Search Results (635)

Hyaloserositis, also known as the icing sugar phenomenon, may be commonly observed during autopsies; however, it is not a well-documented topic with varying nomenclature and etiology, which can be generally defined as an organ being covered with a shiny, fibrous hyaline membrane. In our work, we present the case of a 71-year-old female patient with alcohol-induced liver cirrhosis and subsequent ascites and recurrent peritonitis. During the autopsy, a cirrhotic liver and an enlarged spleen were observed, both exhibiting features consistent with hyaloserositis, accompanied by acute fibrinopurulent peritonitis. Histological examination revealed the classical manifestation of hyaloserositis, further proven by Crossmon staining. The cause of death was concluded as hepatic encephalopathy. During our literature review, a total of seven cases were found. It must be emphasized that no publication describing hyaloserositis from the perspective of a pathologist was discovered. Regarding etiology, abdominal presentations were most commonly caused by serohepatic tuberculosis, while pleural manifestation was observed following trauma. Hyaloserositis may prove to be a diagnostic difficulty in imaging findings, as it can mimic malignancy; therefore, a scientific synthesis is necessary. 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

The objective of the present study was to evaluate the association between liver cirrhosis (LC) and subsequent Heart failure (HF). This retrospective cohort study utilized data from the Disease Analyzer database (IQVIA) and included adults with a first-time diagnosis of LC in 1293 general practices in Germany between January 2005 and December 2023. A comparison cohort without liver diseases was matched to the cirrhosis group using 5:1 propensity score matching. Univariable Cox proportional hazards models were used to assess the association between alcoholic vs. non-alcoholic LC and HF. The final study cohort included 5530 patients with alcoholic LC and 27,650 matched patients without liver disease, as well as 7063 patients with non-alcoholic LC and 35,315 matched patients without liver disease. After up to 10 years of follow-up, HF was diagnosed in 20.9% of patients with alcoholic LC compared to 10.3% of matched cohort, and in 23.0% of patients with non-alcoholic LC, compared to 14.2% in matched cohort. Alcoholic LC (Hazard Ratio (HR): 2.07 (95% CI: 1.85–2.31) and non-alcoholic LC (HR: 1.70; 95% CI: 1.56–1.82) were associated with an increased risk of HF. The association was also stronger in men than in women. LC, both alcoholic and non-alcoholic, is significantly associated with an increased long-term risk of HF. The association is particularly pronounced in patients with alcoholic cirrhosis and in men. To the best of the authors’ knowledge, this is the first real-world evidence for the positive association between LC and subsequent HF from Europe. Full article

(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by liver damage similar to alcoholic fatty liver disease, including triglyceride infiltration of hepatocytes, regardless of alcohol consumption. It leads to progressive liver damage, such as loss of liver function, cirrhosis, and liver cancer, and the response rate of drugs under clinical research is less than 50%. There is an urgent need for biomarkers to evaluate the efficacy of these drugs. (2) Methods: MASLD was induced in mice using a High-Fat diet (HF), Western diet (WD), and Methionine/Choline-Deficient diet (MCD) for 20 weeks (4 weeks for MCD). Liver tissue biopsies were performed, and the treatment effects of saponin and non-saponin feeds were evaluated. Fat accumulation and hepatic inflammation were measured, and mRNA sequencing analysis was conducted. The therapeutic effects were validated using patient-derived liver organoids. (3) Results: The NAFLD Activity Score (NAS) significantly increased in all MASLD models compared with controls. Saponin treatment decreased NAS in the HF and WD groups but not in the MCD group. RNA sequencing and PCA analysis showed that the HF saponin response samples were similar to normal controls. DAVID analysis revealed significant changes in lipid, triglyceride, and fatty acid metabolic processes. qRT-PCR confirmed decreased fibrosis markers in the HF saponin response group, and GSEA analysis showed reduced HAMP1 gene expression. (4) Conclusions: Among the diets, red ginseng was most effective in the HF diet, with significant effects in the saponin-treated group. The therapeutic efficacy was better when HAMP1 expression was increased. Therefore, we propose HAMP1 as a potential exploratory biomarker to assess the saponin response in a preclinical setting. In addition, the reduction of inflammation and hepatic iron accumulation suggests that saponins may exert antioxidant effects through modulation of oxidative stress. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders. Full article

Cirrhosis remains a significant global health burden, responsible for nearly 4% of annual deaths worldwide. Despite progress in antiviral therapies and public health measures, its prevalence has plateaued, particularly in regions affected by viral hepatitis, alcohol misuse, and metabolic syndrome. This review presents a comprehensive synthesis of the multifactorial drivers of cirrhosis, including hepatocyte injury, liver stellate cell activation, and immune-mediated inflammation. The emphasis is on the central role of metabolic dysfunction, characterized by mitochondrial impairment, altered lipid and glucose metabolism, hormonal imbalance, and systemic inflammation, in exacerbating disease progression. While current therapies may slow the progression of early-stage disease, they are very often ineffective in reversing established fibrosis. Emerging molecular strategies offer promising alternatives by targeting key pathogenic pathways. These include AMPK activators (e.g., metformin, AICAR), FGF21 analogs, and mitochondria-targeted agents (e.g., MitoQ, urolithin A, NAD+ precursors) to restore bioenergetic balance and reduce oxidative stress. Other approaches, such as mesenchymal stem cell therapy, inflammasome inhibition, and hormonal modulation, aim to suppress fibrogenesis and restore liver homeostasis. The integration of systems biology and multi-omics profiling supports patient stratification and precision medicine. This review highlights a shift toward mechanism-based interventions that have the potential to alter cirrhosis outcomes and improve patient survival. Full article

Background/Objectives: The liver, the body’s primary detoxifying organ, is often affected by various inflammatory diseases, including hepatitis, cirrhosis, and non-alcoholic fatty liver disease (NAFLD), many of which can be exacerbated by secondary infections such as spontaneous bacterial peritonitis, bacteremia, and sepsis—particularly in patients with advanced liver dysfunction. The global rise in these conditions underscores the need for effective interventions. Natural products have attracted attention for their potential to support liver health, particularly through synergistic combinations of plant extracts. Epavin, a dietary supplement from Erbenobili S.r.l., formulated with plant extracts like Taraxacum officinale (L.), Silybum marianum (L.) Gaertn., and Cynara scolymus (L.), known for their liver-supporting properties, has been proposed as adjuvant for liver functions. The aim of this work was to evaluate of Epavin’s antioxidant, anti-inflammatory, and protective effects against heavy metal-induced toxicity. In addition, the antibacterial effect of Epavin against a panel of bacterial strains responsible for infections associated with liver injuries has been evaluated. Methods: The protection against oxidative stress induced by H₂O₂ was evaluated in HepG2 and BALB/3T3 cells using the dichlorofluorescein diacetate (DCFH-DA) assay. Its anti-inflammatory activity was investigated by measuring the reduction in nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages using the Griess assay. Additionally, the cytoprotecting of Epavin against heavy metal-induced toxicity and oxidative stress were evaluated in HepG2 cells using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) and DCFH-DA assays. The antibacterial activity of Epavin was assessed by determining the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) against Gram-positive (Enterococcus faecalis ATCC 29212, and BS, Staphylococcus aureus 25923, 29213, 43300, and BS) and Gram-negative (Escherichia coli 25922, and BS, Klebsiella pneumoniae 13883, 70063, and BS) bacterial strains using the microdilution method in broth, following the Clinical and Laboratory Standards Institute’s (CLSI) guidelines. Results: Epavin effectively reduced oxidative stress in HepG2 and BALB/3T3 cells and decreased NO production in LPS-stimulated RAW 264.7 macrophages. Moreover, Epavin demonstrated a protective effect against heavy metal-induced toxicity and oxidative damage in HepG2 cells. Finally, it exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains, with MIC values ranging from 1.5 to 6.0 mg/mL. Conclusions: The interesting results obtained suggest that Epavin may serve as a valuable natural adjuvant for liver health by enhancing detoxification processes, reducing inflammation, and exerting antibacterial effects that could be beneficial in the context of liver-associated infections. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the fastest-growing hepatic disorders worldwide. During its natural course, MASLD tends to progress from isolated steatosis of the liver to Metabolic Dysfunction-Associated Alcoholic Steatohepatitis (MASH), advanced fibrosis, and finally cirrhosis, with the risk of developing hepatocellular carcinoma (HCC). Although frequently related to overweight or obesity and other components of the metabolic syndrome (MS), MASLD can also be present in individuals without such risk factors. The mechanisms leading to MASLD are incompletely elucidated and may involve many proinflammatory and pro-fibrotic pathways, disrupted biliary acid homeostasis, and gut microbiota dysbiosis. Aldosterone and its interaction with the mineralocorticoid receptor (MR) are thought to participate in the pathogenesis of MASLD through the modulation of inflammation and fibrosis. Remarkably, blockade of the MR in experimental models was shown to improve MASH and fibrosis through mechanisms that need further characterization. So far, however, few clinical studies have explored the effect of MR blockade in the management of MASH and associated fibrosis. This review is intended to summarize the recent animal and human data concerning the interaction between MR pathways and MASLD. Full article

Background: Liver fibrosis, a consequence of various chronic liver diseases, is characterized by excessive accumulation of extracellular matrix (ECM), leading to impaired liver function and potentially progressing to cirrhosis or hepatocellular carcinoma. The molecular mechanisms underlying liver fibrosis are complex and not fully understood. In vivo experiments are essential for studying the molecular mechanisms of the disease. However, the diverse principles behind mouse modeling techniques for liver fibrosis can complicate the elucidation of specific fibrotic mechanisms. Methods: Five distinct liver fibrosis models were utilized: CONTROL, NASH (non-alcoholic steatohepatitis), BDL (bile duct ligation), TAA (thioacetamide), and CCl₄ (carbon tetrachloride). Patents for these drugs were reviewed using Patentscope^® and Worldwide Espacenet^®. ScRNA-seq was performed to analyze and compare the cellular and molecular differences in these models. Results: The analysis revealed that, particularly in the drug-induced fibrosis models, hepatic stellate cells (HSCs), Kupffer cells, and T-cell subsets exhibit distinct regulatory patterns and dynamic remodeling processes across different liver fibrosis models. These findings highlight the heterogeneity of immune responses and extracellular matrix (ECM) remodeling in various models, providing important insights into the complex mechanisms underlying liver fibrosis. Conclusions: The study enhances our understanding of liver fibrosis development and provides valuable insights for selecting the most representative animal models in future research. This comprehensive analysis underscores the importance of model-specific immune responses and ECM remodeling in liver fibrosis. Full article

Background and Objectives: Alcoholic hepatitis (AH) is a growing public health concern with its rising incidence and its contribution to nearly half of all cirrhosis-related deaths in the United States. In this systematic review, we aimed to comprehensively evaluate the current evidence and trials on the use of anti-interleukin-1 (anti-IL-1) drugs in patients with AH, assessing their efficacy and adverse events compared to routinely prescribed drugs like corticosteroids. Materials and Methods: A comprehensive literature search was conducted across five databases to identify randomized controlled trials (RCTs) evaluating the role of anti-IL-1 agents like canakinumab and anakinra among patients diagnosed with AH. Data was extracted and pooled in the form of mean and standard deviation for continuous variables and event and total for dichotomous variables. Results: Three RCTs were included for quantitative synthesis, encompassing 307 patients. Using canakinumab, 58% of patients showed improvement in histology. Prednisolone was associated with higher 90-day survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14–0.83, p = 0.018) and transplant-free survival. Overall, a higher incidence of acute kidney injury and new-onset cardiac disorders was noted in the anti-IL-1 arm when compared to placebo. Conclusions: This study concludes the lack of efficacy of anti-IL-1 agents in causing improvement in patient outcomes when compared to standard therapies. A higher incidence of adverse events was also noted in the anti-IL-1 arm. These results emphasize the need for future clinical trials to evaluate the use of anti-IL-1 agents in AH objectively. Full article

Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives. Full article

Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and remains one of the leading causes of cancer-related mortality. Its incidence continues to rise worldwide, and it is currently the fastest-growing cancer by incidence in the United States. HCC most often arises in the context of chronic liver disease, particularly cirrhosis. While chronic viral hepatitis (hepatitis B and C) has traditionally been the primary etiologic factor, recent advances in antiviral therapies and prevention strategies have shifted the epidemiological landscape. Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease are increasingly prominent risk factors, especially in Western populations. This shift underscores the need for targeted risk factor modification, improved early detection, and enhanced surveillance protocols. The management of HCC necessitates a multidisciplinary approach, incorporating locoregional therapies, surgical resection, liver transplantation, and systemic therapies for advanced-stage disease. Recent advances in systemic treatments, including immune checkpoint inhibitors and combination therapies, have transformed the therapeutic landscape. Despite these developments, significant challenges persist in optimizing treatment, identifying predictive biomarkers, and personalizing therapy. Ongoing research is focused on refining molecular classifications and advancing precision medicine strategies to improve outcomes. This review provides a comprehensive overview of the etiology, surveillance strategies, diagnostic approaches, molecular features, and current treatment modalities for HCC. Full article

Hepatobiliary diseases, which include disorders of the liver, gallbladder, and bile ducts, remain a major global health concern. A significant proportion of deaths worldwide are attributed to hepatic diseases, accounting for 4% of the total global mortality in 2023. Among benign hepatobiliary diseases, metabolic dysfunction-associated steatotic liver disease is the most prevalent liver pathology, with a concerning rise in incidence, while it is recognized as the leading cause of liver transplantation in the United States. However, there is a notable rise over time in cases of autoimmune hepatobiliary disorders, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Meanwhile, hepatocellular carcinoma still remains the most frequently diagnosed hepatobiliary malignancy, constituting the third leading cause of malignancy-related mortality globally. Meanwhile, cholangiocarcinoma and gallbladder cancer are the second and third most common hepatobiliary malignancies, respectively, both exhibiting highly aggressive malignant behavior. Despite the notable advances in biomarkers and the development of therapeutic tools, early diagnosis and monitoring are considered pivotal for the management of the aforementioned pathologies. The development of new non-invasive biomarkers that can effectively identify, monitor these pathologies, and guide their management is considered a necessity. Extracellular vesicles (EVs) constitute nanoparticles with several embedded cargoes, with a significant role in intercellular communication, which are considered promising biomarkers in several diseases, including viral, metabolic, autoimmune, and malignant diseases. In this review, we will shed light on the role of EVs as novel frontiers in hepatobiliary diseases. Full article

Background and Objectives: Fetuin-A is mostly synthesized in the liver. It is a hepatokine, which is an extracellular inhibitor of growth factors. There is a scarcity of data on the clinical utility of serum fetuin-A (SFA) in alcohol-associated cirrhosis (AC). We first investigated the association between SFA levels and disease phenotypes in alcoholic liver disease (ALD) patients, including alcohol-associated steatotic liver (ASL) and alcohol-associated hepatitis (AH), along with AC patients. Materials and Methods: There were 26 healthy controls and 64 ALD patients in this case–control study. The severity of the disease in the AC patients was evaluated using the Child–Pugh classification (CPC-A, -B, and -C), and the FH and AC patients’ Maddrey’s differential function scores and the Model of End-Stage Liver Disease Sodium (MELD-Na) scores were computed. We measured SFA levels using a human fetuin-A enzyme-linked immunosorbent assay (ELISA) kit. Results: The SFA concentrations were lower in the AC group and higher in the ASL group [670.72 (412.36) mg/L vs. 1484.61 (858.16) mg/L, respectively; p < 0.001]. When compared to patients with ASL, the SFA levels in AC patients were noticeably lower. However, similar SFA levels were observed for the AH group and the healthy controls, as well as for the ASL group and the healthy controls. Within the AC group, the CPC-A subgroup had the highest median SFA values, while the CPC-C subgroup had the lowest median SFA value. Furthermore, the median SFA levels demonstrated significant and inverse correlations with the CPC scores and the MELD-Na scores (rho = −0.671, p < 0.001; rho = −0.742, p < 0.001, respectively). A negative correlation was observed between the SFA levels and the MELD-Na scores in the AH group (ρ = −0.621, p = 0.013). Conclusions: In ALD patients, decreased SFA levels, which exhibit disease severity, might be an auxiliary biomarker for the follow-up of AC patients. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with metabolic-dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease (ALD) emerging as major etiologies. This review explores the epidemiological trends, pathogenesis, and clinical management of HCC arising from MASH and ALD, highlighting both the shared and distinct mechanisms. MASH-HCC is driven by metabolic dysregulation, including obesity, insulin resistance, and lipotoxicity, with genetic polymorphisms such as PNPLA3 and TM6SF2 playing critical roles in disease progression. ALD-HCC, in contrast, is propelled by the toxic byproducts of ethanol metabolism, including acetaldehyde and reactive oxygen species, which induce chronic inflammation, and fibrosis. Both conditions also involve immune dysregulation, gut dysbiosis, and increased intestinal permeability, contributing to hepatic carcinogenesis. The review emphasizes that, while there is consensus regarding the screening of HCC in cirrhosis patients, there is lack of consensus on screening strategies for non-cirrhotic MASH patients who are also at risk for HCC. This underscores the importance of the early detection of cirrhosis using advanced diagnostic tools such as transient elastography and fibrosis scores. Current therapeutic approaches, ranging from surgical resection, liver transplantation, and locoregional therapies to systemic therapies like immune checkpoint inhibitors, are discussed, with an emphasis on the need for personalized treatment strategies. Finally, the review highlights future research priorities, including the development of novel biomarkers, exploration of the gut–liver axis, and deeper investigation of the interplay between genetic predisposition and environmental factors. By synthesizing these insights, the review aims to inform multidisciplinary approaches to reduce the global burden of MASH- and ALD-related HCC and improve patient outcomes. Full article