UNASSIGNED: Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes.
UNASSIGNED: Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage.
UNASSIGNED: Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC.
UNASSIGNED: Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.

UNASSIGNED: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are prevalent conditions linked to obesity and metabolic disturbances, with potential complications such as cirrhosis and cardiovascular risks. This systematic review and meta-analysis aimed to evaluate the efficacy of pemafibrate, a drug targeting fat and sugar metabolism genes, in treating patients with MASLD/MASH.
UNASSIGNED: Databases such as MEDLINE, Web of Science, Cochrane Library, and Scopus were searched until September 2023 to identify relevant studies. Selected studies underwent a thorough quality assessment using tools like Risk of Bias 2 tool (ROB-2) and the National Institutes of Health (NIH) Quality Assessment Tools. Comprehensive meta-analysis software was used for statistical evaluations, with a focus on lipid profiles, liver function tests, and fibrosis measurements.
UNASSIGNED: A total of 13 studies were included; 10 of them were included in the quantitative analysis. Our findings showed that pemafibrate significantly decreased low-density lipoprotein cholesterol (LDL-C) (effect size (ES) = -9.61 mg/dL, 95% confidence interval (CI): -14.15 to -5.08), increased high-density lipoprotein cholesterol (HDL-C) (ES = 3.15 mg/dL, 95% CI: 1.53 to 4.78), and reduced triglycerides (TG) (ES = -85.98 mg/dL, 95% CI: -96.61 to -75.36). Additionally, pemafibrate showed a marked reduction in liver enzyme levels, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), with significant effect sizes and P values. For liver stiffness outcomes, pemafibrate decreased AST to platelet ratio index (APRI) (ES = -0.180, 95% CI: -0.221 to -0.138).
UNASSIGNED: Pemafibrate, with its enhanced efficacy and safety profile, presents as a pivotal agent in MASLD/MASH treatment. Its lipid-regulating properties, coupled with its beneficial effects on liver inflammation markers, position it as a potentially invaluable therapeutic option.

UNASSIGNED: The lack of effective non-invasive diagnostic methods for liver fibrosis hinders timely treatment for chronic hepatitis B (CHB) patients, leading to the progression of advanced liver disease. Circulating microRNAs offer a non-invasive approach to fibrosis assessment. MicroRNA-15a/16-1 (miR-15a/16) was reported to be implicated in fibrosis development, but the role of plasma miR-15a/16 in liver fibrosis assessment remains poorly understood. This study explored the importance of plasma miR-15a/16 in assessing liver fibrosis severity of CHB patients.
UNASSIGNED: Quantitative PCR was utilized to measure the levels of plasma miR-15a/16 in 435 patients with CHB and 74 healthy controls. We assessed the correlation between plasma miR-15a/16 levels and liver fibrosis and cirrhosis using Pearson correlation coefficients, multivariate linear and logistic regression models, and smooth curve fitting. Utilizing the receiver operating characteristic (ROC) curve, we examined the diagnostic potential of plasma miR-15a/16 in severe fibrosis and cirrhosis.
UNASSIGNED: Plasma levels of miR-15a/16 in patients with CHB were significantly reduced compared to those in healthy controls. In the CHB cohort, levels were notably decreased in individuals with severe fibrosis or cirrhosis compared to those without severe fibrosis or cirrhosis. Plasma miR-15a/16 levels exhibited a negative relationship with the severity of liver fibrosis, gradually decreasing as the histological fibrosis stage progressed from S0 to S4. Reduced levels of plasma miR-15a/16 were linked to an elevated risk of severe liver fibrosis (miR-15a: odds ratio [OR] = 0.243; 95 % confidence interval [CI]: 0.138, 0.427; miR-16: OR = 0.201; 95 % CI: 0.097, 0.417) and cirrhosis (miR-15a: OR = 0.153; 95 % CI: 0.079, 0.298; miR-16: OR = 0.064; 95 % CI: 0.025, 0.162). MiR-15a achieved an area under the ROC curve of 0.886 and 0.832 for detecting moderate-to-severe fibrosis (S2-S4) and cirrhosis, respectively. MiR-16 demonstrated similar diagnostic values.
UNASSIGNED: Plasma miR-15a/16 levels were negatively correlated with the severity of liver fibrosis in CHB patients and could serve as a new non-invasive indicator in evaluating liver fibrosis.

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.

Non-alcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis (accumulation of fat in the liver to over 5% of its weight) in the absence of secondary causes of fat accumulation in the liver such as excessive alcohol use. NAFLD is divided into two types: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Therefore, in this clinical guideline, we sought to determine general and important policies for this disease and modify its managment approaches. We adapted this guideline for the management of NAFLD in Isfahan Province. This guideline was developed by clinical appraisal and review of the evidence, available clinical guidelines, and in consultation with members of the Isfahan Chamber of the Iranian Association of Gastroenterology and Hepatology. Biopsy is recommended as the most reliable method (gold standard) to diagnose steatohepatitis and fibrosis in patients with NAFLD. NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) are recommended as the test with the highest predictive value for advanced fibrosis in patients with NAFLD compared to other serologic tests. Among the noninvasive methods used to assess liver fibrosis, transient elastography (TE) is preferable to other methods.

BACKGROUND: India is currently facing an epidemic of type 2 diabetes mellitus (T2DM) and obesity which are high-risk factors for the development of non-alcoholic fatty liver disease (NAFLD). A non-invasive tool, the vibration-controlled transient elastography (VCTE; FibroScan, Echosens, Paris, France) is used to diagnose NAFLD.
OBJECTIVE: To identify the prevalence, spectrum, and metabolic determinants of NAFLD in Indian adult women using liver function tests (LFT) and non-invasive FibroScan (liver stiffness measure, i.e., LSM score) of the liver through a cross-sectional population-based study in the city of Belagavi.
METHODS: The subjects were screened for the presence of liver disease with a detailed history, anthropometric measurements, LFTs, blood sugars, and FibroScan of the liver to assess liver steatosis and liver fibrosis.
RESULTS: The study included 2448 women with 860 (35.13%) having NAFLD (controlled attenuation parameter {CAP}≥275 dB/m) as detected by FibroScan. Nearly, 58.8% of the participants with T2DM had NAFLD. Participants with NAFLD had higher BMI and waist circumference. When univariate logistic regression was applied, those with T2DM were 14.5 times (95% CI, 4.55, 6.52) likely to have CAP≥275 dB/m. Similarly, those with higher BMI>23 mg/m2 were 1.34 (95% CI, 1.68, 2.37) times more likely to have CAP ≥275 dB/m. The risk of NAFLD increases by ~1% for every one-year increase in age.
CONCLUSIONS: NAFLD in women is the most common non‑communicable disease in India; a prevalence of 35.13% was observed in the present study in women. Higher BMI, presence of metabolic risk factors, and incremental age were associated with a high risk of developing NAFLD in women.

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.

BACKGROUND: The neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) has emerged as a promising biomarker for assessing inflammation and lipid dysregulation. Increasing evidence indicates that these metabolic disturbances play a crucial role in the development of metabolic dysfunction-associated steatotic liver disease(MASLD). This study aims to investigate the association between NHR, MASLD, and liver fibrosis.
METHODS: This cross-sectional study analyzed data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Weighted multivariate logistic regression models were used to investigate the association between NHR and both MASLD and liver fibrosis. Smoothed curve fitting and threshold effect analysis were performed to detect potential nonlinear relationships. Subgroup analyses were conducted to assess the consistency of these associations across different groups.
RESULTS: The study involved 4,761 participants. We observed a significant positive association between NHR and MASLD (OR = 1.20, 95% CI: 1.09-1.31). However, there was no significant association between NHR and liver fibrosis (OR = 1.01; 95% CI: 0.94-1.09). The analysis of smoothed curve fitting and threshold effect revealed an inverted U-shaped relationship between NHR and MASLD, with a turning point at 5.63.
CONCLUSIONS: Our findings indicate a positive correlation between elevated NHR levels and MASLD prevalence. However, we did not observe a significant association between NHR and liver fibrosis prevalence. Further prospective research is needed to validate these findings in a longitudinal setting.

Liver fibrosis is often undetected whereas it is the determinant of liver-related mortality. We evaluate a pathway based on the systematic calculation of FIB-4 to screen for advanced hepatic fibrosis. Systematic calculation of FIB-4 was implemented in the centralized laboratory of a French University Hospital in 4 pilot departments. If ≥ 2.67, the FIB-4 result was returned to the prescribers, for patients between 18 and 70 years of age, with an incentive to measure liver stiffness by vibration controlled transient elastography. During a 2-years period, a FIB-4 was calculated in 2963 patients and 135 were ≥ 2.67 (4.6%). After exclusion of patients with a known cause of elevated FIB-4, 47 patients (34.8%) were eligible for elastography. Forty patients underwent elastography, but only 15% (7/47) at the spontaneous request of the referring physician. Fifteen patients were identified with significant fibrosis, among which 8 attended the scheduled specialist consultation, all with a confirmed diagnosis of cirrhosis. A sequential pathway based on the systematic calculation of FIB-4 enables the identification of patients with significant unknown liver fibrosis, allowing to refer them to specialized care. Raising awareness is essential to improve the care pathway.

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