic pathways, but the epidemiologic evidence linking SGLT2i use to HCC risk remains heterogeneous. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating SGLT2i exposure and incident HCC in adults with type 2 diabetes. PubMed, Embase, and the Cochrane Library were searched up to 15 March 2026. Adjusted time-to-event estimates were pooled using a restricted maximum likelihood (REML) random-effects model. The certainty of evidence was assessed using the GRADE framework and judged to be very low. Results: Six observational studies including 526,446 participants were included. SGLT2i exposure was associated with a lower observed risk of incident HCC (pooled HR 0.59, 95% CI 0.45–0.77), but between-study heterogeneity was substantial (I² = 75.2%, τ² = 0.074). The association remained directionally similar after exclusion of Huynh et al. (HR 0.61, 95% CI 0.45–0.81) and in a DPP-4 inhibitor-restricted active-comparator analysis (HR 0.60, 95% CI 0.39–0.92). However, the 95% prediction interval crossed the null (0.25–1.37), indicating that future comparable studies may plausibly show no protective association. Conclusions: SGLT2i exposure was associated with a lower observed risk of incident HCC across available observational studies. However, the certainty of evidence was judged to be very low, and substantial heterogeneity, comparator variation, mixed time-to-event estimands, residual confounding, and a prediction interval crossing the null preclude causal interpretation. These findings should be considered hypothesis-generating rather than practice-changing evidence and support further hepatology-oriented validation. Full article

Hepatitis E is a liver inflammation caused by the hepatitis E virus (HEV). In pregnant women, the infection significantly increases the risk of acute liver failure, fetal loss, and maternal death. According to the World Health Organization, infection by HEV during the third trimester of pregnancy may increase the risk of maternal mortality in 20–25% of cases. In Tunisia, little is known about HEV infection and its outcome, especially in pregnant women. This study aims to evaluate the prevalence of HEV infection in a large cohort of pregnant women in Tunisia. A total of 891 women who attended the Centre of Maternity and Neonatology of Tunis during 2021–2023 were included. Serum samples were screened to detect HEV-antibodies and RNA using commercial ELISA tests and molecular assays, respectively. Statistical analyses were conducted using SPSS 21.0 software and the EPISTAT package version 7.2.6. Seroprevalence of HEV infection was 3.82%, based on the detection of anti-HEV IgG. The distribution of the seroprevalence according to age was statistically significant (p < 0.05), showing a higher seroprevalence among women over 30 years. Among the 51 women with composite outcomes, viral RNA was detected in one case by real-time RT-PCR. Our findings indicate a low HEV prevalence among pregnant women in Tunisia. Expanding the study to other cohorts and to environmental surveillance would improve understanding of HEV burden in Tunisia and support hepatitis elimination efforts. Full article

The liver circadian clock coordinates hepatic lipid metabolism, bile acid synthesis, and glucose homeostasis through interlocking transcription–translation feedback loops. Disruption of this temporal organization is increasingly recognized as a shared pathological feature across the chronic liver disease spectrum. Transcriptomic profiling alone cannot capture the full scope of circadian dysregulation. Approximately half of rhythmically abundant hepatic proteins lack correspondingly rhythmic mRNAs. Roughly 25% of hepatic phosphosites oscillate with a 24-h period. Integrating transcriptomics, proteomics, post-translational modification profiling, metabolomics, and emerging single-cell and spatial approaches is therefore necessary for an accurate account of how circadian programs are remodeled in disease. This narrative review delineates the multi-omics landscape of circadian clock dysregulation across six chronic liver disease categories. These encompass metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), liver fibrosis, and cholestatic disease. Four molecular features recur across these contexts. BMAL1 functional downregulation, REV-ERBα oscillatory output attenuation, NAD⁺ oscillatory amplitude reduction, and gut–liver axis circadian desynchronization together constitute an inferential framework for hepatic circadian failure. These features represent recurring disease-associated motifs rather than an established pan-disease mechanism. The upstream mechanisms and evidence depth differ substantially by disease category. Oncogenic kinase-driven CLOCK post-translational modifications in HCC, phosphoproteomic remodeling in MAFLD, and epigenomic clock disruption persisting after HCV clearance represent findings that transcriptomics alone would not resolve. The near-complete absence of temporally resolved human tissue data remains the principal barrier to translational progress. This evidence gap limits the clinical actionability of current mechanistic findings across all disease categories. Circadian phase inference algorithms and prospective temporally designed cohort studies offer a methodologically grounded path toward clinically actionable circadian hepatology. Full article

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating processes such as assembly, genome packaging, and virion maturation. Despite their biological importance, these interactions remain challenging to study and are relatively underexploited as therapeutic targets. Split reporter systems, based on protein-fragment complementation, provide quantitative platforms to measure PPIs by reconstituting reporter activity when interacting protein partners are brought into proximity. These systems can be applied in vitro and in live cells which enables detection of dynamic and multimeric interactions in physiologically relevant contexts. Major classes of split reporter systems include β-lactamase, alkaline phosphatase, luciferase-based platforms, green fluorescent protein, and horseradish peroxidase. Assay performance depends on factors such as fusion protein stability, expression levels, and reporter kinetics, which influence sensitivity, dynamic range, and reliability. These approaches have been applied to study viral protein interactions across diverse systems, including HIV-1 matrix and nucleocapsid proteins, flaviviral capsid proteins, hepatitis B virus core protein, and chikungunya virus capsid. Split reporter assays also enable high-throughput screening for small-molecule inhibitors that disrupt viral PPIs and multimerization. This provides a functional readout linked to viral replication. Despite the challenges that exist in assay optimization and protein stability, the sensitivity and versatility of these systems provide a framework to interrogate viral protein interactions and support the development of antiviral therapeutics.: Full article

Viral comorbidities elicit complex host responses by activating redox-sensitive signaling pathways, prominently those regulated by NADPH oxidase (Nox) enzymes. Nox are critical components of host defense, generating reactive oxygen species (ROS) that modulate key cellular signaling cascades. Under normal physiological conditions, Nox activity is tightly controlled; however, viral infections frequently disrupt this regulation, leading to aberrant upregulation of specific Nox isoforms. Elevated expression of individual Nox enzymes has been observed in infections such as influenza A and hepatitis C virus, while simultaneous activation of multiple Nox isoforms occurs in HIV and SARS-CoV infections. Similar patterns of dual or multi-isoform Nox activation are also reported in complex disease states, including diabetes, thrombosis, and fibrosis. MicroRNAs play a crucial role in this process by selectively regulating Nox isoform expression during viral infection, thereby remodeling the host redox environment. Nox-derived ROS influence multiple downstream signaling pathways, including SMAD, MAPK, CXCR-mediated signaling, and the JNK/ERK axis, promoting inflammation and fibrosis that worsen viral disease outcomes. Additionally, several FDA-approved drugs, investigational agents, and microRNA-based therapeutics show promise in modulating Nox activity. Therefore, this article substantiates how viral infections reprogram host transcriptomic and redox signaling networks, contributing to viral pathogenesis and offering potential therapeutic intervention strategies. Full article

Controlled delivery using nanoparticle-based systems has attracted considerable attention; however, achieving cell-type specificity remains a major challenge. To address this issue, we focused on the intrinsic cell tropism of viruses. The hepatocyte tropism of hepatitis B virus (HBV) is mediated by interactions between its large envelope protein (L protein) and host factors, including the sodium taurocholate cotransporting polypeptide (NTCP). In this study, we explored viral-like secretory vesicles (VLSVs) displaying HBV spike proteins as a virus-inspired vesicle platform for hepatocyte targeting. We previously established a method for producing VLSVs from HBV L- and S-expressing HEK293T cells. In the present study, we developed an improved protocol using exosome-depleted fetal calf serum and optimized ultracentrifugation, resulting in VLSVs with comparable particle numbers and sizes but approximately tenfold higher protein content per particle. VLSVs were concentrated using a two-layer sucrose cushion, labeled with DiI, and purified by sucrose density gradient ultracentrifugation. We evaluated DiI uptake in hepatocyte-derived cells (HepG2 and Huh7), non-hepatic cells (MDA-MB231, H1299, HeLa, and Vero), and NTCP-overexpressing HepG2 cells. VLSVs showed preferential uptake in the following order: NTCP-overexpressing HepG2 > HepG2 > Huh7 > non-hepatic cells. Furthermore, removal of the N-terminal Flag tag from the L protein enhanced hepatocyte-associated uptake, suggesting the importance of preserving the native structure of the preS1 domain. While vesicle characterization and mechanistic validation remain to be further investigated, these findings provide a proof-of-concept for a virus-inspired vesicle platform exhibiting preferential uptake in hepatocyte-derived cells. Full article

This study investigated the role of microglia-derived insulin-like growth factor 1 (IGF-1) in modulating host defense and disease progression in a viral model of neuroinflammation and demyelination. Intracranial infection of susceptible mice with the glial-tropic JHM strain of mouse hepatitis virus (JHMV) induces acute encephalomyelitis, followed by an immune-mediated demyelinating disease that mimics many clinical and histologic features of multiple sclerosis (MS). Utilizing an inducible fractalkine receptor (Cx3cr1) promoter-driven Cre-loxP recombinant system, we performed timed ablation of Igf1 in microglia to assess its impact on the central nervous system (CNS) response to JHMV. While the loss of microglial IGF-1 did not impair the control of viral replication, it significantly exacerbated spinal cord demyelination. CyTOF and imaging mass cytometry analysis of spinal cords indicated increased myelin damage was associated with increased accumulation of CD8⁺Ly6C⁺ effector T cells and reduced expression of TREM2 that impaired transition into a disease-associated microglia (DAM) phenotype capable of sensing and potentially mitigating myelin damage. Collectively, these findings argue that microglial IGF-1 is a non-redundant coordinator of the CNS immune responses that occur in response to CNS viral infection. Full article

Background: Chronic hepatitis B and C remain major causes of progressive liver disease, while HBV–HCV coinfection is associated with accelerated fibrosis and hepatocellular injury. Methods: This study evaluated integrated biochemical, histopathological, and immunohistochemical features in patients with chronic hepatitis B (CHB, n = 29), chronic hepatitis C (CHC, n = 15), and CHB+C coinfection (CHB+C, n = 10). Liver biopsies were assessed using Ishak and METAVIR scoring systems, alongside immunohistochemical analysis of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), CD5L, and glial fibrillary acidic protein (GFAP), quantified by H-score. These findings were correlated with biochemical, hematological, and prognostic parameters. Results: Coinfected patients exhibited significantly higher serum ALT, AST, and GGT levels (p ≤ 0.011) and increased CD5L expression (median H-score 197.5 vs. 135 in CHB, p = 0.009), indicating enhanced macrophage-associated inflammatory activity. Although fibrosis stages were comparable across groups, median H-scores for α-SMA, TGF-β1, and GFAP showed a consistent upward trend in CHB+C, suggesting intensified profibrogenic signaling. Principal Component Analysis identified distinct biochemical clusters related to hepatocellular injury, hepatic functional impairment (synthetic and excretory axis), and lipid metabolism. Conclusions: These findings highlight a multidimensional pattern of liver injury in chronic viral hepatitis, with CHB+C coinfection amplifying profibrogenic and hepatocellular markers, both biochemically and histologically. Full article

Hepatitis E virus (HEV) is an emerging zoonotic pathogen of increasing concern in developed regions and represents a major cause of acute viral hepatitis worldwide, primarily transmitted via the fecal–oral route. Although most infections are self-limiting, immunocompromised individuals, such as people living with human immunodeficiency virus (PLWH) and pregnant women, are at risk of severe outcomes, including chronic infection and fatal liver failure, respectively. This study was aimed at evaluating the prevalence and genetic diversity of HEV in PLWH and relevant ecological niches (swine and wastewater) in Venezuela. A total of 417 serum samples from PLWH, 85 wastewater samples, and 67 swine fecal samples were tested for serological or molecular HEV markers. The seroprevalence of anti-HEV antibodies among PLWH was 0.2% for IgM and 5.5% for IgG. HEV RNA was not detected in samples from PLWH or wastewater; however, a 1.5% prevalence of active infection was identified in swine. Phylogenetic analysis of a complete HEV genome revealed an unassignable subtype within genotype 3, tentatively designated as 3p. To the best of our knowledge, this study provides the first molecular characterization and report on HEV frequency in PLWH, wastewater, and swine in Venezuela. Full article

Background and clinical significance: Autoimmune hepatitis (AIH) and ankylosing spondylitis (AS) are distinct immune-mediated disorders that only rarely coexist. Diagnostic interpretation becomes especially challenging when the liver biochemistry is not classically hepatocellular and the histology is unavailable. Case presentation: We report a 51-year-old man with inflammatory back pain, polyarthralgia, weight loss, fatigue, night sweats and fever. Laboratory tests showed marked systemic inflammation, anemia and a cholestatic-predominant liver profile with associated aminotransferase elevation. Imaging demonstrated bilateral sacroiliitis and syndesmophytosis. Liver workup excluded viral, obstructive, metabolic, hereditary and inflammatory bowel disease-associated cholangiopathic causes. Antinuclear antiboidies (ANA) and anti liver cyotsole 1 antiboidies (anti-LC-1) were positive, IgG was mildly elevated, magnetic resonance cholangio-pancreatography (MRCP) was negative for primary sclerosing cholangitis and the simplified AIH score was six. A liver biopsy was proposed but refused. The patient received a short course of prednisone for rheumatologic flare control, followed by nonsteroidal anti-inflammatory treatment and sulfasalazine, with normalization of liver tests during follow-up. Conclusions: This case is suggestive, but not diagnostic, of autoimmune hepatitis in a patient with ankylosing spondylitis. In the absence of histology and in the setting of a cholestatic-predominant biochemical profile, the findings may be more appropriately interpreted as an autoimmune hepatitis-like syndrome. The main teaching point is that abnormal liver tests in AS warrant structured evaluation beyond drug toxicity and viral hepatitis, particularly when autoimmune serology is positive, even in a cholestatic-predominant presentation. Full article

Background/Objectives: Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a major global etiology of chronic liver disease. However, the prognostic impact of MASLD in patients with non-B, non-C HCC (NBNC-HCC) following curative resection remains poorly defined. This study aimed to evaluate the prognostic significance of histologic SLD and MASLD-related components in this growing patient population. Methods: We retrospectively reviewed consecutive patients with NBNC-HCC receiving curative-intent hepatectomy between 2014 and 2023, excluding those with viral hepatitis or significant alcohol use. MASLD was defined as hepatic steatosis (≥5%) combined with at least one cardiometabolic risk factor (obesity, type 2 diabetes, dyslipidemia, or hypertension). Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Cox proportional hazards models were used to identify independent prognostic factors. Results: 169 (61.7%) patients fulfilled MASLD criteria. The MASLD group showed significantly better RFS (p = 0.039) and OS (p = 0.016). Notably, after multivariate adjustment, histologic SLD remained independently associated with reduced mortality (HR 0.55, 95% CI 0.32–0.93; p = 0.027), while MASLD status was attenuated. Subgroup analysis revealed that this survival benefit was most pronounced in non-cirrhotic patients (p = 0.027 for OS). Patients with MASLD also exhibited lower liver-related mortality (p = 0.028). Conclusions: Steatotic liver disease was independently associated with improved survival in NBNC-HCC patients undergoing curative hepatectomy, particularly in non-cirrhotic individuals. Given the increasing prevalence of MASLD, incorporating hepatic steatosis, metabolic components, and fibrosis status into risk stratification may help improve postoperative management in this distinct subgroup. Full article

Hepatitis C virus (HCV) infection is still a major worldwide health concern. It is distinguished by a high degree of genetic variation that affects the course of the illness and the effectiveness of treatment. The epidemiological profile of HCV is prone to rapid change in areas where there is significant human migration, like Turkey. The purpose of this study was to evaluate the impact of long-term migration on local viral diversity by analyzing the distribution and temporal trends of HCV genotypes among Turkish citizens and asylum seekers in Kayseri, Turkey, over an eight-year period. From January 2014 to December 2021. 1173 HCV RNA-positive patients at Kayseri City Training and Research Hospital were the subject of a retrospective analysis. Genotypes were determined using the Abbott RealTime HCV Genotype II assay and Montania 4896 assay (Anatolia Geneworks, Türkiye). The most prevalent genotypes were Genotype 1b (48.3%, 95% CI: 45.5–51.2%), Genotype 4 (25.0%, 95% CI: 22.5–27.5%), and Genotype 1a (10.3%, 95% CI: 8.6–12.1%). Turkish patients exhibited the highest prevalence of Genotype 1b (98.2%), while asylum seekers demonstrated greater relative burdens of Genotype 4 (8.5% of total GT4) and Genotype 5 (83.3% of total GT5). Genotype 3a emerged in 2018, with a predominance in males (73.9%). The Cochran–Armitage trend test revealed statistically significant increasing trends for Genotype 3 (Z = 3.572, p = 0.0004) and Genotype 3a (Z = 2.600, p = 0.009). This eight-year retrospective study demonstrates that the HCV genotype distribution in Kayseri has undergone significant changes in the context of migration and demographic shifts. The statistically significant increasing trends of Genotypes 3 and 3a, particularly among younger male populations, suggest evolving transmission dynamics. These findings underscore the necessity of demographically targeted and culturally appropriate screening and treatment strategies for both resident and migrant populations to achieve HCV elimination goals. Full article

Bats are recognized reservoirs for a vast array of viral diversity, including members of the Hepadnaviridae family. Within a One Health framework, genomic surveillance of these animals is fundamental to understanding viral diversity and the potential risks of zoonotic spillover in high-density human population areas. This study describes the detection of a bat hepadnavirus through agnostic viral metagenomics in samples from passive surveillance collected in urban and peri-urban areas in Brazil. Sequencing was performed using the Oxford Nanopore Technologies (MinION) platform, and the bioinformatics pipeline involved de novo assembly and taxonomic identification against viral databases. We identified several contigs with similarity to the Tent-making bat hepatitis B virus (TBHBV) in a single liver sample. The largest contig (3182 bp) represents the complete genome, exhibiting a nucleotide identity of 80.93% with the original reference isolate. Our findings document the circulation of this viral lineage in a new epidemiological setting (the Brazilian urban interface), underscoring the importance of continuous surveillance to monitor the evolution and geographic distribution of bat orthohepadnaviruses and their relevance to public health. Full article