Search Results (13,874)

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals notable for their high persistence and extensive applications. With the advancement of detection technologies in recent years, PFAS have been frequently identified in environmental media and human biological samples, raising significant global concerns about their potential health risks. PFAS exhibit distinctive toxicokinetic behaviors, including efficient absorption, strong protein binding, limited metabolism, and slow excretion, which lead to prolonged biological half-lives and considerable bioaccumulation in humans. These properties contribute to a range of adverse health outcomes, such as endocrine disruption, immune suppression, liver damage, reproductive toxicity, carcinogenic potential, and cardiovascular disease. This review synthesizes evidence on PFAS-associated health risks from a multisystem, multitarget perspective, elucidating the key molecular pathways involved, thereby providing a scientific basis for understanding their complex toxicological effects and for developing targeted prevention and control strategies. Future research should prioritize characterizing the toxicological profiles of individual PFAS compounds, evaluating the health impacts of combined (mixture) exposures, and assessing risks associated with chronic, low-dose exposure to support the development of public health strategies and regulatory decisions. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Its main contributors are obesity, insulin resistance, diabetes and metabolic syndrome. Liver pathogenesis exacerbates when oxidative stress, inflammation, lipid accumulation, and attenuated autophagy signals coexist together with the main determinants of the liver disease. These findings may indicate that the suppression of the disease requires multi-targeting compounds to alleviate more than one factor, resulting in improved histopathological outcomes. This review studies natural compounds, given as supplements, with antioxidant and anti-inflammatory properties. The compounds included are vitamins, carotenoids, low-molecular-weight thiol-containing compounds, fatty acids and others that have been investigated for their pleiotropic activity alone or in combination. They act at different pathways and signals, and at gene expression control, modulating oxidative stress and inflammation, such as collagen, TNF-α, NF-κB, Nrf2 and PPARs genes. Their mechanism of action and characteristics may be encouraging treatment options as multi-targeting compounds for NAFLD and other diseases whose pathophysiology is closely related to metabolic syndrome. However, extensive study on their safety, toxicity, mechanisms of action and dosage regimen is needed before their final establishment as potential treatment options. Full article

Background/Objectives: The objective of this study was to map and synthesize the current evidence on hemostasis in chronic and acute liver disease within the framework of Patient Blood Management (PBM). Methods: Because research in this field is heterogeneous—spanning mechanistic studies, observational data, randomized controlled trials, guidelines, and expert reviews—a scoping review was selected to comprehensively map concepts. Findings were synthesized narratively to reflect the breadth and heterogeneity of available research. Results: Hemostasis in liver disease is characterized by a fragile state of rebalanced coagulation, where parallel reductions in pro- and anticoagulant factors coexist with variable fibrinolytic disturbances and thrombocytopenia. Conventional coagulation tests (CCTs) do not accurately reflect bleeding risk, whereas viscoelastic assays and thrombomodulin-modified thrombin generation testing provide a more physiologic assessment, though with limitations. Most bleeding events arise from portal hypertension rather than coagulopathy, and the routine prophylactic correction of abnormal results of CCTs is not supported by evidence. PBM-aligned strategies—such as restrictive transfusion, targeted fibrinogen replacement, and use of thrombopoietin receptor agonists (TPO-RAs)—reduce unnecessary blood product use. Thrombosis burden is increasingly recognized in this patient population. Anticoagulation is generally safe when individualized to liver function and clinical context, however significant variability persists in clinical practice, and high-quality data remain limited for advanced disease. Conclusions: Hemostasis in liver disease reflects a dynamic and unstable equilibrium rather than a simple bleeding tendency. Diagnostic and therapeutic strategies grounded in PBM principles improve safety by avoiding unnecessary transfusion and emphasize individualized care. Despite advances in understanding rebalanced hemostasis, major gaps remain in predicting thrombotic risk, standardizing advanced coagulation testing, and defining optimal management across disease stages. Full article

Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular endothelial cells, HMEC-1) were exposed to sera from patients in five disease groups (n = 20 patients/group)—liver cirrhosis with portal hypertension, idiopathic pulmonary arterial hypertension, placental disorders such as intrauterine growth restriction, coronary artery disease with acute myocardial infarction, and chronic kidney disease—or matched controls, in the absence/presence of anti-inflammatory (apixaban) and antioxidant (EUK134) compounds. We explored changes in: VCAM-1, ICAM-1, eNOS, VWF, extracellular matrix thrombogenicity, and reactive oxygen species (ROS). In serum samples, proteomics and metabolomics analyses (including lipids, amino acids, and polar metabolites) were performed through an extraction protocol to identify common ED biomarkers. Expression of VCAM-1, ICAM-1, VWF, platelet adhesion, and ROS increased in most groups versus controls (p < 0.05). Both drugs decreased all biomarker levels except eNOS (n = 6 for in vitro experiments). For serum ED biomarkers, 18 metabolites and 24 proteins showed AUC-ROC and hit rates >77.5%, and six metabolites were associated with event-free survival. These diseases share ED driven by systemic inflammatory, oxidative, and metabolic stress, are partially reversible in vitro, and are linked to biomarkers associated with clinical outcomes. Overall, ED emerges as a modifiable pathological axis with potential prognostic value. Full article

Steatosis, characterized by excessive fat accumulation in the liver, is a significant precursor to chronic liver disease and hepatocarcinoma. This condition is influenced by multiple contributing factors such as obesity, alcohol consumption, and exposure to chemicals or drugs. Systems biology approaches including transcriptomics and metabolomics can aid in grouping chemicals according to their mode of action. In this study, we analyze transcriptomic and metabolomic data from primary human and transformed hepatocytes, respectively, to differentiate between steatotic and non-steatotic chemicals. Rather than assessing each steatotic compound individually, we pooled several steatotic chemicals in order to minimize compound-specific noise and better identify features associated with the underlying process of steatosis. Differential gene expression analysis revealed established mechanisms involved in steatosis, consistent with the recently updated adverse outcome pathway. Likewise, metabolomic data enabled clear discrimination between steatotic and non-steatotic chemicals. These findings highlight the potential of omics technologies to support chemical grouping based on insights into the molecular mechanisms that drive steatosis development. Full article

Background/Objectives: Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH) and chronic viral hepatitis (CVH), are major global health concerns due to their potential progression to cirrhosis, liver failure, and hepatocellular carcinoma. Because liver biopsy, despite meeting the diagnostic gold standard, is invasive and associated with complications, non-invasive fibrosis assessment tools have been increasingly recommended in clinical practice. This study aimed to compare the diagnostic performance of several non-invasive fibrosis markers (ARR, APRI, FI, FIB-4, API, NFS, BARD) and transient elastography in detecting advanced liver fibrosis (F4) in patients with MASH and CVH. Methods: This retrospective study included 237 adult patients (77 MASH, 160 CVH) who underwent liver biopsy between 2017 and 2025 at the University Clinical Center of Serbia. CVH included chronic hepatitis B (CHB) and C (CHC). Patients were evaluated using serum fibrosis indices and TE, and results were compared to histological staging (F0–F4). ROC analysis assessed diagnostic performance. Results: Cirrhosis (F4) was more common in CVH than MASH (p < 0.001). In MASH, NFS (AUROC 0.931), FIB-4 (0.915), BARD (0.872), and APRI (0.878) showed high diagnostic accuracy for F4. In CHC, APRI (0.931), FIB-4 (0.863), and TE (0.938) had strong performance, while in CHB, TE (0.987) outperformed FIB-4 (0.821). Sensitivity and specificity varied by test and cohort, with TE consistently yielding the best results where available. Conclusions: Non-invasive methods, particularly NFS and FIB-4 for MASH and TE for CVH, effectively identify advanced fibrosis. Their application could significantly reduce the need for biopsy, especially in high-risk groups. TE demonstrated superior accuracy, but access limitations highlight the continued relevance of serum-based scores. Full article

Background: Intrahepatic cholangiocarcinoma (ihCC) is a rare aggressive liver malignancy with rising incidence. For resectable cases, surgery is the only curative approach, but recurrence rates remain high. These challenges highlight the need for personalized, evidence-based clinical decision-making to improve patient outcomes. To address this, we developed the Multiphasic Evidential Decision-making Matrix (MedMax) to support systematic, individualized therapeutic strategies for ihCC. Methods: In this retrospective single-center study, between 2010 and 2020, we assessed the ability of the MedMax matrix to make treatment decisions in 489 consecutive patients with ihCC or suspected ihCC. Patients were divided into two cohorts depending on whether their tumor was operable (surgical cohort, n = 335) or non-operable (non-surgical cohort, n = 154). We assessed the accuracy of diagnostic confirmation and treatment allocation by MedMax and evaluated how the model’s recommendations corresponded to those made by the tumor board. Results: In the surgical cohort, MedMax achieved 100% accuracy in diagnostic confirmation and 97.9% accuracy in treatment allocation. There was 74.3% concordance between the resection type proposed by MedMax and actual extent of resection. This discrepancy was caused by deviations from the preoperative plan based on intraoperative findings, which could not have been predicted preoperatively. In the non-surgical cohort, MedMax again achieved 100% accuracy in diagnostic confirmation and 98.7% accuracy in treatment allocation. All discrepancies between the decisions made by MedMax and those made by the tumor board were attributed complex, high-risk patient profiles. MedMax reliably identified risk factors (such as advanced comorbidities and multifocal disease) in both cohorts. Conclusions: The MedMax matrix can make accurate, reliable and transparent decisions about the diagnosis and treatment of patients with ihCC thanks to its modular, evidence-based approach. It can also stratify and document risks in both surgical and non-surgical settings. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and a major contributor to the global cardiometabolic burden. Early identification of patients at risk of metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis is essential to prevent liver-related and cardiovascular complications. In Spain, the burden of MASLD is increasing, yet information on routine clinical management by gastroenterologists remains limited. Methods: A nationwide cross-sectional online survey was conducted among members of the Spanish Society of Digestive Diseases (SEPD). The questionnaire explored five domains: MASLD knowledge, use of non-invasive biomarkers and imaging, awareness and implementation of clinical guidelines, cardiometabolic and alcohol-related risk assessment, and coordination with primary care. Results: A total of 429 specialists responded, 33.1% reported more than 20 years of practice and most worked in public hospitals, including 29.2% in large tertiary centers. Awareness of the MASLD definition was high, and 91.2% identified fibrosis as the main prognostic determinant. Non-invasive fibrosis biomarkers were widely used, whereas steatosis biomarkers were less frequently applied. Elastography was available to 96.1%. Guideline knowledge was reported by 80.4%, although implementation was lower. Cardiovascular risk evaluation varied: 75.1% reported systematic screening. Alcohol consumption was usually assessed. Coordination with primary care was limited: 91.1% expressed concerns regarding physicians’ familiarity with MASLD classification, and only 31.1% reported shared protocols. Conclusions: Spanish gastroenterologists show high awareness of MASLD and broad access to non-invasive diagnostic tools. However, important gaps remain in cardiovascular and alcohol risk assessment, guideline implementation, and coordination with primary care. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex, multifactorial disease heavily influenced by the gut–liver axis. While enterotoxigenic Bacteroides fragilis (ETBF) and its principal virulence factor, B. fragilis toxin (BFT)—a zinc-dependent metalloprotease—are well-known for disrupting intestinal barriers, their potential systemic impact on distant organs remains an emerging area of interest. Although various gut-derived factors contribute to hepatic inflammation, the precise molecular triggers that exacerbate the transition from simple steatosis to progressive fibrosis remain incompletely understood. This review proposes the “Direct Structural Disruption” hypothesis, examining the biological activity of BFT and its proposed role in MASH pathogenesis. We postulate that under permissive conditions, systemic BFT may target hepatic structural proteins (e.g., cadherins). This hypothesized architectural impairment amplifies canonical fibrogenic signaling and hepatic stellate cell (HSC) activation. In addition, we discuss current challenges in the detection and characterization of systemic BFT, particularly the technical limitations in clinical diagnostics stemming from its profound structural homology with host metalloproteinases. Future research integrating advanced diagnostic methodologies and liver-specific in vivo models is essential to elucidate these pathophysiological mechanisms and evaluate the ETBF-BFT axis as a complementary target in progressive MASH. Full article

Intestinal dysfunction and parenteral nutrition (PN) can trigger a spectrum of liver disorders collectively referred to as intestinal failure-associated liver disease (IFALD), for which therapeutic options remain limited. In the present study, we investigated the modulatory effects of the bioactive xanthophyll carotenoid lutein in an in vitro IFALD model utilizing human THLE-2 hepatocytes exposed to lipopolysaccharide and Intralipid to mimic PN–associated inflammatory and metabolic stress. Because lutein is poorly water-soluble and patients receiving PN lack enteral intake of this compound, we also evaluated the cyto- and hemocompatibility of a human serum albumin–based lutein nanoformulation developed to enable intravenous administration. A bead-based multiplex immunoassay revealed that lutein attenuated dysregulation of inflammatory and metabolic signaling by modulating total and phosphorylated levels of MAPKs, NF-κB, Akt, STAT5, CREB, and p70S6K. Lutein also affected lipid metabolism–related gene expression, decreasing SREBF2 and restoring ABCA1 and PRKAA2 mRNA toward control levels, as determined by qPCR. Nanoformulated lutein, with a mean particle size of approximately 160 nm, was non-toxic in THLE-2 cells and exhibited hemocompatibility in a human erythrocyte hemolysis assay. Together, our findings provide both biological and technological rationale for further exploration of lutein-based strategies to mitigate IFALD in patients receiving PN. Full article

Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA’s full potential as a broader therapeutic class. Full article

Ethanol exposure causes microbial imbalance, damages the gut barrier, and increases oxidative stress along the gut–liver axis, leading to the development and progression of alcohol-associated liver disease (ALD). Arginine is a conditionally essential amino acid that may play a key role in maintaining redox homeostasis and mediating host–microbiota crosstalk. We hypothesized that supplemental arginine provided during chronic ethanol exposure in mice would mitigate oxidative damage via the gut–liver axis. Our findings suggest that arginine supplementation mediated hepatic steatosis, preserved body weight and fat, and reduced oxidative stress in the gut–liver axis. These changes were associated with alterations in gut microbiota composition and function. These data support a potential role for arginine supplementation in mitigating ethanol-induced oxidative damage via the gut–liver axis. Full article

Objective: This study aimed to evaluate maternal serum afamin levels in women with intrahepatic cholestasis of pregnancy (ICP), examine their relationship with fasting bile acid concentrations, and assess their association with perinatal outcomes. Methods: This prospective case-–control study included 80 singleton pregnancies followed at a tertiary perinatology center between October 2025 and March 2026. Forty women with ICP, defined by pruritus and fasting bile acids > 10 μmol/L, were compared with 40 healthy pregnant controls. Women with ICP were further stratified according to fasting bile acid levels as <40 and ≥40 μmol/L. Maternal serum afamin concentrations were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Maternal characteristics, liver biochemistry, fetal biometric and Doppler parameters as well as obstetric and neonatal outcomes were compared. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of afamin for ICP, and logistic regression analysis was used to assess its association with ICP. Results: Baseline maternal characteristics were comparable between groups. Maternal serum afamin levels were significantly higher in the ICP group than in controls (6.18 ± 4.24 vs. 3.98 ± 1.95 ng/mL, p = 0.004). Afamin correlated positively with fasting bile acids (r = 0.372, p = 0.018), but not with transaminases, gestational age at delivery, birth weight, or neonatal outcomes. In logistic regression, afamin was independently associated with ICP (adjusted odds ratio [aOR] 1.260; 95% confidence interval [CI] 1.059–1.500; p = 0.009). ROC analysis showed poor discrimination for ICP (area under the curve [AUC] 0.634, 95% CI 0.51–0.76, p = 0.039), whereas afamin did not discriminate between subgroups defined by fasting bile acid levels (<40 vs. ≥40 μmol/L). The optimal cut-off value of 4.93 ng/mL predicted ICP with 55% sensitivity, 67.5% specificity, a positive likelihood ratio of 1.69, and a negative likelihood ratio of 0.67. Conclusions: Maternal serum afamin levels are elevated in ICP and show a modest association with fasting bile acid burden. Its discriminatory performance is limited, and it does not reliably distinguish patients defined by a ≥40 μmol/L threshold. These findings suggest that afamin reflects the maternal response to cholestasis rather than disease severity and may serve as a complementary biomarker. Full article

Background/Objectives: Hepatic diseases frequently present with ocular manifestations that aid diagnosis, provide prognostic data, and guide therapy. Despite the clear utility of the liver–eye axis, the literature lacks reviews that categorize these manifestations by etiology. This review evaluates current evidence to identify ocular findings that serve as clinical tools for diagnosis, prognosis, and therapeutic monitoring of hepatic pathologies. Methods: A narrative review was conducted using PubMed and Google Scholar to identify English-language articles addressing ocular manifestations associated with liver disease. The primary search encompassed publications from 2000 to 2025, with inclusion of select foundational works published prior to 2000 when they represented seminal studies establishing diagnostic criteria, pathophysiological mechanisms, or natural history data not superseded by subsequent research. Search terms included combinations of liver, hepatic, hepatitis, cirrhosis, cholestasis, eye, ocular, retina, cornea, sclera, conjunctiva, ophthalmic manifestations, and specific disease names. All study designs were eligible. Society guidelines, systematic reviews, and studies from high-impact journals were prioritized. The final selection comprised 59 references representing the most authoritative sources across the spectrum of hepatic conditions. Results: A spectrum of ocular findings linked to distinct hepatic conditions was identified. Manifestations with established clinicopathologic associations were categorized into congenital and acquired etiologies. Congenital liver pathologies included metabolic disorders (Wilson disease, galactosemia, lysosomal storage disorders) and syndromic/genetic causes (Alagille syndrome, hereditary hemochromatosis). Acquired liver diseases encompassed infectious (hepatitis B/C), drug-induced and iatrogenic (interferon, immune checkpoint inhibitors), nutritional (vitamin A deficiency), neoplastic (metastatic hepatocellular carcinoma), and cirrhotic causes. Conclusions: Specific ocular signs raise clinical suspicion for underlying liver disease and warrant targeted hepatic evaluation. Recognizing these associations facilitates earlier diagnosis and improves outcomes. Systematic screening for these signs is supported in at-risk populations, and prospective validation studies should establish their sensitivity and specificity. Full article

Background: Cigarette smoking exposes the human body to a complex mixture of toxic and carcinogenic compounds that can exert widespread biological effects across different organ systems. From addictive responses and consequence maladaptive neuroendocrine responses, cigarette smoke delivers a variety of reactive oxygen species, polycyclic aromatic hydrocarbons, nitrosamines, and heavy metals that collectively contribute to oxidative stress, inflammation, endothelial dysfunction, and metabolic disruption. The liver, as the primary organ responsible for xenobiotic metabolism, plays a central role in processing these harmful substances and is therefore uniquely susceptible to their effects. This narrative review will aim to provide an overview of the current evidence of cigarette smoking effects on hepatic structure and function and discuss clinical implications. Methods: This narrative review synthesizes evidence from in vitro studies, animal models, and human clinical research examining the effects of cigarette smoking on liver biology. Mechanistic pathways of injury, metabolic and vascular alterations, and clinical consequences for liver disease were considered. Results: Smoking influences hepatic function both directly—through biotransformation pathways generating reactive intermediates—and indirectly via vascular impairment, immune modulation, hormonal alterations, and changes in lipid and glucose metabolism. Emerging evidence indicates that cigarette smoking contributes to hepatic steatosis, accelerates fibrosis progression, worsens outcomes in viral and alcohol-related liver disease, and increases the risk of hepatocellular carcinoma. Conclusions: Cigarette smoking exerts multifaceted deleterious effects on the liver. Recognition of smoking as a modifiable risk factor for liver-related morbidity underscores the importance of smoking cessation in patients with or at risk for liver disease and highlights implications for research and clinical practice. Full article