Visceral Fat and Diabetes: Associations With Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is increasing globally. Noninvasive methods, such as bioelectrical impedance analysis (BIA), which measures body composition, including visceral fat, are gaining interest in evaluating MASLD patients. Our study aimed to identify factors associated with significant liver fibrosis, compare noninvasive scores, and highlight the importance of visceral fat measurement using BIA. Methods: MASLD patients seen in our out-patient department underwent comprehensive evaluations, including liver stiffness using transient elastography, body composition analysis using BIA, and metabolic measurements. Significant fibrosis was defined as a liver stiffness measurement of ≥8.2 kPa. Using multivariate analysis, we identified factors associated with significant liver fibrosis and compared four noninvasive scores with a novel diabetes-visceral fat 15 (DVF15) score. Results: We analyzed data from 609 MASLD patients seen between February 2022 and March 2023. The median age was 43 years (81% male). Among these, 78 (13%) had significant fibrosis. Patients with significant fibrosis had higher rates of type 2 diabetes (41% vs 21%, P < 0.001) and elevated levels of aspartate aminotransferase, alanine aminotransferase, hemoglobin A1c, Fibosis-4, aspartate-aminotransferase-to platelet-ratio index, and NAFLD fibrosis scores. They also exhibited higher visceral and subcutaneous fat. Binary logistic regression revealed type 2 diabetes and a visceral fat level of >15% as associated with significant liver fibrosis. Additionally, the DVF15 score, combining these factors, showed a modest area under the receiver operating characteristic curve of 0.664 (P < 0.001). Conclusion: Our study identified diabetes and high visceral fat as factors associated with significant liver fibrosis in MASLD patients. We recommend that visceral fat measurement using BIA be an essential part of MASLD evaluation. The presence of either diabetes or a visceral fat level of >15% should prompt clinicians to check for significant fibrosis in MASLD patients. Further research is warranted to validate our findings and evaluate the utility of the DVF15 score in larger cohorts and diverse populations.

Inhibition of hepatic stellate cell activation by nutraceuticals: an emphasis on mechanisms of action.

Liver diseases emerge as a serious threat to humans worldwide due to increasing morbidity and mortality. Liver disease related deaths accounts for one third of all disease related death globally. A simple fatty liver if unattended advances further to liver fibrosis, cirrhosis and hepatocellular carcinoma. During liver fibrogenesis, hepatic stellate cells gets activated into myofibroblast like cells and exhibit proliferative and fibrogenic features. Targeting these activated hepatic stellate cells offer promising therapeutic approach towards liver fibrosis management. To date there is no Food and Drug Administration approved treatments for liver fibrosis. However, a large number of clinical trials are being conducted employing monoclonal antibodies, drugs, dietary supplements and herbal medicines. A vast number of research findings demonstrated nutraceuticals to be effective against experimental liver fibrosis both in vitro and in vivo. Nutraceuticals typically regulate key signaling pathways in activated hepatic stellate cells and exhibit anti-fibrotic effect. In this review, the mechanistic action of nutraceuticals targeting activated hepatic stellate cells were summarized to establish them as a possible therapeutic candidate for liver fibrosis.

Cabozantinib prevents the progression of metabolic dysfunction-associated steatohepatitis by inhibiting the activation of hepatic stellate cell and macrophage and attenuating angiogenic activity.

Cabozantinib, a multiple tyrosine kinase inhibitor targeting AXL, vascular endothelial growth factor receptor (VEGFR), and MET, is used clinically to treat certain cancers, including hepatocellular carcinoma. This study aimed to assess the impact of cabozantinib on liver fibrosis and hepatocarcinogenesis in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). MASH-based liver fibrosis and hepatocarcinogenesis were induced in rats by feeding them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for eight and 16 weeks, respectively. Cabozantinib (1 or 2 mg/kg, daily) was administered concurrently with the diet in the fibrosis model and after eight weeks in the carcinogenesis model. Treatment with cabozantinib significantly attenuated hepatic inflammation and fibrosis without affecting hepatocyte steatosis and ballooning in CDAHFD-fed rats. Cabozantinib-treated rats exhibited a marked reduction in α-smooth muscle actin+ activated hepatic stellate cell (HSC) expansion, CD68+ macrophage infiltration, and CD34+ pathological angiogenesis, along with reduced hepatic AXL, VEGF, and VEGFR2 expression. Consistently, cabozantinib downregulated the hepatic expression of profibrogenic markers (Acta2, Col1a1, Tgfb1), inflammatory cytokines (Tnfa, Il1b, Il6), and proangiogenic markers (Vegfa, Vwf, Ang2). In a cell-based assay of human activated HSCs, cabozantinib inhibited Akt activation induced by GAS6, a ligand of AXL, leading to reduced cell proliferation and profibrogenic activity. Cabozantinib also suppressed lipopolysaccharide-induced proinflammatory responses in human macrophages, VEGFA-induced collagen expression and proliferation in activated HSCs, and VEGFA-stimulated proliferation in vascular endothelial cells. Meanwhile, administration of cabozantinib did not affect Ki67+ hepatocyte proliferation or serum albumin levels, indicating no negative impact on regenerative capacity. Treatment with cabozantinib also reduced the placental glutathione transferase+ preneoplastic lesions in CDAHFD-fed rats. In conclusion, cabozantinib shows promise as a novel option for preventing MASH progression.

Clinical significance of liver biopsy in the diagnosis of liver disease and the evaluation of the clinical efficacy of antiviral treatment for chronic hepatitis B.

OBJECTIVE: To explore the diagnostic value of liver biopsy in patients with acute/chronic liver diseases and to evaluate the application value of repeated liver biopsy in assessing the efficacy of antiviral therapy in patients with chronic hepatitis B. METHODS: This retrospective study involved 146 patients with acute and chronic liver diseases who underwent liver biopsy at the Affiliated Hospital of Putian University from January 2018 to December 2023. Differential diagnoses were made for patients with liver diseases based on their pathological results from liver biopsy. Additionally, the effectiveness of antiviral treatment and changes in liver fibrosis in patients with hepatitis B infection before and after antiviral therapy were assessed using repeated liver biopsy. RESULTS: The overall concordance rate between clinical and histopathological diagnoses was 79.45% (116/146). Specifically, the highest concordance rate was for chronic hepatitis B at 82.61% (76/92), followed by fatty liver disease at 77.78% (7/9), autoimmune liver disease at 75% (12/16), and drug-induced liver injury at 72.72% (16/22), and lastly, hepatitis B-related cirrhosis at 71.43% (5/7). After antiviral therapy, the number of cases with positive HBeAg and HBV-DNA significantly decreased compared to before treatment, while the number of cases with negative HBeAg increased, showing a statistically significant difference (P<0.001). The number of patients at fibrosis stages S3-S4 decreased after antiviral therapy compared to before treatment (P=0.040 and P=0.028), while the number of patients at stage S2 increased (P=0.040). CONCLUSION: Liver biopsy aids in the diagnosis of liver diseases and can effectively evaluate the degree of liver fibrosis before and after antiviral therapy for chronic hepatitis B.

Emerging Therapies for Non-Alcoholic Steatohepatitis (NASH): A Comprehensive Review of Pharmacological and Non-Pharmacological Approaches.

Non-alcoholic steatohepatitis (NASH) has emerged as a significant global health concern, closely linked to the obesity epidemic and metabolic syndrome. This review explores emerging therapies for NASH that go beyond traditional lifestyle modifications. The complex pathophysiology of NASH, involving insulin resistance, lipotoxicity, oxidative stress, and chronic inflammation, offers multiple targets for therapeutic intervention. While lifestyle changes remain fundamental, their limitations in achieving sustained improvements highlight the need for effective pharmacological and interventional therapies. This review discusses novel pharmacological approaches, including farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and agents addressing metabolic dysfunction, inflammation, and fibrosis. Promising candidates such as obeticholic acid, lanifibranor, and semaglutide are highlighted, along with combination therapies targeting multiple pathways simultaneously. Non-pharmacological interventions, including bariatric surgery, endoscopic bariatric and metabolic therapies, and innovative exercise regimens, are also examined for their potential in NASH management. Despite significant advancements, NASH drug development faces challenges due to the disease's complexity, patient heterogeneity, and stringent regulatory requirements. This review also addresses these limitations and explores future directions, including personalized medicine approaches, non-invasive diagnostic tools, and the potential of microbiome modulation and regenerative therapies. The evolving landscape of NASH research emphasizes the need for multidisciplinary approaches integrating advances in diagnostics, therapeutics, and digital health technologies. As the field progresses, the focus remains on developing more effective, personalized, and accessible strategies for preventing, diagnosing, and treating NASH, with the ultimate goal of improving outcomes for patients affected by this increasingly prevalent liver disease.

Integrating text mining with network models for successful target identification: in vitro validation in MASH-induced liver fibrosis.

An in silico target discovery pipeline was developed by including a directional and weighted molecular disease network for metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. This approach integrates text mining, network biology, and artificial intelligence/machine learning with clinical transcriptome data for optimal translational power. At the mechanistic level, the critical components influencing disease progression were identified from the disease network using in silico knockouts. The top-ranked genes were then subjected to a target efficacy analysis, following which the top-5 candidate targets were validated in vitro. Three targets, including EP300, were confirmed for their roles in liver fibrosis. EP300 gene-silencing was found to significantly reduce collagen by 37%; compound intervention studies performed in human primary hepatic stellate cells and the hepatic stellate cell line LX-2 showed significant inhibition of collagen to the extent of 81% compared to the TGFß-stimulated control (1 µM inobrodib in LX-2 cells). The validated in silico pipeline presents a unique approach for the identification of human-disease-mechanism-relevant drug targets. The directionality of the network ensures adherence to physiologically relevant signaling cascades, while the inclusion of clinical data boosts its translational power and ensures identification of the most relevant disease pathways. In silico knockouts thus provide crucial molecular insights for successful target identification.

Dynamic strategies and optimal control analysis for hepatitis C management: non-invasive liver fibrosis diagnosis.

This study proposes a novel model employing nonlinear ordinary differential equations to dissect HCV dynamics. Six distinct population groups are delineated: Susceptible, Treatment, Responder, Non-Responder, Cured, and Fibrosis. A detailed numerical analysis of this model was conducted, tracking the predicted trends over a span of 20 years. The primary objective of this analysis is to assess and confirm the model's predictive accuracy and its potential to supplant invasive diagnostic methods in monitoring the progression of liver fibrosis. By incorporating various control parameters, namely u1(t),u2(t), and u3(t), the model offers a nuanced perspective on disease progression and treatment outcomes. Parameter u1(t) modulates treatment-induced fibrosis progression, providing a crucial lever for mitigating treatment-related side effects. u2(t) reflects treatment effectiveness, capturing the proportion of responders within the treatment cohort. Meanwhile, u3(t) governs fibrosis progression in non-responders, shedding light on the disease's natural trajectory without effective treatment.

Clinical characteristics of lean metabolic-associated fatty liver disease and the impact of concurrent diabetes mellitus.

Objectives: Metabolic-associated fatty liver disease (MAFLD) was proposed in 2020 to replace the original term nonalcoholic fatty liver disease (NAFLD) with new diagnostic criteria. The disease risks of lean and overweight/obese MAFLD patients remain controversial. Materials and Methods: The participants from the Taiwan biobank cohort were included. Advanced liver fibrosis is defined as NAFLD fibrosis score (NFS) >0.675. We use carotid plaques of duplex ultrasounds to diagnose atherosclerosis. Results: A total of 20,058 participants (age 55.67 ± 10.32; males 37.6%) were included in the final analysis. Seven thousand eight hundred and forty-three (39.1%) participants were diagnosed with MAFLD. Of them, 965 (12.3%) were lean MAFLD patients. Among lean MAFLD patients, 25.6% were comorbid with diabetes mellitus (DM). Lean MAFLD patients were older and had higher percentages of females and DM than overweight/obese MAFLD patients. After propensity score matching for age and sex, they had lower levels of NFS but a higher percentage of carotid plaques. Among four subtypes of MAFLD including "lean with DM," "lean without DM," "overweight/obese with DM," and "overweight/obese without DM," logistic regression showed that "lean with DM" subjects had the highest risk of atherosclerosis and "overweight/obese with DM" subjects had the highest risk of advanced liver fibrosis in MAFLD patients. Conclusion: The population-based study revealed that lean MAFLD patients make up 12.3% of all MAFLD patients, and they have a higher proportion of coexisting diabetes. Among lean MAFLD patients concurrent with diabetes, they have the highest risk of atherosclerosis and should receive special attention clinically.

Characteristics of diabetes mellitus patients with nonviral chronic liver disease who developed hepatocellular carcinoma.

AIM: Type 2 diabetes mellitus (T2DM) is a well-known risk factor for hepatocellular carcinoma (HCC). However, HCC is often diagnosed at an advanced stage in patients with diabetes because of the lack of the best criteria for surveillance candidates. The aim of this study was to identify risk factors for HCC development in patients with diabetes with nonviral chronic liver disease. METHOD: Three hundred thirty T2DM patients with nonviral chronic liver disease who underwent surveillance for HCC by imaging techniques between 2009 and 2020 were enrolled in this multicenter cross-sectional retrospective study. The clinical and laboratory parameters of patients with and without HCC were compared. RESULTS: Age ≥65 years, alcohol intake, lack of hepatic steatosis, triglyceride level <111 mg/dL, Mac2 binding protein glycosylation isomer (M2BPGi) ≥0.9 cut-off index (COI), α-fetoprotein concentration ≥5 ng/mL, and des-γ-carboxy prothrombin concentration ≥26 mAU/mL were independently associated with HCC development. When stratified by age, only alcohol intake (odds ratio [OR] 114.19, p < 0.001) was associated with HCC development in patients aged <65 years, and medication for diabetes mellitus (OR 5.72, p = 0.001), lack of hepatic steatosis (OR 4.47, p = 0.002), lactate dehydrogenase ≥198 IU/L (OR 2.751, p = 0.031), M2BPGi ≥1.18 COI (OR 9.05, p < 0.001), and FIB-4 index ≥2.59 (OR 3.22, p = 0.017) were associated with HCC development in patients aged ≥65 years. CONCLUSIONS: In addition to age and advanced liver fibrosis, alcohol intake in younger T2DM patients and medication for DM and lack of hepatic steatosis in older T2DM patients should be considered for HCC surveillance by imaging.

Biological aging accelerates hepatic fibrosis: Insights from the NHANES 2017-2020 and genome-wide association study analysis.

INTRODUCTION AND OBJECTIVES: This study aimed to investigate the association between biological aging and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). MATERIALS AND METHODS: We analyzed NHANES 2017-2020 data to calculate phenotypic age. Hepatic steatosis and fibrosis were identified using controlled attenuation parameters (CAP), fatty liver index (FLI) and transient elastography (TE). The odds ratios (ORs) and 95% confidence intervals (CI) for significant MASLD fibrosis were calculated using multivariate logistic regression, and subgroup analyses were performed. We explored the potential causal relationship between telomere length and liver fibrosis using Mendelian randomization (MR). Additionally, we used the expression quantitative trait loci (eQTL) method and GSE197112 data to identify genes related to liver fibrosis and senescence. Finally, the APOLD1 expression was validated using GSE89632. RESULTS: Phenotypic age was associated with liver fibrosis occurrence in MASLD (OR = 1.08, 95% CI 1.05-1.12). Subgroup analyses by BMI and age revealed differences. For obese or young to middle-aged MASLD patients, phenotypic age is significantly associated with liver fibrosis. (OR = 1.14, 95% CI 1.10-1.18; OR = 1.07, 95% CI 1.01-1.14 and OR = 1.14, 95% CI 1.07-1.22). MR revealed a negative association between telomere length and liver fibrosis (IVW method: OR = 0.63288, 95% CI 0.42498-0.94249). The gene APOLD1 was identified as a potential target through the intersection of the GEO dataset and eQTL genes. CONCLUSIONS: This study emphasized the link between biological aging and fibrosis in young to middle-aged obese MASLD patients. We introduced phenotypic age as a clinical indicator and identified APOLD1 as a potential therapeutic target.

FLI and FIB-4 in diagnosing metabolic dysfunction-associated steatotic liver disease in primary care: High prevalence and risk of significant disease.

INTRODUCTION AND OBJECTIVES: Public health policies in metabolic dysfunction-associated steatotic liver disease (MASLD) are still lacking. This study aims to estimate the prevalence and severity of MASLD in primary health care (PHC) through non-invasive markers. PATIENTS AND METHODS: Two-phase study, including a retrospective (RETR) and a prospective (PROS) one, was carried out in PHC in Brazil. In RETR, metabolic and hepatic profiles of 12,054 patients, including FIB-4, were evaluated. In PROS, 350 patients were randomly selected and submitted to a clinical and nutritional assessment. RESULTS: RETR (65.4 % women, mean age 55.3 years old): dyslipidemia, hypertension, and type 2 diabetes mellitus (T2DM) present in 40.8 %, 34.3 %, and 12.2 % of the electronic health records, respectively. Fasting glucose >100 mg/dL in 34.5 %, and glycated hemoglobin higher than 5.7 % in 51.5 %, total cholesterol >200 mg/dL and triglycerides >150 mg/dL in 40.8 % and 32.1 %, respectively. Median FIB-4 was of 1.33, 5 % >2.67. No one had MASLD as a diagnostic hypothesis; PROS(71.8 % women, mean age 58 years old): body mass index (BMI) ≥30 kg/m² in 31.8 %. MASLD prevalence (FLI≥ 30 + cardiometabolic features) of 62.1 %; 39.4 % of patients had FLI ≥60, with higher BMI, waist circumference, fasting glucose, triglycerides, AST, ALT and GGT, as well as lower HDL-cholesterol (p < 0.001). FIB-4>1.3 in 40 % and NAFLD Fibrosis Score (NFS)>-1.45 in 59.2 % of steatotic patients. CONCLUSIONS: There is a high prevalence of MASLD in PHC, with a significant risk of liver fibrosis. These findings reinforce we need to develop public policies to defeat MASLD epidemics.

Active role of the immune system in metabolic dysfunction-associated steatotic liver disease.

Non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a complex multifactorial disease that progresses from steatohepatitis (MASH) to liver cirrhosis and liver cancer. Recent research has revealed that crosstalk between innate immune cells and hepatic parenchymal and non-parenchymal cells is involved in the pathogenesis of liver disease in MASLD/MASH. Of particular importance, novel inflammatory mechanisms, including macrophage diversity, neutrophil NETosis, B-cell biology, auto-reactive T cells, unconventional T cells, and dendritic cell-T cell interactions, are considered key drivers for disease progression. These mechanisms and factors are potential targets for the therapeutic intervention of MASLD/MASH. In this review, we focus on recent discoveries related to liver inflammation and discuss the role of innate immune cell subsets in MASLD/MASH.

Nano-encapsulation of drugs to target hepatic stellate cells: Toward precision treatments of liver fibrosis.

Liver fibrosis is characterized by excessive extracellular matrix (ECM) deposition triggered by hepatic stellate cells (HSCs). As central players in fibrosis progression, HSCs are the most important therapeutic targets for antifibrotic therapy. However, owing to the limitations of systemic drug administration, there is still no suitable and effective clinical treatment. In recent years, nanosystems have demonstrated expansive therapeutic potential and evolved into a clinical modality. In liver fibrosis, nanosystems have undergone a paradigm shift from targeting the whole liver to locally targeted modifying processes. Nanomedicine delivered to HSCs has significant potential in managing liver fibrosis, where optimal management would benefit from targeted delivery, personalized therapy based on the specific site of interest, and minor side effects. In this review, we present a brief overview of the role of HSCs in the pathogenesis of liver fibrosis, summarize the different types of nanocarriers and their specific delivery applications in liver fibrosis, and highlight the biological barriers associated with the use of nanosystems to target HSCs and approaches available to solve this issue. We further discuss in-depth all the molecular target receptors overexpressed during HSC activation in liver fibrosis and their corresponding ligands that have been used for drug or gene delivery targeting HSCs.

Synthesis and Anti-Liver Fibrosis Research of Aspartic Acid Derivatives.

Liver fibrosis plays an important role in the progression of liver disease, but there is a severe shortage of direct and efficacious pharmaceutical clinical interventions. Literature research indicates that aspartic acid exhibits hepatoprotective properties. In this paper, 32 target compounds were designed and synthesized utilizing aspartic acid as the lead compound, of which 22 were new compounds not reported in the literature. These compounds were screened for their inhibitory effects on the COL1A1 promoter to assess in vitro anti-liver fibrosis activity and summarized structure-activity relationships. Four compounds exhibited superior potency with inhibition rates ranging from 66.72% to 97.44%, substantially higher than EGCG (36.46 ± 4.64%) and L-Asp (11.33 ± 0.35%). In an LPS-induced inflammation model of LX-2 cells, both 41 and 8a could inhibit the activation of LX-2 cells, reducing the expression of COL1A1, fibronectin, and α-SMA. Upon further investigation, 41 and 8a ameliorated liver fibrosis by inhibiting the IKKß-NF-κB signaling pathway to alleviate inflammatory response. Overall, the study evaluated the anti-liver fibrosis effects of aspartic acid derivatives, identified the potency of 41, and conducted a preliminary exploration of mechanisms, laying the foundation for the discovery of novel anti-liver fibrosis agents.

A Systematic Review of Metabolic Syndrome: Key Correlated Pathologies and Non-Invasive Diagnostic Approaches.

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half-fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients.

Liver fibrosis in inflammatory arthritis patients treated with methotrexate and hydroxychloroquine: A FIB-4 index analysis.

OBJECTIVES: To evaluate the risk of liver fibrosis and associated factors with the non-invasive fibrosis score-4 (FIB-4) index in patients with inflammatory arthritis using methotrexate (MTX). METHODS: Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB-4 index was could be calculated at methotrexate initiation and follow-up were included. The FIB-4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × âˆšALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate-high risk FIB-4 index at last visit were determined. RESULTS: A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate-high risk FIB-4 index. Comorbidities and the rate of ≥3-4 Charlson comorbidity index were more common in patients with intermediate-high risk FIB-4 index. A total of 37 (34.5%) patients had intermediate-high risk FIB-4 index at the last visit after median 3.6 (0.3-22.06) years follow-up. The median cumulative MTX dose was 2550 mg (1050-13.991). Cumulative MTX dose [OR 1.18 (1.01-1.33), p = .03] and diabetes mellitus [OR 4.60 (1.74-12.50), p = .002] were associated factors with intermediate-high risk FIB-4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low-risk factor for FIB-4 index [OR 0.28 (0.10-0.78) p = .015]. CONCLUSION: The FIB-4 index is a non-invasive method that can be used in daily rheumatology practice for the evaluation and follow-up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis.

Novel insights into the role of immunomodulatory extracellular vesicles in the pathogenesis of liver fibrosis.

Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis.

Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction-associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways.

Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction-associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high-fructose/high-fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high-fructose/high-fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non-alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP-1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1ß/IL6/TNF-α), fibrosis (TGF-ß1/α-SMA), and apoptosis (TUNEL/Caspase-3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin-dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL-10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose-transporting and lipid-regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co-therapy against diabetes-induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti-inflammatory, anti-oxidative, and anti-fibrotic pathways.

Comparison of Two-Dimensional Shear Wave Elastography Between Two Different Instruments for Hepatocellular Carcinoma Patients.

OBJECTIVES: This study aimed to investigate and compare 2-dimensional shear wave elastography (2D-SWE) measurements and influencing factors among 2 different devices and to evaluate the ability and influencing factors of these measurements to assess liver fibrosis. METHODS: From October 2022 to September 2023, 290 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers were prospectively included. The 2D-SWE measurements were performed using AixPlorer V (SEmean) and APLIO i900 (CEmean). This study compared 2D-SWE measurements between instruments for evaluating the liver fibrosis stage and analyzed the potential influencing factors. RESULTS: The 2D-SWE measurements obtained by the 2 instruments were significantly different (P < .001), but the differences were significant only for patients with stage F4 liver fibrosis (P < .001) and not for volunteers or patients with stage F0-F3 liver fibrosis (all P > .050). Multivariate linear regression analysis revealed that the factors independently influencing the SEmean were alanine aminotransferase (ALT) (P = .034) and liver fibrosis stage (P < .001), while fibrosis stage (P = .028) was the only factor influencing the CEmean. CONCLUSIONS: Although 2D-SWE from the 2 different instruments was capable of detecting liver fibrosis, it yielded varying results in HCC patients. These discrepancies were predominantly observed in patients with F4 liver fibrosis but not in healthy adults or patients with F0-F3 liver fibrosis. One potential contributing factor to the differences between instruments could be ALT levels.

The association of liver fibrosis and chronic kidney disease in patients with metabolic associated fatty liver disease: A cross-sectional study.

OBJECTIVES: To examine the relation between liver fibrosis and chronic kidney disease (CKD) in metabolic-associated fatty liver disease (MAFLD) patients and its risk factors. METHODS: The current study was carried out at Tanta University Hospital, Tanta, Egypt, from May 2021 to January 2023 and included 84 MAFLD patients with CKD and 80 MAFLD patients without CKD. All participants had been examined by abdominal ultrasonography and transient elastography with controlled attenuation parameter. RESULTS: Chronic kidney disease patients exhibited a greater incidence of fibrosis compared to patients without CKD (75.6% vs. 24.4%). Logistic analysis demonstrated that the presence of multiple health conditions, such as MAFLD, diabetes mellitus, hypertension, and cardiovascular disease, were individually linked to CKD. Gender and body mass index were not independent factors related to CKD. Additionally, factors such as age, hyperuricemia, hypertriglyceridemia, hypercholesterolemia, hypoalbuminemia, hyperbilirubinemia, and viral hepatitis, apart from MAFLD comorbidities, were independently linked to CKD. CONCLUSION: Chronic kidney disease may represent a potential risk influence for liver fibrosis development in MAFLD patients.