Search Results (1,312)

Background: Aflatoxin B1 (AFB1) is a potent hepatocarcinogen commonly found in staple foods from tropical regions. Aim: This scoping review collated existing evidence on AFB1 contamination in rice, maize, and peanut-based products across ASEAN countries to estimate chronic dietary exposure, Margin of Exposure (MOE), and the associated liver cancer risk. Methods: A systematic search was performed in five databases. Estimated Daily Intake (EDI) and risk metrics were calculated using sample-size weighted mean concentrations, along with regional consumption data. Risk characterisation used the benchmark dose lower confidence limit (BMDL₁₀) of 400 ng/kg BW/day, while liver cancer potency levels were adjusted according to Hepatitis B virus (HBV) prevalence for each population. Results: Twenty studies from Malaysia, Thailand, Vietnam, and the Philippines met the inclusion criteria. Peanuts and maize had the highest AFB1 concentrations among all food groups. Peanuts showed the highest contamination in the Philippines, followed by Malaysia, Vietnam, and Thailand. Maize exhibited a similar trend, with the highest levels observed in the Philippines. Most MOE values calculated were below 10,000, indicating a major public health concern. An exception was peanuts in Thailand, where MOE values exceeded 10,000, thus indicating a lower genotoxic carcinogenicity risk. The estimated liver cancer burden due to dietary AFB1 varied widely among countries and commodities. Conclusions: These findings show significant differences in AFB1 exposure in the ASEAN region. There is a need for improved surveillance, better post-harvest management, and harmonised regional risk management strategies. Full article

Aristolochic acid (AA), a naturally occurring compound found in Aristolochia plants, is a well-established nephrotoxin and Group 1 carcinogen. Emerging evidence suggests a potential link between AA exposure and hepatocellular carcinoma (HCC), one of the leading causes of cancer-related mortality worldwide. This review critically evaluates current knowledge on AA’s hepatic metabolism, its formation of persistent DNA adducts, and the induction of inflammatory responses in the liver. Based on preclinical and indirect human evidence, we propose a working hypothesis that AA may contribute to hepatocarcinogenesis through a dual mechanism: genotoxic (primarily via H-ras and p53 mutations resulting from AA-DNA adducts) and non-genotoxic (via chronic inflammation involving IL-6, TNF-α, and NF-κB activation, as well as epithelial–mesenchymal transition). We note, however, that these mechanisms remain to be validated in human cohorts and do not yet establish causality. Recent studies have identified novel mechanisms, including PDK4-mediated mitochondrial dysfunction, ferroptosis inhibition via p53 hijacking, and ARID1A deficiency as a susceptibility factor. A recent meta-analysis quantified a significantly increased risk of liver cancer following AA exposure in epidemiological studies. While direct causal evidence in humans remains limited, the high mutational burden observed in AA-exposed liver tissues warrants caution. Nevertheless, the primary public health priority pertains to the prevention of AA exposure. Further epidemiological and mechanistic studies are urgently needed. Full article

Objectives: This study aimed to evaluate very low HBV DNA viral load below the limit of quantification and to identify correlational factors in different patient groups, including individuals with chronic hepatitis B (CHB), occult HBV infection (OBI), and others. Methods: We retrospectively analyzed 390 patients with very low-level viremia (VLLV). HBV DNA levels were measured in plasma samples using real-time quantitative PCR (qPCR). Serological markers were evaluated in serum samples using chemiluminescence microparticle immunoassay (CMIA). Demographic variables, HBV serological markers (anti-HBs, anti-HBe, anti-HBc), and DNA results were evaluated. Results: The study included 193 CHB patients with maintained virological suppression and 197 patients in the other group; of which, 60 patients had occult hepatitis B infection (HBV DNA positive, HBsAg negative) and 137 had no occult hepatitis B infection. Very low viral load was more common in men (53.3%) and in individuals aged ≥50 years (63.3%). In univariate analysis, OBI was associated with anti-HBe (odds ratio (OR) = 2.874, 95% CI: 1.255–6.579, p = 0.013), and anti-HBc seropositivity (OR = 5.750; 95% CI: 2.626–12.591, p < 0.001). In multivariate analysis, anti-HBe positivity and anti-HBc positivity were independently associated with OBI. Anti-HBs positivity was independently and inversely associated with OBI. Conclusions: In patients with VLLV cohort, anti-HBc and anti-HBe seropositivity were independently associated with detectable but unquantifiable HBV DNA. Although anti-HBe positivity reflects reduced viral replication, it does not indicate complete viral suppression and may be detected at very low viremia levels, especially in occult HBV infection. These findings highlight the complex interplay between viral replication dynamics and host immune responses across the VLLV spectrum, characterize the serological landscape associated with detectable but unquantifiable HBV DNA, and warrant validation in prospective studies. Full article

Background and Objectives: Access to medicines is a fundamental determinant of health equity and a core pillar of universal health coverage, encompassing the timely availability, affordability, and appropriate use of essential medicines. Socioeconomic disparities may limit actual and timely access to pharmacological treatment, particularly in healthcare systems characterized by mixed public–private financing and significant out-of-pocket expenditures. This study aimed to evaluate socioeconomic determinants of access to medicines among Romanian patients with chronic diseases, focusing on income level, prescription reimbursement, perceived affordability, and substitution behavior during medicine shortages. Materials and Methods: A cross-sectional study was conducted between October and December 2024 using a structured online questionnaire administered to 200 adult patients diagnosed with cardiovascular diseases, diabetes mellitus, chronic hepatitis B and C, or oncological conditions, recruited at the “Prof. Dr. D. Hociotă” Institute of Phonoaudiology and Functional ENT Surgery, Bucharest, Romania. Associations between income and access-related variables were assessed using Spearman’s rank correlation coefficients with 95% confidence intervals. Binary logistic regression identified independent predictors of perceived difficulty in accessing medicines (p < 0.05). Results: Lower income was significantly associated with greater reliance on reimbursed prescriptions (r_s = −0.241, 95% CI: −0.37 to −0.10, p = 0.001) and fully reimbursed prescriptions (r_s = −0.305, 95% CI: −0.43 to −0.17, p < 0.001). Income was strongly correlated with perceived affordability of treatment (r_s = 0.601, 95% CI: 0.50–0.69, p < 0.001). In multivariate logistic regression analysis, income below 3000 RON/month (adjusted OR = 1.94, 95% CI: 1.05–3.58, p = 0.034) and insufficient affordability (adjusted OR = 4.12, 95% CI: 2.15–7.89, p < 0.001) were independently associated with perceived difficult access to treatment. Additionally, 80% of respondents reported purchasing substitute medicines when prescribed medicines were unavailable. Conclusions: This cross-sectional study indicates that socioeconomic status and perceived affordability are significant determinants of access to medicines among Romanian patients with chronic diseases attending a tertiary ENT centre. Financial vulnerability remains a major barrier despite existing reimbursement mechanisms. Policy interventions aimed at strengthening income-sensitive reimbursement strategies and ensuring consistent pharmaceutical availability may improve equitable access and therapeutic continuity. Full article

Background/Objectives: Hepatitis B core-related antigen (HBcrAg) is a surrogate marker that reflects the transcriptional activity of covalently closed circular DNA (cccDNA). However, the impact of switching nucleos(t)ide analogs on HBcrAg levels remains unclear. The current study evaluated changes in HBcrAg levels following a switch from entecavir (ETV) to tenofovir alafenamide (TAF) compared with continued ETV therapy. Methods: This retrospective study included patients with chronic hepatitis B who either switched from ETV to TAF between 2017 and 2022 (ETV–TAF group) or continued ETV therapy during the same period (ETV group). HBcrAg levels were measured annually, and longitudinal changes over 3 years were analyzed based on an index year defined for each patient. Propensity score matching for age, sex, HBcrAg levels, liver transplantation status, and ETV treatment duration yielded 10 patients per group. Results: Baseline characteristics were well balanced after matching. HBV DNA and HBsAg levels remained suppressed in both groups throughout follow-up. The ETV-TAF group showed greater declines in HBcrAg than the ETV group at year 2 (−0.20 vs. −0.10 log U/mL, p = 0.007) and year 3 (−0.30 vs. −0.10 log U/mL, p = 0.006). No virological breakthroughs occurred. Conclusions: Switching from ETV to TAF was associated with greater reductions in HBcrAg levels over 3 years than continued ETV therapy, even in patients with suppressed HBV DNA. These findings suggest that switching to TAF may be associated with further suppression of viral transcriptional activity reflected by HBcrAg reduction and support its potential clinical utility for achieving deeper viral suppression. Full article

Background: Hepatitis D virus (HDV) causes one of the most severe forms of chronic viral hepatitis. Despite its severity, universal screening of hepatitis B surface antigen (HBsAg)-positive individuals, as recommended by European guidelines, is not widely implemented. This study aimed to evaluate the yield of reflex HDV testing and to characterize HBV carriers who tested positive or negative for anti-HDV. Methods: A retrospective cohort study was conducted using the Clalit Health Services database in northern Israel (2014–2024). HBsAg-positive patients were categorized into two groups: those screened for HDV via reflex testing (2019–2024) and those tested based on clinical discretion (2014–2019). We compared these cohorts to evaluate the impact of reflex screening on coverage, diagnostic yield, and time to diagnosis. Results: Among 1336 HBsAg-positive individuals, HDV screening rates increased from 57.5% to 93.1% following reflex implementation. HDV seropositivity increased from 3.17% to 6.48% (p = 0.02). Ethiopian-born individuals had significantly higher positivity than others (10.4% vs. 3.9%, p = 0.0221). The average time from HBV diagnosis to HDV testing decreased from 38.1 ± 31 months (median 37.5) to 1.3 ± 6.1 months (median 0). Conclusions: Anti-HDV reflex testing significantly improved screening coverage, increased detection of anti-HDV seropositive cases and was associated with shorter time to serologic identification. These findings support the integration of reflex testing into national screening policies to enable earlier diagnosis and reduce the burden of infection. Full article

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

Chronic intermittent hypoxia (CIH), the cardinal pathophysiological feature of obstructive sleep apnea, is increasingly recognized as an important modifier of metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. In this study, male C57BL/6 mice were fed a standard diet or a high-fat diet (HFD) and exposed to normoxia or CIH for 8 weeks. Histological, ultrastructural, biochemical, transcriptomic, proteomic, and metabolomic analyses were integrated to characterize hepatic alterations induced by CIH under metabolic stress. CIH markedly aggravated HFD-induced liver injury, as evidenced by increased body fat, hepatomegaly, serum transaminases, steatosis, mitochondrial ultrastructural alterations, and inflammatory infiltration. Mechanistically, CIH promoted hepatic lipid metabolic reprogramming by suppressing the PPARα/CPT1A fatty acid β-oxidation axis while enhancing the SREBP-1c/FASN/PLIN2 lipogenic pathway, impaired the Nrf2/HO-1/SLC7A11/GPX4 antioxidant defense system, increased lipid peroxidation and iron accumulation, and activated NF-κB/NLRP3 signaling. These findings support a multifactorial model in which CIH functions as an additional hypoxic stressor that exacerbates HFD-induced MASLD-like liver injury through coordinated metabolic, oxidative, and inflammatory dysregulation. Full article

Background: Hepatitis C virus (HCV) remains a major cause of preventable liver-related mortality in the United States despite highly effective direct-acting antivirals (DAAs). Contemporary assessment of mortality trends and disparities is essential for elimination efforts. Methods: Using CDC WONDER multiple cause-of-death data (1999–2023), we identified HCV-related deaths using ICD-10 codes for acute and chronic HCV (B17.1, B18.2) and calculated age-adjusted mortality rates (AAMRs) per 100,000 (2000 US standard). Rates were stratified by sex, race/ethnicity, census region, and 2013 NCHS urban–rural classification. Joinpoint regression quantified temporal inflection points and annual percent changes (APCs). Results: Overall HCV-related AAMR increased from 1.8 (1999) to a peak of 5.0 (2014), then declined to 2.3 (2023), with a marked post-2014 decrease (APC −8.2%). Mortality was consistently higher in males than females (2023 rate ratio 2.57). In 2023, American Indian/Alaska Native individuals had the highest mortality (AAMR 8.7; rate ratio 3.48 vs. non-Hispanic White), followed by non-Hispanic Black individuals (AAMR 6.2; rate ratio 2.48). Mortality remained highest in the West and was higher in non-metropolitan than metropolitan counties (AAMR 2.8 vs. 2.3; rate ratio 1.22), with a slower post-2014 decline in non-metropolitan areas. Conclusions: Our findings indicate that while the DAA era has been associated with a substantial reduction in HCV-related mortality at the national level, this progress has not been uniform across all populations. Persistent excess mortality among Native American and non-Hispanic Black individuals may reflect inequities in the HCV care cascade, including screening, confirmatory testing, linkage to specialty care, insurance-related restrictions, and the high cost of antiviral therapy. These results highlight the need for policies and public health strategies that improve equitable and affordable access to curative HCV treatment. Full article

Background: Southeast Asian Americans (SEAAs) experience a disproportionately high burden of hepatocellular carcinoma (HCC), with incidence in several subgroups (i.e., Cambodian, Laotian, and Vietnamese individuals) reaching up to nine times that of non-Hispanic Whites. HCC in SEAAs is largely driven by chronic hepatitis B (HBV), hepatitis C (HCV), metabolic dysfunction–associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). Despite established screening guidelines, under-detection and delayed diagnosis remain common. Objective: To summarize epidemiologic patterns, risk factors, screening challenges, and potential interventions aimed at reducing HCC disparities among SEAAs. Design and Methods: This narrative review synthesized evidence from population based epidemiologic studies, community-based interventions, health services research, and policy analyses. Attention was given to studies reporting disaggregated SEAA subgroup data. Findings derived from SEAA specific studies were distinguished from evidence drawn from broader Asian American or general cirrhosis populations, with inferential steps explicitly noted where subgroup specific data were limited. Key Findings: HCC incidence varies widely across SEAA subgroups, with elevated HBV- and HCV-related HCC in Vietnamese, Cambodian, and Laotian communities, and increasing MASLD-related HCC including among lean individuals who fall outside many surveillance frameworks. Screening and surveillance remain suboptimal, with fewer than 30% of patients with cirrhosis receiving recommended semiannual HCC surveillance and even lower uptake among SEAAs. Barriers include low HBV/HCV screening rates, limited disease awareness, language barriers, underinsurance, provider knowledge gaps, and lack of automated EHR-based reminders. Structural challenges such as poverty, transportation barriers, and limited access to specialty care further delay diagnosis. Proposed Interventions: Culturally tailored outreach programs, bilingual navigators, and community-based screening initiatives have demonstrated improved HBV/HCV testing and linkage to care. AI-enabled EHR tools may enhance identification of high-risk patients, streamline follow-up, and increase surveillance adherence. Expanded use of non-invasive fibrosis assessment and recognition of MASLD-related risk in non-obese individuals may support earlier detection. Policy priorities include mandatory Asian subgroup data disaggregation, expanded insurance coverage, and strengthened community-level healthcare infrastructure. Conclusions: SEAAs face a substantial and preventable HCC burden. A coordinated approach combining culturally tailored community engagement, improved provider support systems, and policy reforms is essential to improving early detection and reducing HCC disparities in this diverse population. Full article

Background and Aims: Understanding regulatory interactions between hepatitis B virus (HBV) and host factors is essential for the development of next generation host-directed antiviral therapies and the achievement of a functional HBV cure. Here, we investigated HBV-induced alterations in host gene expression in primary human hepatocytes (PHH) to identify host factors exploited by the virus for replication and persistence. Whole-transcriptome sequencing (WTS) of HBV-infected PHH identified host pathways with potential roles in the HBV life cycle. RNA interference-based functional screening of dysregulated candidate genes identified cyclin L1 (CCNL1) as a key host factor. RNAi-mediated knockdown of CCNL1 reduced HBV gene expression, including hepatitis B surface antigen (HBsAg). Mechanistically, CCNL1 regulates phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) at serine 2 (S2), consistent with a role in transcriptional regulation. CCNL1 knockdown further reduced the binding of total and phospho- (Ser2/Ser5) RNAPII, pan-acetylated histone H3 (H3ac), and H3K27ac to HBV covalently closed circular DNA (cccDNA), indicating impaired cccDNA-dependent transcription. In addition, CCNL1 expression was elevated in chronic hepatitis B patients compared with those with resolved infection. Collectively, these data demonstrate that CCNL1 promotes HBV transcription and replication through modulation of RNAPII phosphorylation and chromatin-associated transcriptional activity, identifying CCNL1 as a potential host susceptibility factor for HBV. Importance: Hepatitis B virus infection remains a major threat to human health in areas with high prevalence. There is need to fully understand the complex interactions between the virus and human host factors/processes to support ongoing efforts to develop anti-HBV therapies that can be used with existing therapies to achieve a better cure. HBV relies on host cellular factors and biological processes to establish and maintain efficient infection, making host–virus interactions attractive targets for therapeutic intervention. Thus, identifying host factors that support and/or restrict HBV infection is essential for understanding the molecular basis of chronic HBV infection and for developing host-targeting anti-HBV drugs. This study identifies cyclin L1 (CCNL1) as a host susceptibility factor that promotes HBV transcription and replication through regulation of RNA polymerase II activity and or post-transcriptional mechanisms. 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

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 B virus (HBV) remains a leading cause of chronic liver disease worldwide, contributing to cirrhosis and hepatocellular carcinoma. Sub-Saharan Africa accounts for an estimated 68% of incident HBV infections, where co-infection with human immunodeficiency virus (HIV) is common and associated with poorer clinical outcomes. In Botswana, limited HBV screening and the absence of established HBV management guidelines persist despite reported HIV-HBV co-infection rates ranging from 1.1% to 10.6%. This scoping review aimed to summarise existing research on HBV and HIV-HBV co-infection in Botswana and assess clinical and policy implications. Following PRISMA methodology, searches were conducted across PubMed, Google Scholar, Semantic Scholar, and Consensus databases. Thirty eligible peer-reviewed studies were identified and evaluated for prevalence data, virological characteristics, genotypes, mutations, treatment outcomes, vaccination programs, and the availability of guidelines. Findings indicate intermediate-to-high HBV and HIV-HBV disease burden, substantial occult HBV infection, and gaps in diagnostic and preventive practices. The lack of routine screening, deficient infant birth-dose and adult vaccination, and established treatment pathways likely increase the risk of HBV-associated morbidity and mortality. Strengthened public health interventions, including expanded testing, enhanced vaccination coverage, and prevention of mother-to-child transmission strategies, are recommended to improve disease control and clinical outcomes in Botswana. Full article

Background & Aim: The entry of Hepatitis D Virus (HDV) depends on HBV surface proteins (HBsAg) composed of three isoforms: large-, middle, and small HBsAg. Here, we investigate the levels of total HBsAg and HBsAg isoforms and their correlations with HDV-RNA, HBcrAg, and transaminases in the setting of untreated chronic hepatitis D (CHD). Methods: This study includes 316 HBeAg-negative patients: 192 CHD and 124 with chronic hepatitis B (CHB) as a control group. HBsAg isoforms were quantified by ad hoc-designed ELISAs. Results: The composition of HBsAg isoforms varied between the two groups of patients, with remarkably higher small HBsAg, middle-HBsAg, and large HBsAg in CHD than in CHB. This data was confirmed by multivariable analysis (p < 0.0001). Among CHD, HBsAg isoforms positively correlated with HDV-RNA (p < 0.0001) and HBcrAg (p < 0.0001) but not with HBV-DNA. The results were confirmed by stratifying patients according to HDV-RNA (< or >1000 IU/mL) and HBcrAg (< or >3 logU/mL). Furthermore, CHD patients with ALT > upper limit of normal presented significantly higher S-HBsAg and M-HBsAg levels. Conclusions: CHD is characterized by a more elevated HBsAg isoform production, paralleling HDV-RNA and HBcrAg release. This may suggest a preferential recruitment of HBsAg isoforms in HDV virions at the expense of HBV virions. The association of HBsAg isoforms with higher ALT also suggests their potential contribution in supporting HDV-induced pro-inflammatory stimuli. Full article