Search Results (681)

The hepatic lymphatic system, long underappreciated, plays a critical role in liver physiology by maintaining interstitial fluid balance, removing metabolic waste, and facilitating immune surveillance. Emerging evidence indicates that lymphatic dysfunction contributes to the pathogenesis and progression of multiple liver diseases, including non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes current knowledge on hepatic lymphatic anatomy, physiology, and molecular regulation, highlights pathological alterations, and discusses potential therapeutic implications. A better understanding of the hepatic lymphatic system may enable the development of novel lymphatic-targeted strategies to improve liver health and treat liver disease. Full article

Non-alcoholic fatty liver disease (NAFLD) is a silent condition that can lead to fatal cirrhosis, with dietary factors playing a central role. The effect of various dietary interventions on male Wistar rats were evaluated in four diets: control, arsenic, sucrose, and arsenic–sucrose. SHG microscopy images from the right ventral lobe of the liver tissue were analyzed with a neural network trained to detect the presence or absence of collagen fibers, followed by the assessment of their orientation and angular distribution. Machine learning classification of SHG microscopy images revealed a marked increase in fibrosis risk with dietary interventions: <10% in controls, 24% with arsenic, 40% with sucrose, and 62% with combined arsenic–sucrose intake. Angular width distribution of collagen fibers narrowed dramatically across groups: 26° (control), 24° (arsenic), 15.7° (sucrose), and 2.8° (arsenic–sucrose). This analysis revealed four key statistical features for classifying the images according to the presence or absence of collagen fibers: (1) the percentage of pixels whose intensity is above the 15% noise threshold, (2) the Mean-to-Standard Deviation ratio (Mean/std), (3) the mode, and (4) the total intensity (sum). These results demonstrate that a diet rich in sucrose, particularly in combination with arsenic, constitutes a significant risk factor for liver collagen fiber remodeling. Full article

Background: Chemokine CCL5 may drive inflammation and vascular risk in advanced liver disease, but its cardiovascular implications are unclear. Secreted by hepatic, endothelial, macrophage, and lymphocytic cells, CCL5 is involved in cytokine regulation. Its serum levels rise in acute liver injury and hepatocellular carcinoma (HCC), but decline with fibrosis progression in end-stage liver disease (ESLD). CCL5 has also been linked to atherosclerosis. This study aimed to evaluate serum CCL5 levels in ESLD patients listed for liver transplantation (LT) and to assess their potential role as markers of cardiovascular (CV) risk and portal hypertension. Methods: We conducted an observational cohort study. Between 2019 and 2022, patients with ESLD evaluated for LT were enrolled. Data on liver pathology, CV risk, and laboratory parameters were collected. Serum CCL5 concentrations were measured using Sigma Aldrich^® CCL5 ELISA kits (MilliporeSigma, St. Louis, MO, USA). The database was analyzed with IBM^® SPSS^® Statistics version 20 (Chicago, IL, USA). Results: Overall, 46 patients were included, 50% with viral hepatitis and 28.3% with alcohol-related liver disease. HCC was present in 37% of cases. The median CV risk scores (CAD_LT = 7, mCAD_LT = 7, CAR_OLT = 18) placed the population at moderate CV risk. Serum CCL5 levels did not vary significantly between viral vs. non-viral cirrhosis (5511.8 vs. 6272.5 pg/mL, p = 0.15) and were not influenced by the presence of HCC (6098.4 vs. 5771.3 pg/mL, p = 0.55). We did not detect a correlation with MELD score (p = 0.21) or CV risk scores (CAD_LT: p = 0.58; mCAD_LT: p = 0.70; CAR_OLT: p = 0.22). Patients with thrombocytopenia (<100,000/µL, 54.3%) or a history of esophageal variceal ligation had lower CCL5 levels (5170.9 vs. 6750.8 pg/mL, p = 0.002 and 4252.0 vs. 6237.5 pg/mL, p = 0.003, respectively). Similarly, patients with a history of previous variceal bleeding and spontaneous bacterial peritonitis (SBP) had lower levels of CCL5 (4373.8 vs. 6119.9 pg/mL, p = 0.02 and 3404.3 vs. 6606.7 pg/mL, p = 0.01, respectively). We found a negative correlation between CCL5 and QTc interval duration (τ = −0.216, p = 0.037), left ventricle size (LV: τ = −0.235, p = 0.027), and pulmonary artery pressure (RV/RA gradient: τ = −0.225, p = 0.03). CCL5 correlated positively with the inflammatory markers C-reactive protein (CRP) (τ = 0.246, p = 0.018) and fibrinogen (r = 0.216, p = 0.04). Conclusions: In liver transplant candidates, serum CCL5 is not associated with cardiovascular risk scores or coronary atherosclerotic burden, but is inversely associated with clinical markers of portal hypertension severity. These findings suggest that CCL5 may serve as a potential non-invasive surrogate marker of portal hypertension rather than a cardiovascular risk biomarker in ESLD. Full article

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP–PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS–STING pathways to engage a coordinated network of IRFs—including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9—that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies. 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

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

Objective: To analyze demographic traits, clinical complications, and healthcare use in patients with chronic liver disease across major etiologies in a large Romanian cohort. Methods: A retrospective study (2019–2023) of 2359 patients with chronic hepatitis C (CHC), hepatitis associated with alcohol (ALH), cirrhosis associated with alcohol (ALC), or non-alcoholic cirrhosis (NALC). Data on demographics, clinical outcomes, and hospitalizations were analyzed using descriptive statistics, regression modeling, and clustering in IBM SPSS 27.0.1. Results: CHC patients were oldest (mean 67.5 ± 12.3 years), while ALH patients were youngest (56.0 ± 11.0 years). CHC prevalence increased with age (10.0% in ≤30-year-olds to 87.1% in ≥81-year-olds; γ = 0.535, p < 0.001). Females comprised 60–70% of CHC cases, males > 85% of ALH and >78% of ALC. Mean hospitalization duration decreased from 13.80 days (2019) to 9.10 days (2023), yet cirrhotic patients had the longest stays (NALC: 16.37 ± 14.34; ALC: 17.66 ± 12.96) versus CHC (10.38 ± 10.14). Etiology was the strongest predictor of hospitalization length. Portal hypertension (PH) was the most common complication (54.3%), with males bearing more severe hepatic complications (ascites—38.3%; PH—66.8%). Conclusions: Hospital-based Romanian cohort analysis revealed that patient presentation and outcomes are fundamentally shaped by the interplay of etiology, sex, and age. We found a distinct female predominance in CHC, a pronounced male predominance in alcohol-related diseases, and evolving trends in non-alcoholic cirrhosis. These determinants dictate specific epidemiological patterns, hospitalization burdens, and complication risks, underscoring the critical need for a paradigm shift toward personalized, etiology-driven, and sex-tailored clinical management. Full article

Background: Cirrhosis represents the final common pathway of chronic liver injury, arising from diverse etiologies such as metabolic, viral, autoimmune, and alcohol-related liver diseases. Despite similar exposures, disease progression varies considerably among individuals, suggesting a genetic contribution to susceptibility and outcome. Objective: This narrative review examines how specific genetic variants influence the risk, progression, and phenotypic expression of cirrhosis. It provides a structured synthesis of established and emerging gene associations, emphasizing their biological mechanisms and potential clinical relevance. Methods: This narrative review synthesizes evidence from all major biomedical and scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, as well as reference lists of relevant articles, covering literature published between 2005 and 2025 on genetic polymorphisms associated with cirrhosis and its etiological subtypes. Content: Variants are categorized into four mechanistic domains—metabolic regulation, immune modulation, liver enzyme activity, and ancestry-linked expression patterns—representing a novel integrative framework for understanding genetic risk in cirrhosis. Well-characterized variants such as PNPLA3, TM6SF2, HSD17B13, and MBOAT7, along with less commonly studied loci and chromosomal alterations, are discussed in relation to major etiologies, including MASLD/MASH, viral hepatitis, alcohol-related liver disease, and autoimmune conditions. Conclusions: Genetic insights into cirrhosis offer pathways toward early risk stratification and personalized disease management. While polygenic risk scores and multi-omic integration show promise, their clinical translation remains exploratory and requires further validation through large-scale prospective studies. Full article

Background: The transition from the term non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD), an umbrella term for several related conditions, offers benefits, particularly in identifying cardiometabolic risk factors more effectively. However, the impact of alcohol consumption on liver disease progression remains significant, leading to the recognition of a new entity: MetALD (metabolic dysfunction-associated steatotic liver disease with moderate alcohol intake). Aim: This study aimed to compare characteristics associated with liver disease progression in diabetic patients diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD) versus those with MetALD. Materials and Methods: In this prospective study, 286 diabetic patients were followed for 12 months. All patients underwent transient elastography (TE) and ultrasound to assess hepatic steatosis. Participants were classified into MASLD and MetALD groups. The performance of fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) were also evaluated. Results: MASLD was diagnosed in 58.2% (167 patients), of whom 4.9% (7 patients) had TE values suggestive for liver cirrhosis. Among those with MetALD, 17.6% (21 patients) had TE values compatible with advanced fibrosis. MASLD subjects presented a slight decrease in liver fibrosis values from 6.58 ± 2.27 kPa to 6.03 ± 1.57 kPa in the 12 months. On the contrary, MetALD subjects had an increase of liver stiffness measurements (LSM) values from 11.83 ± 6.27 kPa to 12.24 ± 8.66 kPa. Conclusions: in diabetic patients, the coexistence of moderate alcohol intake and cardiometabolic risk factors (MetALD) is associated with more advanced liver fibrosis and impaired long-term glycemic control, compared to MASLD alone. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, and its pathogenesis and progression mechanisms remain incompletely understood. An increased activation of innate immune cells in the liver contributes to hepatic fibrogenesis via a chronic loop of inflammation and regeneration processes. Among them are mast cells (MCs), whose role in hepatic cirrhosis secondary to MASLD remains poorly studied. Our aim was to evaluate differences in MC density in cirrhotic liver tissue among patients with MASLD and other chronic liver disease etiologies. For this, a retrospective study of MC count was performed in cirrhotic liver explants obtained from MASLD, alcohol-related liver disease (ALD), and autoimmune hepatitis (AIH). We included a control group of subjects without liver damage. Tryptase-positive MCs were identified by indirect immunofluorescence and quantified as MC density per low-power field (MC/LPF). Group differences were analyzed using the Kruskal–Wallis test with Dunn’s multiple comparisons, considering p < 0.05 as statistically significant. A significantly higher MC density was observed in MASLD, ALD, and AIH patients compared with the control group. The group analysis showed that ALD patients exhibited higher MC density than AIH, with no observed difference between ALD and MASLD. MC density was correlated positively with tobacco smoking and alcohol use in the full analyzed group, suggesting them as risk factors of high MC liver infiltration. We conclude that MC density is augmented in MASLD-related cirrhosis, highlighting potential links between lifestyle factors and MC-mediated hepatic inflammation. Future studies should explore the mechanisms driving this association and evaluate whether targeting MCs could help mitigate fibrosis progression. Full article

Cirrhotic cardiomyopathy encompasses structural and functional cardiac abnormalities occurring in patients with liver cirrhosis despite the absence of pre-existing heart disease, yet its diagnosis remains challenging. Although echocardiography is the standard diagnostic tool, circulating biomarkers may provide complementary value when imaging findings are inconclusive. This study evaluated the association between N-terminal pro-B-type natriuretic Peptide (NT-proBNP), soluble Suppression of Tumorigenicity 2 (sST2), and diastolic dysfunction in cirrhotic patients without known cardiac disease. We conducted a prospective case–control study including 83 participants (43 patients with non-alcoholic cirrhosis and 40 healthy controls), assessed clinically, biochemically, and echocardiographically between June 2020 and July 2021. Cirrhotic patients showed significantly higher NT-proBNP (94.17 ± 151.36 pg/mL vs. 19.2 ± 5.47 pg/mL, p < 0.001) and sST2 levels (5.4 ± 2.31 ng/mL vs. 2.4 ± 0.99 ng/mL, p < 0.001). NT-proBNP demonstrated limited diagnostic accuracy for diastolic dysfunction (accuracy 52.6%, sensitivity 50%, specificity 60%, AUC 0.51), but it correlated modestly with congestion markers such as left atrial volume and pulmonary artery systolic pressure. A multimarker model combining age, NT-proBNP, and sST2 substantially improved diagnostic performance for diastolic dysfunction (accuracy 75%, sensitivity 77.1%, specificity 71.4%, AUC 0.925). In conclusion, NT-proBNP is associated with diastolic dysfunction but is influenced by cirrhosis congestion status. A combined NT-proBNP and sST2 assessment enhances diagnostic precision and may aid therapeutic decision-making, particularly regarding congestion and diuretic management in cirrhotic patients. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease worldwide, with an increasing prevalence, mainly due to the increase in childhood obesity and sedentary lifestyle. The pathogenesis of NAFLD is multifactorial, but the mechanisms by which the factors involved, namely the genetic, intrauterine and environmental factors responsible for its onset and progression to NASH, are not fully known. Children with NAFLD are usually asymptomatic or show nonspecific symptoms, and NAFLD is generally diagnosed incidentally by screening tests in overweight or obese children. NAFLD is associated with severe metabolic deficiencies that may progress to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Current treatment of NAFLD in children consists of lifestyle changes to decrease caloric intake and increase physical activity, with no currently approved pharmacological medication for the pediatric population. Although pediatric studies that focus on alternative treatments targeting key pathogenic factors are promising, no pharmacological agent is currently approved for children, validated non-invasive fibrosis biomarkers remain limited, and long-term outcome data are scarce. Further validation through large prospective pediatric cohorts and phase III trials is urgently needed. Full article

Metabolic dysfunction–associated fatty liver disease (MASLD) is associated with severe forms of liver injury, including fibrosis and cirrhosis. The main risk factors for MASLD—obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and insulin resistance (IR)—contribute to metabolic disturbances that initiate hepatic steatosis. Metabolic and alcohol-related liver disease (MetALD) describes patients with MASLD who also present alcohol-associated hepatic injury. Chronic oxidative and inflammatory stress promotes the progression of steatosis in both conditions. T2DM and chronic alcohol consumption are independent lifestyle-related risk factors for cirrhosis within the spectrum of metabolic dysfunction–related liver disease (MASLD and MetALD). The coexistence of both conditions may exacerbate hepatic pathological alterations. IR, which is frequently observed in patients with cirrhosis, can lead to the development of a condition known as hepatogenic diabetes (HD). HD is characterized by hyperinsulinemia, IR, and β-cell dysfunction occurring during the onset of cirrhosis and is associated with hepatic inflammation even in the absence of traditional metabolic risk factors such as obesity or a prior history of T2DM. In this context, alcohol intake enhances lipolysis in peripheral tissues, promotes hepatic steatosis, and aggravates metabolic dysfunction, ultimately contributing to excessive mitochondrial production of reactive oxygen species (ROS). Therefore, the present review examines the role of oxidative stress—both alcohol-related and non-alcohol–related—in the pathogenesis of HD, with particular emphasis on ethanol metabolism, oxidative stress, and their interactions in conditions such as T2DM and MetALD. Full article

Background: Micro-RNAs (miRNAs) are emerging as pivotal regulators of pathophysiological processes, reflecting systemic responses to stress, inflammation and metabolic imbalance. Their role in advanced liver disease and in modulating responses to therapeutic interventions, such as fecal microbiota transfer (FMT), remains insufficiently characterized. Methods: We conducted a prospective study including six male patients with toxic ethanolic liver cirrhosis undergoing FMT and six healthy controls. Stool and blood samples were collected pre- and post-FMT. Fecal micro-RNA expression (miR-21, miR-122, miR-125, miR-146 and miR-155) was quantified using RT-qPCR and normalized to miR-26c. Associations with noninvasive fibrosis markers (FIB-4, APRI, elastography, CAP) and biological parameters were analyzed through multivariable regression and Pearson correlation, with internal validation by bootstrapping. Results: One week after fecal microbiota transfer, miR-21 and miR-146 exhibited significant expression changes, while miR-122, miR-125, and miR-155 showed non-significant trends toward increased expression. Post-FMT increases in miR-21, miR-122, miR-146 and miR-155 were consistently associated with reductions in hepatic fibrosis markers (FIB-4, APRI and liver stiffness), whereas no significant associations were observed with CAP. Conclusions: Fecal micro-RNAs reflect interconnected molecular networks that capture systemic adaptations to FMT. Despite a limited cohort, these findings highlight their potential as integrative biomarkers and as therapeutic targets in advanced liver disease. Larger-scale studies are warranted to validate clinical utility. Full article

Objectives: Liver steatosis is one of the main causes of liver disease with several clinical implications, such as steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. It is associated with increased cardiovascular risk. Reliable, non-invasive methods to classify and evaluate improvement or worsening of liver steatosis at the diagnosis and during follow-up are therefore essential. This study aims to evaluate the accuracy of ultrasound fat fraction (USFF) in a population of patients with moderate to morbid obesity. Method: A total of 95 obese patients were evaluated for liver steatosis with ultrasound visual assessment and USFF measurement using the Samsung RS85 Prestige system. 84 patients were included (exclusion criteria were morphological features of advanced liver disease or cirrhosis, active viral hepatitis, alcohol use disorder, liver enzymes alteration and heart failure) Based on the visual assessment, patients were classified into four categories: absent, mild, moderate, and severe steatosis. The distribution of USFF values across groups was analyzed using one-way ANOVA with post-hoc comparisons. Receiver Operating Characteristic (ROC) curves were generated, and the Youden index was applied to determine optimal USFF cut-off points for each steatosis grade. Results: Mean USFF values increased progressively across the severity spectrum and significant differences in mean USFF values were observed across all four steatosis grades groups (p < 0.001). Based on the Youden index, the following cut-offs have been proposed: no steatosis USFF < 7.33, mild steatosis USFF < 11.66, moderate steatosis USFF < 16.30. Conclusions: Our findings suggest that USFF may offer a valuable tool for objectively quantifying liver fat content with a more easily comparable parameter, improving the accuracy of steatosis grading and follow-up. Full article