Search Results (541)

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

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: 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

Background: Periodontal dysbiosis contributes to liver injury through systemic inflammation, oral–gut microbial translocation, and endotoxemia. Lipopolysaccharides (LPSs) and virulence factors derived from periodontal pathogens, particularly Porphyromonas gingivalis (P. gingivalis) activate Toll-like receptor (TLR) signaling, trigger NF-κB-mediated cytokine release (e.g., TNF-α, IL-1β, IL-6), and promote oxidative stress and Kupffer cell activation within the liver. The present systematic review summarized clinical evidence supporting these mechanistic links between periodontal pathogens and hepatic outcomes, highlighting the role of microbial crosstalk in liver pathophysiology. Methods: A PRISMA-compliant systematic review was conducted by searching PubMed, Scopus, and the Cochrane library, as well as gray literature. Eligible study designs were observational studies and trials evaluating P. gingivalis and other periodontal pathogens (Aggregatibacter actinomycetemcomitans, Prevotella intermedia, and Tannerella forsythia) for liver phenotypes (Non-Alcoholic Fatty Liver Disease [NAFLD]/Metabolic Dysfunction-Associated Steatotic Liver Disease [MASLD], fibrosis/cirrhosis, acute alcoholic hepatitis [AAH], and Hepatocellular carcinoma [HCC]). Risk of bias was assessed using the Newcastle–Ottawa Scale adapted for cross-sectional studies (NOS-CS) for observational designs and the RoB 2 scale for single randomized controlled trials (RCTs). Due to the heterogeneity of exposures/outcomes, results were summarized narratively. Results: In total, twenty studies (2012–2025; ~34,000 participants) met the inclusion criteria. Population-level evidence was conflicting (no clear association between anti-P. gingivalis serology and NAFLD), while clinical cohorts more frequently linked periodontal exposure, particularly to P. gingivalis, to more advanced liver phenotypes, including fibrosis. Microbiome studies suggested stage-related changes in oral communities rather than the effect of a single pathogen, and direct translocation into ascitic fluid was not observed in decompensated cirrhosis. Signals from interventional and behavioral research (periodontal therapy; toothbrushing frequency) indicate a potential modifiability of liver indices. The overall methodological quality was moderate with substantial heterogeneity, precluding meta-analysis. Conclusions: Current evidence supports a biologically plausible oral–liver axis in which periodontal inflammation, often involving P. gingivalis, is associated with liver damage. Causality has not yet been proven; however, periodontal evaluation and treatment may represent a low-risk option in periodontitis-associated NAFLD. Well-designed, multicenter prospective studies and randomized trials with standardized periodontal and liver measurements are needed. Full article

Nowadays, nonalcoholic fatty liver disease (NAFLD) represents the most common cause of chronic liver disorder worldwide. From the clinical point of view, it evolves from steatosis to nonalcoholic steatohepatitis, which can lead to cirrhosis and finally to hepatocellular carcinoma. The mechanisms involved in its progression to more pathological stages and NAFLD pathogenesis are not completely understood. The research concerning NAFLD has become urgent and important because the age of NAFLD diagnosis is progressively decreasing, and its relationship with cancer risk is already well known. Because NAFLD ultimately leads to disability and imposes a major socioeconomic burden, timely diagnosis and effective treatment of NAFLD is particularly important. In the development of NAFLD, noncoding RNAs (ncRNAs) represented by microRNAs, long noncoding RNAs, circular RNAs, and piRNAs are epigenetic factors that play important regulatory roles. In the current review, we present updated information regarding the role of miRNAs, lncRNAs, circRNAs, and piRNAs, aiming to develop a good understanding of their regulatory functions in hepatic metabolism and concerning their potential use as biomarkers for early NAFLD/NASH diagnosis and as therapeutic targets. Full article

Introduction: Metabolic dysfunction associated steatotic liver disease (MASLD), previously termed as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern, particularly in South Asia. While PNPLA3 is a well-recognized genetic contributor to MASLD, the role of other metabolic genes, such as ABCC8, remains unexplored in South Asian populations. In this study, we aim to investigate the genetic association and potential synergy between PNPLA3 (rs738409) and ABCC8 (rs146378237) variants in MASLD pathogenesis in a Pakistani cohort. Methods: A two-phased case–control study was conducted. Whole Exome Sequencing (WES) was performed on 6 MASLD cases and 6 healthy controls to identify relevant variants, followed by validation via Sanger sequencing in an extended MASLD cohort (n = 52). Variant frequencies were compared with 96 ethnically matched controls from the 1000 Genomes Project. Furthermore, the association of the variants with clinical, biochemical, and fibrotic parameters was assessed. Results: The PNPLA3 rs738409 G allele (MAF = 0.47) and ABCC8 rs146378237 T allele (MAF = 0.36) were significantly enriched in MASLD cases and strongly associated with cirrhosis. The TT genotype of ABCC8 was also linked to T2DM and low HDL levels. Importantly, eight MASLD patients harbored both GG (PNPLA3) and TT (ABCC8) genotype, and all were known cases of diabetes, suggesting a synergistic genetic interaction. Conclusions: This is the first report of ABCC8 rs146378237 in a South Asian MASLD cohort, revealing population-specific risk and a gene–gene interaction that may inform targeted screening and personalized management of MASLD in high-risk diabetic individuals. Full article

Background and aim: Managing the therapy of patients with chronic liver diseases and comorbidities presents significant challenges for physicians and pharmacists, particularly regarding drug-induced liver damage and polypharmacy. Given the liver’s central role in drug detoxification, polypharmacy in liver disease requires special attention. The aim of the review was to assess the prevalence of polypharmacy among patients with chronic liver diseases. Approach and Results: A literature search focused on randomized controlled trials, database reviews, and medical records. Review of PubMed, SCOPUS, and ScienceDirect databases identified 2578 manuscripts, however only 11 studies met the inclusion criteria. The results of studies showed that the prevalence of polypharmacy among patients with chronic liver disease can exceed 50%, and can lead to high prevalence of MRP and pDDI among those patients. Conclusions: Findings reveal a critical link between polypharmacy and adverse outcomes in chronic liver diseases, including cirrhosis, hepatitis, and non-alcoholic fatty liver disease. Individualized treatment plans, considering factors such as age, gender, comorbidities, and liver disease severity are essential. The interventions focused on mitigating MRP and reducing pDDI need to be implemented in order to reduce the potential harm of polypharmacy. Full article

The importance of H. pylori infection in the development of non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, insulin resistance, and non-alcoholic steatohepatitis has been shown in earlier studies. Our work aims to assess the risk of developing hepatic fibrosis in patients with or without H. pylori, using noninvasive scores such as the APRI index, the BARD score, or the FIB-4 index, and to evaluate a possible association between the severity of fibrosis scores and histopathology evidence (such as chronic gastritis, gastric atrophy, gastric metaplasia, and gastric dysplasia). Moreover, the risk of preneoplastic stomach lesions was assessed in patients with hepatic fibrosis. The study enrolled a total of 110 patients: 65 were H. pylori-positive and 45 were negative. The differences in BARD, APRI, and FIB-4 indexes between H. pylori-positive and negative cases were assessed using the Mann–Whitney test. Noticeably higher BARD scores and APRI indexes were observed when comparing H. pylori-positive patients with NAFLD to H. pylori-negative ones. In terms of the FIB-4 index, an insignificant increase was observed in H. pylori-positive versus H. pylori-negative patients. Multiple linear regression was performed for the BARD scores and APRI indexes, revealing further significant associations with age and H. pylori status. A substantial correlation was demonstrated between H. pylori and elevated hepatic fibrosis scores in individuals with NAFLD and gastritis, suggested by the complexity features of infection and the intricacies of histology. Full article

Patients with concurrent non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) exhibit increased susceptibility to non-alcoholic steatohepatitis (NASH), advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. This study investigated the contribution of ketogenesis to T2DM-mediated NAFLD exacerbation and elucidated the therapeutic mechanism of cynaroside in NASH-complicated T2DM. Male C57BL/6J mice were given CDAHFD combined with streptozotocin to establish stage-specific NAFLD with T2DM models. Hepatic HMGCS2 expression was modulated via tail vein injection of adenoviral vectors for HMGCS2 overexpression or knockdown. Cynaroside was administered orally from week 5 to week 8. The results showed that concurrent T2DM accelerated NAFLD progression, accompanied by a dysregulated ketogenesis that was correlated with disease severity. Hepatic HMGCS2 expression paralleled circulating ketone body concentrations, indicating that HMGCS2-mediated ketogenic dysregulation contributed to NAFLD pathogenesis in T2DM contexts. HMGCS2 overexpression in NASH-T2DM models significantly attenuated steatohepatitis progression through the enhancement of ketogenesis. Cynaroside administration ameliorated hepatic pathology in NASH-T2DM mice by (1) reducing hepatocellular injury and lobular inflammation; (2) decreasing intrahepatic lipid accumulation; and (3) suppressing hepatocyte senescence and the secretion of SASP factors. Mechanistically, cynaroside exerted therapeutic effects via HMGCS2-mediated ketogenesis. Our data demonstrated that ketogenic modulation is a viable therapeutic strategy to delay T2DM-NAFLD progression. Full article

Liver cirrhosis represents the end-stage of chronic hepatic injury, arising from a diverse range of etiologies including viral hepatitis, alcohol abuse and non-alcoholic fatty liver disease. A key driver of cirrhosis is hepatic fibrogenesis, a multifaceted process involving hepatic stellate cell activation, inflammatory signaling and extracellular matrix accumulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as pivotal regulators in this context, modulating gene expression networks that govern inflammation, fibrosis and hepatocarcinogenesis. This review synthesizes current evidence on the role of miRNAs in liver cirrhosis, emphasizing specific miRNAs such as miR-21, miR-122, miR-125, miR-146 and miR-155. These miRNAs influence pathways involving TGF-β, NF-κB and PI3K/Akt signaling, contributing to either fibrogenic progression or its suppression. The unique expression profiles and stability of miRNAs in biological fluids position them as promising non-invasive biomarkers for cirrhosis diagnosis and monitoring. Moreover, therapeutic modulation of miRNA activity through mimics or inhibitors holds future potential, though delivery and safety challenges remain. Advancing our understanding of miRNA-mediated regulation in cirrhosis could transform current diagnostic and therapeutic strategies, enabling more precise and personalized liver disease management. Full article

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver conditions globally. This study aimed to assess the long non-coding RNAs (lncRNAs) growth arrest-specific 5 (GAS5), miR-29a-3p, and neurogenic locus notch homolog protein 2 (NOTCH2) as biomarkers in patients with NAFLD and find out if they are related to any clinical factors. Subjects and Methods: Thirty-eight age-matched healthy persons and thirty-eight NAFLD patients were enrolled. Patients were split into the following three groups: non-alcoholic steatohepatitis (NASH) (n = 12), patients with NAFLD-related cirrhosis (n = 8), and patients with NAFLD-related simple steatosis (n = 18). Real-time PCR was utilized to examine the expression. Results: The lncRNA GAS5 and NOTCH2 were higher in NAFLD cases in comparison to controls. On the other hand, microRNA-29a-3p was underexpressed in NAFLD cases in comparison to controls. Regarding NAFLD diagnosis, lncRNA GAS5 was the best single marker with a sensitivity of 100% and a specificity of 94.7% at the cutoff values of ≥1.16-fold change. Regarding different stages of the disease, the highest level of lncRNA GAS5 was in cirrhosis. lncRNA GAS5 expression, among other studied parameters, is still a significant predictor of NAFLD (adjusted odds ratio of 162, C.I. = 5.7–4629) (p = 0.003). LncRNA GAS5 has a positive correlation with NOTCH2 and a negative correlation with miR-29a-3p. LncRNA GAS5, NOTCH2, and RNA-29a-3p were significantly different in NAFLD cases compared to controls. Conclusions: lncRNA GAS5 appears to be the most effective single marker for detecting NAFLD. LncRNA GAS5 expression is a significant independent predictor of NAFLD. LncRNA GAS5 can differentiate different NAFLD stages. Full article