Search Results (1,537)

Liver fibrosis, the progressive accumulation of scar tissue resulting from chronic liver disease, is increasingly recognized as a multi-system condition, the effects of which extend beyond the liver, affecting brain health. Dementia, characterized by progressively impaired cognition sufficient to impede daily functioning, is a major global health issue with incompletely defined risk factors and pathogenic precursors. To examine the relationship between liver fibrosis and cognitive outcomes, we conducted a comprehensive PubMed literature search, and human studies published in English were included. Evidence is synthesized on the pathophysiology and clinical significance of liver fibrosis, types of dementia, and studies supporting the association between liver fibrosis and cognitive impairment. Meta-analytic data indicate that liver fibrosis is associated with an approximately 30% increased risk of incident dementia (pooled hazard ratio ~1.3), with progressively higher risks across more advanced fibrosis stages. Putative pathomechanisms, potentially modulated by age and sex, include chronic systemic and neuro-inflammation, insulin resistance, vascular dysfunction, and a perturbed intestinal microbiota–liver–brain axis. Non-invasive liver fibrosis diagnostics, advanced neuroimaging, and biomarkers represent key tools for assessing risk. In conclusion, liver fibrosis is a systemic condition that can affect brain health. Early detection, thorough risk assessment and interventions, such as lifestyle changes, metabolic therapies, and antifibrotic treatments, may help protect neural function. Key research gaps are identified, with suggestions for improving understanding of liver fibrosis’s connection to dementia or cognitive impairment. Full article

Background/Objectives: Previous studies have demonstrated that the cessation of liver damage after HCV cure can improve liver function, histological necroinflammation, and portal hypertension. However, scarce data about fibrosis stage or cirrhosis regression have been reported during follow-up. Methods: A prospective study evaluating hepatic biopsies and liver stiffness measurement by vibration-controlled transient elastography (VCTE-LSM) after the end of treatment (EOT) in patients with compensated advanced chronic liver disease (cACLD). Fibrosis was evaluated according to two semi-quantitative grading systems (METAVIR and Laennec) at 6 years after EOT (LB6) and compared with biopsies at 3 years (LB3). Results: Fifty-four patients with LB6 (34 with paired LB3–LB6) were included. Median (IQR) age was 53.9 (48.5–59.3), 38 (70.4%) were men, and 13 (24.1%) were HIV-coinfected. The VCTE-LSM was >15 kPa in 30 (55.6%). The LB6 (81.4 months after EOT) showed non-advanced fibrosis (F1–F2) in 12 (22.4%) patients, bridging (F3) in 26 (48.2%), and cirrhosis (F4) in 16 (29.6%): F4A in 7 (13.0%), F4B in 4 (7.4%), and F4C in 5 (9.3%). The 1-year post-EOT follow-up VCTE-LSM ≤ 8.6 kPa identifies patients without advanced fibrosis (AUROC = 0.929), with a negative predictive value of 88.9% and a positive predictive value of 95.2%. Paired biopsies showed regression in 9 (47.4%) out of 19 patients with cirrhosis: 8 (61.5%) of 13 with F4A but only 1 (16.7%) of 6 with F4B–F4C. Conclusions: Advanced fibrosis persists in most patients with advanced chronic liver disease after HCV eradication. Regression is possible in mild cirrhosis. However, it is a limited and slow event. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to systemic metabolic disturbances and features a lipid-driven cascade that promotes hepatic inflammation and fibrosis. Choline insufficiency contributes to disease advancement by altering phospholipid turnover and redox homeostasis; however, its spatial and temporal regulatory roles throughout MASLD progression remain insufficiently defined. A 10-week high-fat, choline-deficient (HFCD) mouse model was established, and liver pathology was evaluated at weeks 6, 8, and 10. Time-resolved assessments combined untargeted metabolomics, magnetic resonance imaging–proton density fat fraction (MRI-PDFF), serum biochemistry, histological staining, immunofluorescence, and transmission electron microscopy to characterize dynamic alterations in lipid metabolism, redox status, inflammation, and fibrogenesis. The HFCD diet produced a clear temporal sequence of liver injury. Steatosis, phosphatidylcholine depletion, and early antioxidant loss appeared by week 6. By week 8, mitochondrial structural damage and pronounced cytokine elevation were evident. At week 10, collagen deposition and α-SMA activation signaled fibrotic progression. Metabolomics indicated significant disruptions in pathways related to ATP-binding cassette (ABC) transporters, one-carbon metabolism, and the tricarboxylic acid (TCA) cycle. Using integrated analytical strategies, this study suggests that choline deficiency may be associated with a time-dependent pathological cascade in MASLD, beginning with phospholipid destabilization and extending to altered mitochondria–endoplasmic reticulum crosstalk at mitochondria-associated membranes, alongside amplified oxidative–inflammatory responses, which collectively may contribute to progressive fibrogenesis as the disease advances. Full article

Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed. The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response. Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models. The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC. In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ⁹-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressive spectrum of metabolic liver injury in which immune activation, metabolic stress, and stromal remodeling evolve in a tightly interdependent manner. Although early disease stages are dominated by metabolic overload, accumulating evidence indicates that immunometabolic rewiring and fibro-inflammatory amplification critically shape the transition toward metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis. This review synthesizes emerging insights into how hepatocyte stress responses, innate and adaptive immune circuits, and extracellular matrix-producing stromal populations interact to form a dynamic, feed-forward network driving disease progression. Particular emphasis is placed on the deterministic role of immune–fibrotic coupling in shaping clinical phenotypes, disease trajectory, and therapeutic responsiveness. Rather than focusing on individual molecular layers, we highlight how integrated clinical, imaging, and biomarker-informed frameworks can capture immune–fibrotic signatures relevant to risk stratification and precision intervention. Building on this systems-level perspective, we outline next-generation therapeutic strategies targeting immunometabolic circuits, cross-organ communication, and multi-system dysfunction. Finally, we discuss how future precision medicine—supported by integrative biomarker profiling and dynamic physiological assessment—may reshape MASLD management and improve long-term hepatic and cardiometabolic outcomes. Full article

Ketones are metabolites primarily produced by the liver and are utilized by various organs outside of the liver. Recent advances have demonstrated that ketones serve not only as alternative energy sources but also as signaling molecules. Research indicates that ketones can influence cancer development and metastasis, cardiac metabolic and structural remodeling, physical performance, vascular function, inflammation, and the aging process. Emerging evidence from preclinical and early-phase clinical studies suggests that strategies such as ketone salts, ketone esters, and the ketogenic diet may offer therapeutic benefits for conditions like heart failure, acute cardiac injury, diabetic cardiomyopathy, vascular complications, atherosclerosis, hypertension, and aortic aneurysm. This literature review updates the current understanding of ketone metabolism and its contributions to cardiovascular health and diseases. We highlight the underlying molecular mechanism with post-translational modification known as β-hydroxybutyrylation, which affects the fate and function of target proteins. Additionally, we discuss the therapeutic challenges associated with ketone therapy, the potential of using ketone levels as biomarkers for cardiovascular diseases, as well as gender- and age-specific differences in ketone treatment. Finally, we explore future research directions and what is needed to translate these new insights into cardiovascular medicine. Full article

Polyunsaturated fatty acids (PUFAs), particularly omega-3 derivatives such as docosahexaenoic acid (DHA), are precursors of specialized pro-resolving mediators (SPMs) that actively orchestrate the resolution of inflammation. Among these, maresins (MaRs) have gathered increasing attention due to their potent immunomodulatory and tissue-regenerative properties. This review provides a comprehensive synthesis of the current knowledge on the biosynthesis, structural diversity, and biological functions of MaRs, with a focus on MaR1. We discuss the enzymatic pathways involved in the generation of MaR1, MaR2, MaRs conjugates in tissue regeneration (MCTRs), and maresin-like lipid mediators (MaR-Ls), highlighting their roles in modulating inflammatory responses, promoting phagocytosis, and restoring tissue homeostasis. Preclinical evidence from in vitro and in vivo models demonstrates that MaRs exert protective effects in a wide range of pathological contexts, including neuroinflammation, liver injury, cardiovascular dysfunction, pulmonary diseases, and metabolic disorders. Although their therapeutic promise is well-supported, key gaps remain in the understanding of MaRs biosynthesis, receptor specificity, and translational applicability. This review emphasizes the importance of advancing mechanistic and clinical research to fully harness MaRs as part of next-generation therapeutics in inflammation-driven diseases. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer and cancer-related death worldwide. Beyond the well-known factors influencing the risk of HCC, experimental data from animal models and observational human studies support a significant role of the gut microbiota (GM) in HCC initiation and progression. Dysbiosis and increased intestinal permeability synergistically disrupt the ‘gut–liver axis,’ exposing the liver to bacterial metabolites and microbial-associated molecular patterns, thereby contributing to hepatocarcinogenesis. While these findings have expanded our understanding of HCC pathogenesis, a critical translational gap persists as most data derive from preclinical settings, with limited validation in large-scale clinical studies. Methods: This narrative review aimed to contextualise the current evidence on the GM-HCC axis and its clinical translatability. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science up to July 2025 using Medical Subject Headings and related keywords, including HCC, GM, dysbiosis, intestinal permeability, gut–liver axis, microbial metabolites, inflammation/immune modulation, and microbiota-targeted interventions (probiotics, antibiotics, and faecal microbiota transplantation). Reference lists of relevant articles were also screened to identify additional studies. Results: Preclinical models consistently indicate that dysbiosis and impaired gut barrier function can promote hepatic inflammation, immune dysregulation, and pro-tumorigenic signalling through microbe-derived products and metabolite perturbations, supporting a contributory role of the GM in hepatocarcinogenesis. In humans, HCC and advanced chronic liver disease are associated with altered microbial composition and function, increased markers of intestinal permeability, and changes in bile acid and other metabolite profiles; however, reported signatures are heterogeneous across cohorts and analytical platforms. Conclusions: The GM is a biologically plausible and experimentally supported contributor to HCC initiation and progression, with potential for biomarker development and therapeutic targeting. However, clinical translation is limited by predominantly preclinical/associative evidence, interindividual variability, and non-standardised microbiome methods. Large longitudinal studies and adequately powered randomised trials are needed to establish causality, validate biomarkers, and determine whether GM modulation improves HCC prevention, detection, stratification, or outcomes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a continuum of hepatic pathological manifestations of the metabolic syndrome. Pathogenesis is not clearly understood despite recent progress, but Kupffer cells and bone marrow-derived macrophages (BMDMs) have a fundamental role. In this review, the multiple pathophysiological aspects of MASLD are presented, including genetics, insulin resistance, lipotoxicity, and inflammation. The participation of innate and adaptive immunity, as well as the implications of the recently described trained immunity, is presented. The interplay of the liver with the gut microbiota is also analyzed. A recent adipocentric theory and the various mechanisms of hepatocyte death are also described. The fundamental role of Kupffer cells and other liver macrophages is discussed in detail, including their extreme phenotypic plasticity in both the normal and the MASLD liver. The functional differentiation between pro-inflammatory and anti-inflammatory subpopulations and their protective or detrimental involvement is further described, including the participation of Kupffer cells and BMDMs in all aspects of MASLD pathogenesis. The role of macrophages in the development of advanced MASLD, including fibrosis and hepatocellular carcinoma, is analyzed and the lack of explanation for the transition from MASLD to MASH is recognized. Finally, current modalities of drug treatment are briefly presented and the effects of different drugs on macrophage polarization and functions are discussed. Full article

Liver function plays a pivotal role in the management of hepatocellular carcinoma (HCC). Consequently, managing HCC requires a dual focus on both tumour staging and liver function assessment to guide therapeutic decisions. Comprehensive liver function evaluation involves clinical tools such as the Child–Pugh classification and the Model for End-Stage Liver Disease (MELD) score. This is supplemented by newer metrics, including the MELD-Na score, the albumin–bilirubin (ALBI) grade and liver stiffness measurements. These assessments are integral to tailoring treatments, ranging from curative approaches such as surgical resection and liver transplantation to locoregional options (percutaneous ablation, transarterial chemoembolisation and radioembolisation), and systemic therapies. This review explores strategies for balancing the aggressiveness of cancer therapy with the need to preserve hepatic function, particularly in patients with advanced liver dysfunction. A multidisciplinary approach, incorporating expertise from hepatology, oncology, radiology and surgery, is essential for optimising outcomes. Advanced imaging techniques and biochemical markers also improve decision-making and ensure individualised care. Full article

Background/Objectives: Compensated advanced chronic liver disease (cACLD) affects millions and carries risk for portal hypertension, large varices, and clinical decompensation. The HepQuant DuO^® test provides a blood-based assessment of liver function and physiology, generating a disease severity index (DSI) validated for risk stratification. A retrospective, real-world, observational analysis was conducted to evaluate the utility of HepQuant DuO’s DSI cutpoint (18.3) in guiding endoscopy and clinical management decisions for patients with cACLD in the United States. Methods: De-identified data from 87 cases with cACLD were extracted from physician-provided Statements of Medical Necessity documenting the reasons for the HepQuant DuO test. The primary endpoint was concordance of endoscopy decisions with DSI ≤ 18.3 (avoid) or >18.3 (proceed). The secondary endpoint was concordance of clinical management intensity with the same cutpoint. Results: Among the 55 cases analyzed for endoscopy decisions, overall concordance with DSI 18.3 was 93% (p < 0.001 by Fisher’s exact test): 96% of cases with DSI ≤ 18.3 avoided endoscopy, and 90% with DSI > 18.3 underwent endoscopy. For the 45 cases assessing management intensity, overall concordance was 89% (p < 0.001): 90% of cases with DSI ≤ 18.3 had reduced follow-up, and 89% with DSI > 18.3 had intensified management. The cohort exhibited broad functional heterogeneity not captured by standard labs or elastography. Conclusions: HepQuant DuO’s DSI cutpoint 18.3 demonstrated strong concordance with real-world clinical decisions, supporting its utility for risk stratification, optimizing endoscopy use, and tailoring management in cACLD. Full article

Liver fibrosis is a common pathological result of chronic hepatic injury caused by various factors, such as viral hepatitis, alcohol-induced liver disease, and metabolic dysfunction-associated steatohepatitis (MASH). It is characterized by an excessive deposition of extracellular matrix, which disrupts the architecture of the liver and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Globally, nearly 10% of the population has significant fibrosis, with its prevalence increasing with age, obesity, and metabolic syndrome. Despite its significant clinical impact, early detection of liver fibrosis is still limited due to insufficient diagnostic technologies and low public awareness. The increasing burden of MASH emphasizes the urgent need for scalable therapeutic strategies. Currently, liver transplantation is the only definitive treatment, but it is limited by donor shortages and the need for lifelong immunosuppression. However, fibrosis is now recognized as a dynamic and potentially reversible process if the underlying cause is addressed. This shift in understanding has prompted efforts to develop pharmacological agents that target hepatic stellate cell activation, immune system interactions, and metabolic dysfunction. Advances in organoid platforms, multi-omics, and non-invasive diagnostics are accelerating translational research in this area. This review aims to synthesize current knowledge about the molecular drivers of fibrosis, bottlenecks in the current anti-fibrotic drug discovery process, and emerging therapeutic approaches to inform precision medicine strategies and reduce the global burden of chronic liver disease. Full article

Cadmium (Cd) is a highly toxic and pervasive environmental pollutant that exerts detrimental effects on human health through diverse biochemical and molecular mechanisms. As a vital metabolic organ, the liver harbors macrophages that play a crucial role in maintaining hepatic health and function. Current research has paid relatively little attention to the role of macrophages in liver injury induced by heavy metal exposure. This review summarizes current research on the molecular mechanisms underlying cadmium-induced toxicity in hepatic macrophages, focusing on oxidative stress, signaling pathways, gene transcription, and apoptosis. It further examines how cadmium-induced macrophage dysfunction impacts hepatic immunometabolism. Specifically, we detail how cadmium triggers oxidative stress and disrupts intracellular calcium homeostasis, leading to the activation of transcription factors such as NF-κB and Nrf2, and the subsequent engagement of related signaling cascades. These perturbations alter macrophage polarization (M1/M2), promote cellular damage and apoptosis, and ultimately exacerbate hepatic inflammation and fibrosis. By synthesizing recent advances in this field, this review aims to provide a theoretical foundation and future directions for research, with the goal of informing novel strategies for the prevention and treatment of heavy metal-associated liver diseases. Full article

The liver is the primary site of synthesis for most coagulation factors and the central organ responsible for maintaining hemostatic equilibrium. In individuals with advanced liver disease, significant disruptions in coagulation homeostasis occur and consequently predispose patients to both thrombotic and bleeding complications. This review summarizes the pathophysiologic basics of liver cirrhosis-associated coagulopathies and discusses the diagnosis and treatment of common procoagulant conditions such as portal vein thrombosis and post-transplant hepatic artery thrombosis. The review also systematically addresses the most common bleeding complications, including spontaneous, portal hypertension-related, and periprocedural bleeding. The proper pre-procedural assessment of the bleeding risk is often required due to the great number of invasive procedures to which these patients are frequently subjected. The viscoelastic testing (thromboelastogram and thromboelastometry) seems to emerge as the most appropriate diagnostic method. Specific treatment recommendations for the correction of coagulation abnormalities and the management of severe thrombocytopenia are hereby presented. Full article

Uveal melanoma (UVM) is a rare cancer that represents the second most common melanoma (after the cutaneous) and the most common primary intraocular malignancy in adults. Despite recent advances in the understanding of UVM pathogenesis, its prognosis remains unchanged, with half of patients dying because of liver metastasis. Erythropoietin-producing human hepatocellular receptors (EPHs) constitute the largest known family of tyrosine receptors, and, along with their ligands, EFNs, regulate key physiological processes and are implicated in cancer pathogenesis. In this study, we used open-access web bioinformatics platforms to explore and analyze big datasets provided by The Cancer Genome Atlas (TCGA) UVM cohort of patients. We profiled the genomic alterations present in a subset of UVM patients, highlighting a likely pathogenic deep deletion of EPHA7. Survival analysis showed that overexpression levels of EPHA4, EPHA5, EPHA8, EPHB2, and EFNB2 are significantly associated with poor overall survival. Additionally, high expression levels of EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2 correlate with reduced progression-free interval and disease-free survival. Finally, we identified the EPHs (EPHA2, EPHA4, EPHA8, and EPHB4) and EFNs (EFNA1, EFNA3, EFNA4, and EFNB2) that are significantly overexpressed in the aggressive epithelioid histological subtype and revealed that the majority of EPHs/EFNs are overexpressed in metastatic disease. In conclusion, our results highlight that a subset of EPHs and EFNs may be associated with worse clinical outcomes (EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2), and an aggressive histological subtype (EPHA2, EPHA4, EPHA8, EPHB4, EFNA1, EFNA3, EFNA4, and EFNB2). The potential correlation of these genes with clinicopathological parameters of UVM need to be evaluated and validated with bioinformatic and experimental approaches in well-characterized cohorts of UVM patients. Full article