Hepatitis Research Articles

Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Mitochondrial quality control in alcohol-associated liver disease.

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.

Taurocholic acid represents an earlier and more sensitive biomarker and promotes cholestatic hepatotoxicity in ANIT-treated rats.

Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT-induced cholestasis at 8-16 h. The distinguishing features of ANIT-induced liver injury were as follows: T-BAs exceeding G-BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T-BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT-induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine-conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.

Inhibiting Ferroptosis Prevents the Progression of Steatotic Liver Disease in Obese Mice

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Efficacy of Remaxol in complex treatment of chronic viral hepatitis C

Efficacy of Remaxol in complex treatment of chronic viral hepatitis C

Increased serum β-hydroxybutyrate/acetoacetate ratio and aggravated histological liver inflammation in females with metabolic dysfunction-associated steatotic liver disease and polycystic ovary syndrome.

Increased serum β-hydroxybutyrate/acetoacetate ratio and aggravated histological liver inflammation in females with metabolic dysfunction-associated steatotic liver disease and polycystic ovary syndrome.

OPN-Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH-Associated Liver Fibrosis.

Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.

Protective Effect and Mechanism of L-Theanine on Acute Alcoholic Liver Injury in Mice.

Acute alcoholic liver injury (AALI), a global health concern, is exacerbated by excessive episodic drinking. L-theanine (LTA), a compound found in tea leaves, mitigates the AALI-induced liver oxidative stress and inflammation. However, its relationship with alcohol metabolism and its liver-protective mechanism remains unexplored. This study investigates the protective mechanisms of LTA against AALI in mice. The results demonstrate that LTA mitigates liver tissue damage and reduces the serum levels of aspartate aminotransferase and alanine aminotransferase, and liver levels of triglycerides, malondialdehyde, reactive oxygen species (ROS), tumor necrosis factor-α, interleukin-6, and interleukin-1β. However, LTA enhances the activity of ethanol-metabolizing enzymes and decreases ethanol and acetaldehyde serum levels. Mechanistically, LTA accelerates alcohol metabolism by upregulating the hepatic expression of ADH6, ALDH1B1, ALDH2, CAT, and ACSS1 mRNA and protein in AALI mice, LTA downregulates the expression of CYP2E1 mRNA and protein and promoting antioxidative activities thus reducing the accumulation of ROS. This attenuated inflammation by inhibiting the phosphorylation of nuclear factor-kappa B inhibitor alpha (IκBα) and downregulating the hepatic expression of NF-κB p65, TNF-α, IL-1β, IL-6 mRNA, and protein. LTA is a beneficial dietary supplement that protects against AALI by modulating alcohol metabolism and the TNF-α/NF-κB pathway.

Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review

More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12–18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.

Linking antibody against apolipoprotein A-1 to metabolic dysfunction-associated steatohepatitis in mice

Abstract Background Metabolic dysfunction-associated fatty liver disease (MASLD) is a common liver condition associated with increased cardiovascular disease (CVD) risk. Cytokeratin 18 (CK-18) is indicative of liver injury and used as a surrogate biomarker covering MASLD to cirrhosis phenotypes. Autoantibodies against apolipoprotein A-1 (AAA-1) are known CVD risk factors inducing MASLD in vitro, but their role in modulating steatohepatitis and fibrosis in vivo is still elusive. We investigated AAA-1's contribution to systemic low-grade inflammation, liver steatosis, and fibrosis using a MASLD mouse model and a validated passive immunization protocol (PIP). Methods 10 weeks-old male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and immunized with AAA-1 (200ug) or control antibodies for ten days. At sacrifice, plasma samples were collected, and CK-18 levels, and proinflammatory cytokines were measured using the Mesoscale Discovery platform. Hematoxylin and Eosin and Sirius Red Fast Green staining were used to reveal liver steatosis and fibrosis, respectively. RNA were extracted from mouse liver samples and mRNA were then analyzed using a commercial fibrosis-specific genes panel (nCounter Human Fibrosis V2 Panel) and the nCounter Analysis System. Results Compared to control IgG recipients, CDAHFD mice injected with AAA-1 exhibited significantly elevated plasma levels of CK-18 (5.3 vs 2.1, p=0.031), IL-6 (13 vs 6.9, p=0.035), IL-10 (27.3 vs 9.8, p=0.007) and TNF-α (32.1 vs 24.2, p=0.032), and liver steatosis (93.4% vs 73.8%, p=0.007). Nanostring technology experiments revealed upregulation of several pro-fibrotic m-RNAs in liver tissue from AAA-1 immunized mice compared to the IgG immunized control group. These included Serum Amyloid A (Fold Change (FC) AAA-1 vs IgG : 2.5, p=0.02) , G-protein coupled receptors 65 (FC: 2.7, p=0.01), Periostin (FC: 2.6, p=0.001), Phospholipid transfer protein (FC: 2.2, p=0.0004), Vascular Cell Adhesion Molecule 1 (FC: 2.5, p=0.02) and Angiopoietin-like 4 (FC: 2.8, p=0.01). Histologically, the amount of liver fibrosis remained unaffected, probably due to the short time of the study. Conclusions Short AAA-1 PIP induced enhanced liver steatosis and inflammation accompanied by an elevation of the expression of several pro-fibrotic genes in CDAHFD mice, suggesting that AAA-1 may contribute to the transition from MASLD to MASH. Knowing whether increased exposure time to AAA-1 could lead to end stage disease (including cirrhosis and HCC), and if this could apply to humans as well warrant further investigations.

Potential role of predictive models in assessment of liver inflammation in patients with hepatocellular carcinoma: a two-center cohort study

BackgroundHepatic inflammation in patients with hepatocellular carcinoma (HCC) remains unclear. This study aimed to construct a clinically expedient predictive model to grade hepatic inflammation in HCC patients.MethodsThis is a two-center retrospective cohort study of HCC patients comprising Derivation cohort and External Validation cohort of 1201 and 505 patients, respectively. Variables of liver inflammation identified through uni- and multi-variate logistic regression analyses were incorporated into predictive nomograms and applied to Derivation cohort, subject to internal and external validation.ResultsLiver fibrosis severity score, portal hypertension severity, and model for end-stage liver disease-sodium independently predicted hepatic inflammation grade. Performance for distinguishing G1 and non-G1 (≥ G2) patients was good with C-index of 0.810 and 0.817 in Derivation and External Validation cohort, respectively. The nomogram performed poorly to predict grade G2, G3 and G2 + G3, but performed well to predict G4.ConclusionsOur nomogram exhibited good performance for scaling hepatic inflammation (G1 and G4) in HCC, and could be employed as adjunctive diagnostic tools to guide HCC management strategy.

Nonalcoholic fatty liver disease worsens cardiac repair after myocardial infarction

Abstract Background There is a strong epidemiological link between nonalcoholic fatty liver disease (NAFLD) and ischemic heart disease such as myocardial infarction (MI). Yet, a causal relationship between liver injury and post-MI cardiac repair remains to be established. Purpose NAFLD impairs post-MI myocardial repair processes. In particular, we hypothesized that the pathological liver could transmit deleterious signals shaping the inflammatory reaction in the infarcted milieu. Methods To characterize post-MI cardiac function and remodeling in three mouse models of liver damage mimicking different stages of NAFLD without cardiovascular (CV) risk factors : i) choline-deficient, L-amino-acid-defined, high fat diet (CDA-HFD) causing severe non-alcoholic steatohepatitis; ii) NEMOLPC-KO mice deficient for NF-κB in liver parenchymal cells, exhibiting liver inflammation and fibrosis, but mild steatosis; and ATGLLPC-KO animals deficient for Adipose Triglyceride Lipase in liver parenchymal cells displaying strong steatosis. Results In our three experimental models, liver damages were characterized by inflammation, steatosis and fibrosis but were not associated with metabolic syndrome. More interestingly, left ventricular ejection fraction were reduced by 1.2-fold, 1.3-fold and 1.3-fold in CDA-HFD, NEMOLPC-KO and ATGLLPC-KO male and female mice, respectively when compared to their respective controls, at 35 days post-MI (n=12-25 per group). NAFLD-induced cardiac dysfunction was not associated with worsen cardiac remodeling as infarct size, fibrosis and vascular density were not significantly affected. On the same note, flow cytometry experiments, at 7- and 14-days post-MI, showed no changes in the number or type of inflammatory cells, particularly that of cardiac resident macrophages, in CDAHFD, ATGLLPC-KO and NEMOLPC-KO mice. We next hypothesized that reduced left ventricular function could be induced by altered cardiomyocyte contractility. To corroborate this hypothesis, we isolated cardiomyocytes from hearts of infarcted mice with or without NAFLD and assessed cell contractility using IonOptix technology. Our preliminary results, in the CDAHFD model, showed that there was a reduction in contraction amplitude, defining by the ratio of the difference in sarcomere length during contraction/relaxation to the sarcomere length at the time of relaxation. The speed of contraction and relaxation were also decreased in CDAHFD mice compared with control animals. Conclusions NAFLD favors cardiac dysfunction post-MI. We now aim to identify molecular and cellular entities participating to such pathogenic dialogue between the dysfunctional liver and the infarcted heart.

Early detection of liver fibrosis in patients with Fontan circulation using multiparametric magnetic resonance imaging

Abstract Introduction Fontan procedure (FP), serving as the palliative intervention for complex congenital heart diseases characterized by single-ventricle physiology, precipitates a spectrum of late-stage complications. Fontan-associated liver disease (FALD) encompassing liver fibrosis (LF) which may progress to liver cirrhosis (LC) and thereby hepatocellular carcinoma (HCC) is among the most serious. Despite its importance, optimal surveillance of FALD remains undefined. Multiparametric Liver Multiscan (LMS) with corrected T1 (cT1) value emerges as a novel magnetic resonance (MRI) based non-invasive quantitative tool for liver inflammation and fibrosis evaluation. Aim of this study was to ascertain prevalence and severity of LF utilizing LMS, alongside identifying contributory risk factors for LF in adults post-FP. Material and methods Our cohort included 29 adult patients after FP who underwent LMS. Median age was 25y (20-43y) 54% were females. Liver morphology was assessed by ultrasound (USG) and MRI-based LMS protocol. Hepatic scoring systems, including the Aspartate Aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4) Index, and Model for End-Stage Liver Disease (MELD), were computed. Additionally, presence of fenestrations in the Fontan circulation, hemoglobin levels (Hb), and blood oxygen saturation both at rest and during exercise (SatO2%) were evaluated. Results Median cT1 was 914 (±207) ms, in 87% exceeding normal threshold . In those with elevated cT1, LF was undetected by USG in 38%. LC was identified in 27% of the cohort by USG. LC group exhibited significantly higher cT1 values (P<0.001) compared to non-LC group. cT1 value >933ms was associated with a sensitivity of 89% and a specificity of 80% for diagnosing LC (AUC 0.92). Significant correlation was found between cT1 values and Hb (P=0.01) and desaturation (SatO2 <90%/ interventional closure of fenestration, P=0.004). Conventional liver tests and hepatic scoring systems (APRI/FIB-4/MELD) did not predict cT1 nor LC. Conclusion Our study confirmed that LF is almost widely prevalentamong adult patients with single-chamber circulation. Risk factors for LF are systemic desaturation (SatO2 <90% or interventional closure of fenestration) and polyglobulia. However, reliable FALD surveillance remains challenging. Conventional liver assessments and scoring algorithms fall short in delineating the full scope of LF or LC. Consequently, the integration of non-invasive LMS into routine follow-up regimens is advocated, given its pronounced sensitivity for detecting subclinical FALD manifestations and predicting LC. The LMS-derived cT1 value >933ms is a critical predictor for LC, underscoring its importance in guiding further patient monitoring, treatment, and facilitating early HCC detection.

Supplementation of Chlorogenic Acid Alleviates the Effects of H2O2-Induced Oxidative Stress on Laying Performance, Egg Quality, Antioxidant Capacity, Hepatic Inflammation, Mitochondrial Dysfunction, and Lipid Accumulation in Laying Hens

This research examined the impact of chlorogenic acid (CGA) on laying performance, antioxidant capacity, egg quality, hepatic inflammation, mitochondrial function, and lipid metabolism in hens subjected to hydrogen peroxide (H2O2)-induced oxidative stress (OS). Three hundred sixty healthy 43-wk-old Hy-Line brown hens were randomly assigned to six treatments: a basal diet + 0 (control and H2O2), 600 (600 mg/kg CGA and 600 mg/kg CGA + H2O2), and 800 (800 mg/kg CGA and 800 mg/kg CGA + H2O2) mg/kg CGA for 84 d. On the 64th and 78th days of the trial, hens in groups H2O2, 600 mg/kg CGA + H2O2, and 800 mg/kg CGA + H2O2 were injected intraperitoneally with 10% H2O2. The results demonstrated that 600 and 800 mg/kg CGA significantly improved the egg production rate (EPR) and egg quality and reduced lipid peroxidation compared to the control group. The 800 mg/kg CGA showed greater improvements in the EPR and average egg weight (AEW) compared to the 600 mg/kg dose. Conversely, H2O2 exposure significantly decreased the EPR, AEW, and egg quality and increased feed conversion rate and average daily feed intake. H2O2 exposure significantly decreased serum T-AOC and increased serum MDA levels while reducing hepatic T-SOD, GSH-Px, and CAT activities. Meanwhile, H2O2 exposure significantly elevated liver reactive oxygen species levels, pathological damage, and NF-κB, TNFα, and IL-1β gene expression. Additionally, H2O2 treatment disrupted hepatocyte mitochondrial structure and significantly increased the expression of VDAC1 protein, and IP3R, GRP75, MCU, Fis1, and MFF genes, while downregulating the expression of MFN2 protein and PGC1α gene. Oil Red O staining demonstrated that H2O2 induced significant lipid accumulation in hepatocytes. Concurrently, H2O2 significantly increased serum triglycerides, total cholesterol, and liver triglycerides levels while decreasing serum hepatic lipase activity. This was primarily attributed to the significant upregulation of liver SREBP1, FASN, and ACC genes and the downregulation of the liver CPT1 gene induced by H2O2. Furthermore, CGA pretreatment effectively prevented the degeneration in laying performance and egg quality, as well as OS, liver inflammation, pathological damage, and mitochondrial dysfunction induced by H2O2. CGA inhibited H2O2-induced hepatic lipid accumulation by upregulating fatty acid oxidation-related gene expression and downregulating fatty acid synthesis-related gene expression. These findings indicate that the dietary addition of 800 mg/kg of CGA is the optimum supplementation dose. CGA can enhance laying performance and egg quality while alleviating OS, hepatic inflammation, mitochondrial dysfunction, and lipid accumulation in H2O2-challenged laying hens.

The Effect of Copper Nanoparticles on Liver Metabolism Depends on the Type of Dietary Fiber

Background/Objectives: A diet enriched with copper nanoparticles (CuNPs) exhibits a wide range of effects on liver metabolism, both positive and negative. Dietary fibers are the key components that may affect the absorption of minerals, including copper, and change their impact on organisms. Methods: Therefore, this study investigated whether and how supplementation with different sources of dietary fiber (cellulose, pectin, inulin, and psyllium) affects the function of CuNPs in the liver of male Wistar rats. Results: The results showed that CuNPs at different doses had varying effects on lipid metabolism and inflammation in the liver. Specifically, higher doses of CuNPs were associated with increased lipid accumulation and the activation of pro-inflammatory mechanisms. However, combining CuNPs with dietary fibers, such as psyllium and inulin, was beneficial in mitigating the effects of the examined nanoparticles, leading to reduced fat, cholesterol, and triglycerides in the liver. Combining psyllium with CuNPs showed the most substantial effect on liver metabolism and inflammation parameters. Furthermore, hepatic histology analyses showed that adding psyllium to the diet with CuNPs reduces changes associated with fat accumulation and mononuclear cell infiltration. The observed beneficial changes in the liver may have been related to a reduction in the gene expression level of sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor gamma and cyclooxygenase-2. Conclusions: In conclusion, enriching the diet with dietary fibers such as psyllium can regulate the action of CuNPs, thereby improving lipid metabolism and reducing inflammation in the liver.

Incidence rates of hepatocellular carcinoma based on risk stratification in steatotic liver disease for precision medicine: A real-world longitudinal nationwide study.

Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap. In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies. This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

Nucleos(t)ide analogues potentially activate T lymphocytes through inducing interferon expression in hepatic cells and patients with chronic hepatitis B

Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8+ T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury.

Pueraria Extract Ameliorates Alcoholic Liver Disease via the Liver-Gut-Brain Axis: Focus on Restoring the Intestinal Barrier and Inhibiting Alcohol Metabolism.

Alcoholic liver disease (ALD) is one of the causes of hepatocellular carcinoma, accompanied by intestinal leakage and microbial changes. Pueraria has protective effects on liver injury. The aim of this study was to investigate the mechanism of pueraria in the treatment of ALD. UPLC-Q/TOF-MS was used to analyze the composition of the pueraria extract (PUE). Acute and chronic ALD models were established to evaluate the antialcoholic and hepatoprotective effects of PUE. As a result, PUE treatment reduced the serum levels of ALT, AST, TC, and TG and inflammatory factors and alleviated liver inflammation and drunk state. PUE decreased the gene expression of ADH1 and the serum level of acetaldehyde (ACH) to inhibit the generation of ACH from ethanol metabolism, increased the gene level of ALDH2 to accelerate the decomposition of ACH, and thereby alleviated liver inflammation and intestinal barrier damage. Meanwhile, 16 S rDNA revealed that PUE altered the microbiota composition, reduced the amount of Proteobacteria and Desulfobacterota, and thus inhibited the generation of lipopolysaccharide and its downstream-like TLR4/MyD88/NF-κB pathway. PUE also increased the abundance of Bacteroides, Ruminococcus, and Prevotella and producted short-chain fatty acids to protect the intestinal wall. Treatment with fecal microbiota transplantation further confirmed that PUE gut microbiota dependently alleviated ALD. Therefore, PUE regulated gut microbiota and inhibited ethanol metabolism to alleviate ALD through the liver-gut-brain axis. It has good prospects in the future.

Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

Association of IL-6 G-174C (rs1800795) variant with the susceptibility to hepatocellular carcinoma in patients with chronic hepatitis

AimAn ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 − 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC).Patients and methodsWhole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA).ResultsThe primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively).ConclusionThe rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis.