Hepatic fibrosis (HF) is a critical marker of advanced‑stage chronic liver disease and involves pivotal contributions from hepatic stellate cells (HSCs). Currently, there are no effective treatments for HF. Umbelliferone (7‑hydroxycoumarin; UMB) is a natural compound with significant anti‑inflammatory, antioxidant and anti‑tumor activities. However, its potential efficacy in treating HF has not been studied. The present study explored the protective effects of UMB against HF, targeting the TGF‑β1‑Smad signaling pathway to explore the underlying mechanisms of UMB. Carbon tetrachloride (CCl4) was injected intraperitoneally to induce HF in rats and primary HSCs were treated in vitro with UMB to investigate the improvement effect of UMB on HF. The levels of fibrosis markers, inflammation, oxidative stress and TGF‑β1‑Smad signaling pathway in the rat liver tissue and HSCs were detected using hematoxylin and eosin staining, enzyme‑linked immunosorbent assay, reverse transcription‑quantitative PCR, Cell Counting Kit‑8 and western blotting. The improvement in liver histopathology, liver function indexes and fibrosis markers demonstrated that UMB markedly inhibited the CCl4‑induced HF and inflammation in the rats. Additionally, UMB prominently reduced the pro‑inflammatory factors and oxidative stress levels. In vitro, UMB markedly inhibited primary HSC activation and decreased alpha‑smooth muscle actin and collagen I expression. The mechanism experiment proved that UMB inhibited the TGF‑β1‑Smad signaling pathway and ameliorated HF. The present study was the first to demonstrate, to the best of the authors' knowledge, that UMB might be a promising natural active compound for treating HF. Its therapeutic effect is associated with its modulation of the TGF‑β1‑Smad signaling pathway.

Hepatic stellate cells (HSCs) activation and hepatocyte injury contribute to liver fibrosis progression and subsequent cirrhosis. Literature showed that cinnamaldehyde (CA) could alleviate fibrosis procession and steatosis. However, its specific role in liver fibrosis remains largely unexplored.

Liver fibrosis was induced in vivo, and CA was administered for 4 weeks. Liver inflammation, fibrosis, apoptosis, and proliferation were evaluated using histological, western blotting, and immunohistochemistry. CYP2A6 and Notch3 expression levels were also measured. In vitro, TGF-β stimulated LX2 cell activation was used, and siCYP2A6 was employed to evaluate the anti-fibrosis mechanism of CA.

CA effectively improved liver function and reduced fibrosis in CCL4-treated rats, significantly decreasing serum ALT, AST, GGT, TBIL, and HAase levels (all p < 0.05), with a notable increase in ALB in the high-dose group. Histologically, CA reduced hepatic disorganization and collagen proliferation, significantly diminishing fibrotic areas in the CA-H group (p < 0.05). CA also downregulated α-SMA and collagen I expression, and suppressed TGF-β activity. In TGF-β1-stimulated LX2 cells, CA treatment led to significant reductions in CYP2A6 and Notch3 expression (p < 0.05), highlighting its regulatory effects on key fibrotic pathways.

CA alleviated CCL4-induced liver fibrosis with inhibition of HSCs activation and liver inflammation and reduced hepatocyte apoptosis, potentially linked to the HSCs-mediated CYP2A6/Notch3 modulation.

The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.

This study aimed to compare the cumulative incidence of ischemic stroke between patients with and without cancer, estimate the hazard ratio of stroke in patients with cancer compared to those without cancer, and compare our results with those of other nationwide studies.

We recruited 91,424 patients diagnosed with cancer from the Korean National Health Insurance Service database between 2011 and 2015 and enrolled 182,848 controls. These participants were followed up for 5 years. We estimated the hazard ratios for ischemic stroke occurrence in the patient groups for all cancer types and nine specific cancer types during follow-up at 6 months and 1, 3, and 5 years.

For all cancer types, except colorectal, gallbladder, bile duct, and head and neck cancers, the slope of the cumulative increase in ischemic stroke in the early period was higher than that in longer follow-up durations. Ischemic stroke risk was elevated after the 6-month follow-up in patients with cancer compared to patients without cancer (95% confidence interval [CI]: 1.56-1.94). Over 3-5 years, Ischemic stroke risk increased in patients with lung (CI: 1.56-2.04), pancreatic (CI: 1.33-1.95), and liver cancers (CI: 1.07-1.39), compared to cancer-free individuals, whereas no significant increase was observed in patients with thyroid (CI: 0.79-1.13), stomach (CI: 0.92-1.17), colorectal (CI: 0.69-1.48), gallbladder (CI: 0.91-9.89), bile duct (CI: 0.39-3.50), and head and neck (CI: 0.26-74.30) cancers.

Our findings regarding stomach, colorectal, and liver cancers differ from the results of Western studies. Conducting a nationwide study within each country, rather than applying findings from other countries, is preferable for predicting and preventing ischemic stroke development in patients with cancer when using insurance-based data.

Alcohol represents a leading burden of disease worldwide, including alcohol use disorder (AUD) and alcohol-related liver disease (ALD). We aim to assess the global burden of AUD, ALD, and alcohol-attributable primary liver cancer between 2000-2021.

We registered the global and regional trends of AUD, ALD, and alcohol-related liver cancer using data from the Global Burden of Disease 2021 Study, the largest and most up-to-date global epidemiology database. We estimated the annual percent change (APC) and its 95% confidence interval (CI) to assess changes in age-standardized rates over time.

In 2021, there were 111.12 million cases of AUD, 3.02 million cases of ALD, and 132,030 cases of alcohol-attributable primary liver cancer. Between 2000 and 2021, there was a 14.66% increase in AUD, a 38.68% increase in ALD, and a 94.12% increase in alcohol-attributable primary liver cancer prevalence. While the age-standardized prevalence rate for liver cancer from alcohol increased (APC 0.59%; 95% confidence interval [CI] 0.52 to 0.67%) over these years, it decreased for ALD (APC -0.71%; 95% CI -0.75 to -0.67%) and AUD (APC -0.90%; 95% CI -0.94 to -0.86%). There was significant variation by region, socioeconomic development level, and sex. During the last years (2019-2021), the prevalence, incidence, and death of ALD increased to a greater extent in females.

Given the high burden of AUD, ALD, and alcohol-attributable primary liver cancer, urgent measures are needed to prevent them at both global and national levels.

Disturbances of the intestinal barrier enabling bacterial translocation exacerbate alcoholic liver disease (ALD). Lactobacillus rhamnosus GG (LGG) has been shown to exert beneficial effects in gut dysbiosis and chronic liver disease. The current study assessed the combined effects of LGG and metformin, which play roles in anti-inflammatory and immunoregulatory processes, in alcohol-induced liver disease mice. A diet comprising 5% alcohol for 4 weeks was employed to develop an alcohol-induced liver injury model. Mice were orally administered LGG, metformin, or their combination on alternate days. Tight junction (TJ) proteins, gut microbiome composition, inflammatory cytokines, Jun N-terminal kinase (JNK), and p38 signals were assessed. When compared with treatment with LGG or metformin alone, combined LGG and metformin treatment substantially lowered the symptoms of inflammation, steatosis, and elevated liver enzymes caused by alcohol administration. Combination treatment significantly improved intestinal microecology, evidenced by the recovery of intestinal flora, TJ proteins, and intestinal villi. Combination treatment reduced hepatic inflammation by blocking p38 and JNK phosphorylation. The combination of LGG and metformin corrected immune-response dysregulation and improved ALD by enhancing the intestinal microbiome, restoring mucosal barrier integrity, modulating immune function, and decreasing liver injury. These results provide information for the development of intestinal microbiota-based preventive and therapeutic agents against ALD.

To investigate the effect of 1α,25(OH)2D3 on hepatic stellate cells and the mechanism of the TGF-β1/Smad signaling pathway.LX2 cells were treated with TGF-β1 and different concentrations of 1α,25(OH)2D3. Cell proliferation was assessed using the CCK8 assay to determine the optimal concentration of 1α,25(OH)2D3 activity. The cell cycle and apoptotic rates were evaluated using flow cytometry. The expressions of Samd2, Samd3, Samd4, and Samd7 was assessed by western blotting, whereas the expression of MMP1, MMP13, and TIMP-1 was detected by qPCR.Compared with the control group, the 1α,25(OH)2D3 group had a higher apoptotic rate of LX2 cells, the cell cycle was blocked from the G1 stage to the S stage, the expressions of Samd2, Samd7, MMP1, and MMP13 increased, while the expressions of Samd3, Samd4, and TIMP-1 decreased.1α,25(OH)2D3 inhibits hepatic stellate cell activation and exerts anti-hepatic fibrosis effects by downregulating the expression of Samd3, Samd4, TIMP-1 and upregulating the expression of Samd2, Samd4, MMP1, and MMP13.

Liver fibrosis resulting from chronic liver injury is characterized by increased extracellular matrix deposition and inflammation, which leads to excessive scar tissue formation. Targeting activated hepatic stellate cells (HSCs), which are the primary drivers of fibrogenesis, stands out as one of the most compelling therapeutic approaches in this regard. In a healthy liver, HSCs remain quiescent and store vitamin A in cytoplasmic lipid droplets. As a consequence of HSC activation and transdifferentiation to a proliferative myofibroblast-like state upon fibrotic stimuli, the distinctive phenotypic feature of the lipid droplets gets lost. While the reversal of activated HSCs is feasible, understanding the quiescent-like state following injury resolution is crucial for effective fibrosis treatment. This study explores the induced quiescent-like state of naïve immortalized human hepatic stellate (LX-2) cells when treated with soybean phospholipid that contains 75% phosphatidylcholine (S80). The lipid profile of the newly formed lipid droplets was analyzed using Raman imaging, which is a label-free technique well-suited for lipidomics. Results indicate the presence of distinct lipid profiles despite maintaining a quiescent-like state, suggesting that diverse mechanisms govern the active-to-inactive state transition. Additionally, our findings support the fact that each hepatic cell state is composed of heterogeneous subpopulations. This emphasizes the complexity of liver fibrosis and highlights the need for a comprehensive understanding of cellular states to develop targeted therapies.

Due to the emergence of direct-acting antiviral (DAA), more attention has been devoted to the prevalence and antiviral treatment of chronic hepatitis C in the Kashi region of Xinjiang, China, over the past decade. This study aimed to investigate the epidemiology, genotype (GT) distribution, diagnosis, and antiviral treatment of chronic hepatitis C virus (HCV) infection in this region from 2018 to 2022 and to highlight the challenges in achieving effective management. This retrospective study included individuals with HCV antibody (HCV-Ab) positivity at the First People's Hospital of Kashi from January 1, 2018, to August 31, 2022. Clinical data, including HCV RNA data, GT distribution, and DAA treatment history, were collected. Patients were followed up via telephone to assess treatment adherence and reasons for refusal. The HCV-Ab positivity rate increased from 1.7% in 2018 to 2.9% in 2022. Among the 4,928 HCV-Ab-positive individuals, 2174 (44%) underwent HCV RNA testing, with 1,088 (22%) confirmed positive. Of these patients, 707 were genotyped, with GT1b (70.7%) being the most prevalent GT. Due to limited access to DAA, only 327 (30%) RNA-positive patients received antiviral treatment, 243 (74%) of whom completed the course. Barriers to receiving DAA included high costs, low disease awareness, and limited healthcare access. These findings underscore the severity of the chronic HCV epidemic in Kashi, where healthcare access is inadequate, including limited HCV RNA testing and DAA treatment coverage. Tailored public health interventions and improvements in healthcare infrastructure are essential for better managing chronic HCV infection in this high-burden region.

Hepatic encephalopathy (HE) is a common complication following transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, the prognostic significance of overt HE post-TIPS remains controversial.

We screened 2137 patients who underwent TIPS insertion at 8 German tertiary care centers between 2004 and 2021. Patients with pre-emptive TIPS placement, hepatocellular carcinoma, missing data, and non-PTFE covered stents were excluded. Competing risk analysis was performed, considering liver transplantation as a competing event. To correct for immortal time bias, landmark analyses were conducted, with the landmark being set at 30 and 90 days post-TIPS. Outcome data were assessed for up to 30 months post-TIPS insertion.

A total of 1356 patients (median Model for End-stage Liver Disease [MELD], 13 [interquartile range (IQR), 10-17]; age, 60 years [IQR, 54-67 years]; 64% male; 12% HE before TIPS), were included. Overall, HE post-TIPS was linked to impaired survival (P < .001; subdistribution hazard ratio [sHR], 1.41; 95% confidence interval [CI],1.15-1.73). However, this was only confirmed if HE occurred within the first 30 days post-TIPS (early HE; P < .001; sHR, 2.02; 95% CI, 1.59-2.57). Additionally, patients with a history of HE (P < .001; sHR, 1.59; 95% CI, 1.21-2.07) and history of HE and early HE post-TIPS (P < .001; sHR, 3.44; 95% CI, 2.34-5.04) showed impaired survival. These findings were confirmed in the landmark and multivariable analyses.

Early HE post-TIPS is associated with significantly reduced survival. Therefore, patients who experience early HE or have a history of HE should be closely monitored by physicians, as they constitute a particularly vulnerable group with impaired survival.

Introduction. The study of gut microbiota is now an essential dimension in many clinical studies. For instance, microbiota diversity investigation can help us to better manage cirrhotic patients by the identification of markers of severity and the identification of possible sources of pathogens.Hypothesis/Gap Statement. Conducting clinical research on gut microbiota for fragile patients in intensive care units, such as cirrhotic patients, poses significant challenges.Aim. In this study, we developed a comprehensive toolkit for investigating gut microbiota in fragile patients using rectal swabbing combined with straightforward lifestyle and clinical questionnaires.Methodology . We applied this prospective approach to 49 well-phenotyped cirrhotic patients as a function of their compensation status (compensated patients with outpatients' recruitment vs decompensated patients in intensive care units).Results . Our results, consistent with the literature, showed that liver function impairment is associated with lower microbiota diversity. Additionally, we monitored aerobic microbiota in decompensated cirrhotic patients, observing the invasion of extended spectrum beta-lactamase (ESBL)-producing Escherichia coli in the gut's aerobic microbiota prior to severe infection caused by these pathogens.Conclusion. We propose this pragmatic methodology for larger cohort studies, aiming to enhance the monitoring of immunocompromised patients by using microbiota analysis as a predictive tool for the severity of associated pathologies and the identification of agents responsible for severe infections.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and a significant global health challenge due to its high mortality rate. The epidemiology of HCC is closely linked to the prevalence of chronic liver diseases, the predominant etiology being hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcohol consumption, and metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD). HCC incidence varies widely globally, with the highest rates observed in East Asia and sub-Saharan Africa. This geographic disparity is largely attributed to the endemicity of HBV and HCV in these regions. In Western countries, the incidence of HCC has been rising, driven by increasing rates of alcohol abuse and the presence of steatosis liver disease. MASLD-associated HCC has a higher body mass index, a higher rate of type 2 diabetes mellitus, hyperlipidemia, hypertension, and association with cardiovascular diseases. Steatosis-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related liver disease and viral hepatitis. Prevention strategies vary by region, focusing on vaccination against HBV, antiviral treatments for HBV and HCV, alcohol moderation, and lifestyle interventions along with weight reduction to reduce obesity and incidence of MASLD-related HCC incidence.

Due to the rising incidence of patients with cirrhosis and its accompanied extensive management, there is an increasing burden of cirrhosis patients on healthcare resources and costs. However, exact data on Dutch cirrhosis epidemiology and associated costs are lacking.

We aimed to determine the year-prevalence of adults (aged ≥18 years) with cirrhosis registered as active patients in Dutch hospitals (2017-2021) using the Dutch hospital claims database. Next, we assessed average reimbursed annual healthcare costs.

The prevalence of patients with cirrhosis registered as an active patient in Dutch hospitals increased by 54% from 48.7 patients per 100 000 in 2017 to 75.2 per 100 000 in 2021. There were regional differences and prevalence for cirrhosis was at highest of 105.6 patients per 100 000. The yearly incidence of patients for which hospitals requested claims was n  = 3725 in 2018, n  = 3840 in 2019 (+3%), n  = 3749 in 2020 (-2%), and n  = 3695 in 2021 (-1%). Total number of hospital admissions increased by 19% from 2443 in 2017 to 2899 in 2021. The annual reported costs for patients with cirrhosis increased by 120% from €35 million in 2017 to €78 million in 2021. Adjusted for inflation this increase was 143% to €85 million.

The prevalence of patients with cirrhosis registered as a patient in Dutch hospitals increased by more than 50 percent from 2017 to 2021, with regional differences. Consequently, total healthcare costs for Dutch patients with cirrhosis more than doubled in less than 5 years.

To describe the proportion of patients with liver fibrosis in at-risk populations in primary care (PC). To know the agreement between FIB-4 and transitional elastography (TE), interobserver agreement between PC and hospital care (HC) in TE, and associated risk Factors (RF).

Observational, descriptive, cross-sectional study in ≥16 years of age with RF for chronic liver disease. Sex and age, RF (alteration of liver tests [LT], metabolic syndrome, diabetes, obesity, alcohol consumption, hepatic steatosis), and FIB-4, controlled attenuation parameter and TE in PC and in HC, were collected. According to a consensus algorithm, vibration-controlled TE was performed in PC in patients with FIB-4≥1,3, and those with measurement ≥8kPa were referred to HC.

326 patients were studied. 71% were not referred to HC, due to liver stiffness <8kPa. 83 of the 95 derivations did TE in HC. 45 (54%) had TE ≥8, and 25 (30%) ≥12. The proportion of patients with stiffness ≥8kPa was 13,8% (45/326) and ≥12kPa, 7,6% (25/326). The predictive values of the FIB-4 were low. The interobserver correlation coefficient between TE in PC and HC was 0,433. Variables associated with TE ≥8 in PC: LT alteration, diabetes and steatosis. With TE ≥12: LT alteration, diabetes and obesity.

LT alteration and obesity.

The study supports the sequential performance of serum indices and TE as a screening for fibrosis in the at-risk population in PC, which allows a reduction in the percentage of patients referred to AH, and a better stratification of risk patients.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (Panax ginseng C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(S)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.

Patients with cirrhosis are at risk of developing hepatic encephalopathy (HE), which can present with a wide range of symptoms, including confusion, lethargy, inappropriate behavior, and altered sleep patterns. In addition to HE, patients with cirrhosis are at risk of developing mild cognitive impairment, dementia, and delirium, which have features closely resembling HE. Given the similar presentation of these conditions, misdiagnosis can and does occur. Mild cognitive impairment is common in individuals aged 50 years and older and can progress to dementia in those affected. Dementia and HE are both characterized by sleep disturbance and cognitive dysfunction, thus differentiating these conditions can be difficult. Furthermore, delirium can disrupt sleep patterns, and liver disease is recognized as a risk factor for its development. As HE is a cirrhosis-related complication, determining if a patient has undiagnosed cirrhosis is critical, particularly given the large number of patients with asymptomatic, compensated cirrhosis. Separately, underdiagnosis of minimal HE can occur even in patients with diagnosed liver disease, related, in part, to lack of testing. Given the availability of effective therapies for managing symptoms and preventing future episodes, accurate diagnosis of HE is essential.

Drug-eluting microsphere transarterial chemoembolization (DEM-TACE) reduces systemic exposure to chemotherapeutic drugs compared with conventional TACE but permanently occludes the embolized vessels, potentially obviating the possibility of re-treatment with TACE. Temporary embolization by resorbable BioPearl™ microspheres might facilitate subsequent re-treatments. We herein describe the trial protocol of BIOPEARL-ONE, a prospective, single-arm, multicenter, post-market clinical follow-up study. The primary objectives are technical success and safety following the use. DEM-TACE with doxorubicin-loaded BioPearl™ for unresectable hepatocellular carcinoma (HCC). The secondary objectives are tumor response, duration of response, progression-free survival, and survival rate at 18 months. Fifty patients with HCC nodules smaller than 5 cm and within the up-to-7 criteria will be enrolled.Clinical Trial Registration: NCT05911633.

In liver cirrhosis, prognosis is profoundly affected by renal function. This study evaluates the usefulness of renal stiffness measurement by point-shear wave elastography and renal perfusion by duplex.

In this case-control study, organ stiffness was quantified using point-shear wave elastography and duplex sonography to calculate the arterial resistive (RI) and pulsatility indices (PI) in 123 patients, including patients with liver cirrhosis with (LC+A) and without ascites (LC-A) and patients without liver cirrhosis (NLC).

PI and RI were significantly increased in LC-A and LC+A compared to NLC (p<0.001) and correlated with MELD and Child Pugh scores. Point-shear wave elastography showed significantly lower renal stiffness in LC+A compared to LC-A (p<0.01) and NLC (p<0.001). Renal stiffness correlated inversely with MELD and Child Pugh scores. Reduced renal stiffness, but not PI or RI, was associated with the presence of hepatorenal syndrome (p<0.001). Reduced renal stiffness was associated with an increased risk of death due to complications of liver cirrhosis within 3 years (p<0.01).

Point-shear wave elastography and duplex sonography correlate with progression of liver cirrhosis, but only shear wave elastography represents a valuable prognostic tool for hepatorenal syndrome and mortality in patients with liver cirrhosis.

Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant global health issue, affecting over 30% of the population worldwide due to the rising prevalence of metabolic risk factors such as obesity and type 2 diabetes mellitus. This spectrum of liver disease ranges from isolated steatosis to more severe forms such as steatohepatitis, fibrosis, and cirrhosis. Recent studies highlight the role of gut microbiota in MASLD pathogenesis, showing that dysbiosis significantly impacts metabolic health and the progression of liver disease. This review critically evaluates current microbiome-centered therapies in MASLD management, including prebiotics, probiotics, synbiotics, fecal microbiota transplantation, and emerging therapies such as engineered bacteria and bacteriophage therapy. We explore the scientific rationale, clinical evidence, and potential mechanisms by which these interventions influence MASLD. The gut-liver axis is crucial in MASLD, with notable changes in microbiome composition linked to disease progression. For instance, specific microbial profiles and reduced alpha diversity are associated with MASLD severity. Therapeutic strategies targeting the microbiome could modulate disease progression by improving gut permeability, reducing endotoxin-producing bacteria, and altering bile acid metabolism. Although promising, these therapies require further research to fully understand their mechanisms and optimize their efficacy. This review integrates findings from clinical trials and experimental studies, providing a comprehensive overview of microbiome-centered therapies' potential in managing MASLD. Future research should focus on personalized strategies, utilizing microbiome features, blood metabolites, and customized dietary interventions to enhance the effectiveness of these therapies.

Dysgeusia is a distortion of the sense of taste whose prevalence and relationship with nutritional status in Metabolic dysfunction-associated Steatotic Liver Disease (MASLD)-related advanced chronic liver disease (ACLD) have never been systematically explored.

200 MASLD patients [60 ≤ F3 fibrosis, 70 compensated ACLD (cACLD), and 70 decompensated (dACLD)] were enrolled. At baseline, the Child-Pugh (CP) score was determined. Dietary habits, body composition, and frailty were evaluated. The European Working Group (EWGSOP2) criteria defined sarcopenia. Dysgeusia was assessed by the Dysgeusia-Total-Score (DTS). A visual analog scale identified appetite impairment (VASAI). During a 6-month follow-up, liver-related decompensation events (LRDEs) were recorded.

The prevalence of dysgeusia increased with the liver disease progression, appearing significantly higher in ACLD compared with ≤ F3 (65.7% vs 5%, p:0.003), as well as in dACLD compared to cACLD patients (58.5 vs 7.1% p < 0.0001). On 41 dACLD patients presenting dysgeusia, 37 (90.2%) showed a significant impairment of appetite levels. In dACLD, the CP score was positively correlated with both DTS (R:0.742) and VASAI (R:0.704), as well as DTS was directly correlated with VASAI (R:0.765) (all p < 0.0001). Compared with dACLD patients without dysgeusia, dysgeusia-affected dACLD patients presented a lower daily protein intake (g/kg/die) (1.55 ± 0.192 vs 1.34 ± 0.15, p < 0.0001). Sarcopenia (70.7 vs 41.3%) and frailty (69.29 vs 37.9%) were significantly more prevalent in dysgeusia-affected dACLD individuals (both p < 0.0001). These patients showed a higher risk of LRDEs occurrence during the follow-up [HR:2.205; C.I. 95%:1.186-4.099; p:0.01]. Logistic regression analysis revealed dysgeusia (aOR: 3.32), appetite impairment (aOR:1.32), sarcopenia (aOR: 3.75), and frailty (aOR:3.03) significantly associated with this outcome (all p < 0.0001).

Dysgeusia appears predominant in MASLD-dACLD and, via appetite impairment, in a close relationship with malnutrition, sarcopenia, and frailty, negatively influencing patients' outcomes.

Clinically significant portal hypertension in patients with liver cirrhosis can lead to refractory ascites. A TIPS treats clinically significant portal hypertension but may cause overt hepatic encephalopathy (oHE). Our aim was to determine the optimal reduction of the portal pressure gradient (PPG) through TIPS to control ascites without raising oHE risk.

This multicenter study screened 1509 patients from 3 European centers (Hannover, Vienna, and Hamburg) undergoing TIPS implantation between 2000 and 2023. Patients with TIPS indications other than refractory ascites/hepatic hydrothorax, vascular liver disease, HCC, or insufficient PPG data were excluded. PPG was measured before and after TIPS insertion. Outcome data were assessed up to 1 year after TIPS insertion. Analyses were conducted utilizing a modern machine learning model, namely a competing-risk random survival forest, partial dependence plots, and competing risk analyses with liver transplantation/death as competitors. The cohort was divided into a 60% derivation and 40% validation cohort. Overall, 729 patients (median MELD: 13 [IQR 10-16], 66% male, 23% oHE before TIPS) were analyzed. The derivation cohort comprised 438 patients, and the validation cohort comprised 291 patients. The optimal PPG reduction, determined by maximally selected Gray statistic and PDP of the random survival forest, was 60%-80%. In this range, patients showed significantly fewer hepatic decompensations due to ascites (HDA) (subdistribution hazard ratio [sHR]: 0.7 [0.52-0.96]) with similar oHE incidences (sHR: 0.92 [0.67-1.27]). The PPG range was confirmed in the validation cohort (HDA: sHR: 0.66 [0.46-0.96]; oHE: sHR: 0.89 [0.61-1.32]).

A targeted PPG reduction of 60%-80% showed significantly reduced HDA without increased oHE risk. Therefore, PPG reduction within this range could be a valid reduction target.

Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALB+KRT7+ epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALB+KRT7+ epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALB+KRT7+ epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD. KEY POINTS: This study provides single-cell landscape of human liver samples across different ALD stages. The ALB+ KRT7+ epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages. ALB+KRT7+ epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity. The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, and can lead to hepatocellular carcinoma (HCC), a leading cause of cancer-related death. We aimed to determine the extent to which MASLD is an increasing cause of HCC in Sweden and to determine clinical characteristics associated with underlying MASLD. Using the Swedish quality registry for liver cancer (SweLiv), we identified all adults with a diagnosis of HCC in Sweden between 2012 and 2018. Baseline data were retrieved from SweLiv and other nationwide registers. Totally, 3494 patients with HCC were identified. Of them, 757 patients (22%) had MASLD-HCC. The proportion with MASLD-HCC increased from 19% in 2012 to 25% in 2018 (ptrend = 0.012), and MASLD was since 2017 the leading cause of HCC, surpassing hepatitis C. MASLD was the fastest growing cause of HCC with a 33% increment during the study period. Compared to other patients with HCC, those with MASLD-HCC were older (75 vs. 67 years, p < .001), less commonly had cirrhosis (61% vs. 82%, p < .001), had larger tumours (median 5.5 vs. 4.3 cm, p < .001), and more often extrahepatic metastasis (22% vs. 16%, p < .001). Patients with HCC caused by MASLD or by other causes were equally likely to be diagnosed in an early stage (Barcelona Clinic Liver Cancer 0-A, 27% vs. 30%, p = .129). MASLD is now the leading cause of HCC in Sweden.

Liver fibrosis is a significant contributor to global morbidity and mortality, making the identification of non-toxic natural therapies to slow its progression essential. This study evaluated the anti-fibrotic potential of a nutraceutical blend comprising extra virgin olive oil, linseed oil, and ginger extract, formulated in both emulsion and nanoemulsion forms, using a rat model of liver fibrosis. Nanoemulsions were prepared using the ultrasonication technique, and their particle size and stability were analyzed via the DLS method. Twenty-four male albino rats were divided into four groups: normal control, CCl4-treated, oil emulsion-treated, and nanoemulsion-treated. Liver fibrosis was induced by oral administration of carbon tetrachloride (CCl4), while the emulsions were administered daily alongside CCl4 for four weeks. Liver function indices, oxidative stress biomarkers, and gene expressions were assessed, along with histopathological and immunohistochemical analyses. The results revealed that both emulsions significantly improved liver function, enhanced antioxidant capacity, and reduced lipid peroxidation. They downregulated pro-fibrogenic markers (TGF-β1, TIMP-1) and upregulated anti-fibrogenic markers (MMP9, HGF), leading to a reduction in liver fibrosis. The nanoemulsion exhibited superior efficacy compared to the emulsion. These findings demonstrate that the nutraceutical blend, particularly in nanoemulsion form, effectively attenuated liver fibrosis and improved hepatic health markers. This underscores its potential as a natural therapy for liver fibrosis and related conditions, emphasizing its nutritional value in supporting liver health.

Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo.

Liver cancer is a common malignant tumor of the digestive system. We aimed to estimate the trend in the burden of liver cancer in Fujian Province, China, during 2011-2020.

The population-based cancer data was collected from the cancer registry in Fujian Province during 2011-2020. Segi's world standard population was used to calculate the age-standardized incidence rates and age-standardized mortality rates. The temporal trend of liver cancer was displayed by annual percentage change and average annual percentage change (AAPC). Relative survival of liver cancer was calculated as the ratio of observed survival to expected survival. The age-standardized relative survival was calculated according to the International Cancer Survival Standards 1.

There were 14,725 patients diagnosed with liver cancer and 12,698 patients died between 2011 and 2020. For males, there was a downward trend in incidence and mortality (AAPC: -3.86%, -3.44%). Similarly, the downward trend was also shown in females (AAPC: -3.96%, -2.79%). The highest age-specific incidence and mortality were in the 75-79 age group (146.59/100,000 and 137.99/100,000, respectively), and there was no downward trend in this group during the period. The overall age-standardized 5-year relative survival was 10.77% in 2011-2015 and 14.54% in 2016-2020. During the study period, the percentage improvement of survival was higher in males than in females (34.75% and 25.33%). The percentage improvement of survival in urban was higher than that in rural (38.64% and 28.75%). Except for the age group over 75, the survival of patients in other age groups all has improved.

Liver cancer remains a serious public health problem in Fujian Province, China, which needs to be solved, especially in some high-risk groups such as the elderly, high-risk males, and rural populations. Early detection and treatment is the key to the prevention and treatment of liver cancer.

Urinary albumin-to-creatinine ratio (uACR) is an independent predictor of chronic kidney disease (CKD) progression. However there is limited evidence on the burden of CKD according to uACR categories at the population level. This study estimates future clinical and financial burden of CKD according to uACR categories using the Inside CKD microsimulation.

The Inside CKD model is an individual patient level microsimulation that emulates national populations based on demographic, epidemiological, and economic data. The analysis estimates clinical and economic outcomes over time according to the Kidney Disease: Improving Global Outcomes (KDIGO) uACR categories (A1-A3) at a population level for 31 countries and regions.

CKD populations (diagnosed and undiagnosed individuals, stages G3-G5) were projected to be predominantly within uACR categories A1 and A2 in 2022. Projected cumulative incidence of CKD stage transitions (disease progression) and cardio-renal complications (heart failure, myocardial infarction, stroke, and all-cause mortality) occurred mostly in uACR categories A1 and A2 between 2022 and 2027. Patients in uACR categories A1 and A2, who represent the largest proportion of patients with CKD, were projected to incur most of the health care costs associated with CKD management and cardio-renal complications for the diagnosed population (prevalence 2027).

This study highlights the disproportionate population-level clinical and economic burden associated with individuals within KDIGO uACR categories A1 and A2, who represent most of the CKD population. This awareness will help health care decision makers to appropriately allocate resources and interventions to the CKD population, including those with mild to moderately increased albuminuria, to reduce clinical and economic burden associated with CKD.

Background/Objectives: Chronic liver disease (CLD) is highly relevant in clinical practice due to its increasing incidence and associated mortality. We aimed to exhaustively characterize the multimorbidity of patients with CLD. Methods: This is a retrospective observational study of patients aged 18 years and older with a diagnosis of CLD in 2015 in the EpiChron Cohort (Spain). We analyzed the prevalence of comorbidities according to sex and age, conducted a logistic regression analysis with CLD as the independent variable and each of the comorbidities as dependent variables to obtain odds ratios (OR) adjusted for age and sex, and performed an exploratory factor analysis to identify the presence of multimorbidity patterns. Results: A total of 6836 adults had a diagnosis of CLD (mean age 61.6 years; 62.5% women), with an average of 13 co-existing chronic conditions. Arterial hypertension, lipid metabolism disorders, diabetes, obesity, and musculoskeletal diseases were the most frequent diseases. From the list of 110 chronic conditions analyzed, 75 were systematically associated with CLD, including (OR, 95% confidence interval) chronic pancreatitis (41.2, 33.5-50.6) and inherited metabolic disorders (14.9, 11.8-18.8). Three multimorbidity patterns were identified in both men and women, including cardiovascular, metabolic-geriatric, and mental-substance use, with some differences by sex. Conclusions: Multimorbidity is the norm in patients with CLD. Our results reveal that a comprehensive and integral approach based on person-centered care, which should take into account their entire spectrum of multimorbidity, is necessary during the care of this type of patient in clinical practice.

Worldwide, rural populations are recognized to be exposed to increased health challenges due to their living and working environment, socioeconomic status, and access to health services. According to the Romanian Country Health Profile 2023, approximately 46% of all deaths recorded in Romania in 2019 could be attributed to behavioral risk factors such as tobacco smoking, dietary risks, alcohol consumption and low physical activity. No data on rural versus urban areas are available to date, and research is needed to document health inequalities, identify barriers to health services, and explore solutions.

This study is an analysis of data collected during the Health Evaluation Survey carried out by the National Institute of Public Health in 2022 and aimed to reveal differences in health risk factors between rural and urban areas. The analysis was carried out under the methodological framework of the Health Evaluation Survey 2022, which is coordinated by the National Institute of Public Health.

Our study's objectively measured data revealed that the overall health profile of rural communities is characterized by lower education levels, lower incomes, and higher binge drinking rates than those of their urban counterparts. Additionally, rural inhabitants more often have high blood pressure, are more overweight and obese (per body mass index measurements) and have higher fasting plasma glucose. The health profile of the urban population revealed higher education levels and greater proportions of people with adequate monthly income, people with daily alcohol consumption, people who smoke, and people with hypercholesterolemia. Access to primary health care evaluated through proxy indicators was lower in rural areas but was relatively good overall.

Our analysis of the health profile of rural communities revealed a greater prevalence of obesity and overweight, especially among women, and an increased prevalence of heavy drinking among men. Access to primary health care evaluated through proxy indicators is lower in rural areas but is relatively good overall. Lower education levels and the possibility of lower health literacy underpin the need for targeted health education campaigns. Sustainable strategies for rural health need to be identified, especially in the field of health promotion and disease prevention programs.

This study is observational research involving human participants where no interventions were applied to the study population.

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.

Alcoholic liver disease (ALD) poses a significant global health burden, often requiring liver transplantation and resulting in fatalities. Current treatments, like corticosteroids, effectively reduce inflammation but carry significant immunosuppressive risks. This study evaluates Lactiplantibacillus plantarum FB091, a newly isolated probiotic strain, as a safer alternative for ALD treatment. Using an in vivo mouse model, we assessed the effects of L. plantarum FB091 on alcohol-induced liver damage and gut microbiota composition. Alcohol and probiotics administration did not significantly impact water/feed intake or body weight. Histopathological analysis showed that L. plantarum FB091 reduced hepatocellular ballooning and inflammatory cell infiltration in liver tissues and mitigated structural damage in colon tissues, demonstrating protective effects against alcohol-induced damage. Biomarker analysis indicated that L. plantarum FB091 decreased aspartate aminotransferase levels, suggesting reduced liver damage, and increased alcohol dehydrogenase activity, indicating enhanced alcohol metabolism. Additionally, cytokine assays revealed a reduction in pro-inflammatory TNF-α and an increase in anti-inflammatory IL-10 levels in colon tissues of the L. plantarum FB091 group, suggesting an anti-inflammatory effect. Gut microbiota analysis showed changes in the L. plantarum FB091 group, including a reduction in Cyanobacteria and an increase in beneficial bacteria such as Akkermansia and Lactobacillus. These changes correlated with the recovery and protection of liver and colon health. Overall, L. plantarum FB091 shows potential as a therapeutic probiotic for managing ALD through its protective effects on liver and colon tissues, enhancement of alcohol metabolism, and beneficial modulation of gut microbiota. Further clinical studies are warranted to confirm these findings in humans.