Hepatic Medicine : Evidence and Research最新文献

Introduction: This paper reviews the regulatory effects of hydrogen sulfide (H₂S) in non-alcoholic fatty liver disease (NAFLD). The research background indicates that NAFLD has become one of the most common chronic liver diseases worldwide, with a complex pathogenesis involving insulin resistance and lipid metabolism disorders. Hydrogen sulfide, as an important gaseous signaling molecule, exerts protective effects in NAFLD through multiple pathways, including antioxidant, anti-inflammatory, lipid metabolism regulation, apoptosis inhibition, and insulin resistance improvement. This article provides a detailed summary of the research overview of NAFLD, the biological characteristics of hydrogen sulfide, its mechanisms of action in NAFLD, empirical studies, and evaluates and prospects current research, aiming to provide a new theoretical basis and experimental support for the treatment of NAFLD.

Purpose: This literature review aims to systematically synthesize the regulatory roles of hydrogen sulfide (H₂S) in non-alcoholic fatty liver disease (NAFLD). It provides a comprehensive overview of NAFLD research, the biological characteristics of H₂S, the mechanisms underlying H₂S's action in NAFLD, and relevant empirical studies. Additionally, the review evaluates the current state of research and prospects future directions, with the goal of offering novel theoretical foundations and experimental support for NAFLD treatment.

Patients and methods: It adopts a comprehensive literature analysis approach. Analyze literature on NAFLD pathogenesis, H₂S (synthesis/function), and NAFLD treatments (in vitro, animal models, clinical studies).

Results: NAFLD links to insulin resistance/inflammation; H₂S protects against NAFLD by mitigating inflammation, oxidative stress, and lipid accumulation, while improving insulin sensitivity and inhibiting apoptosis. However, its precise mechanisms, stage-specific effects, and therapeutic safety require further clinical validation.

Conclusion: Hydrogen sulfide (H₂S), a gaseous signal, exerts multi-mechanistic protective effects in NAFLD. Current limitations include unclear signaling mechanisms and lack of targeted delivery systems. Future research should focus on stage-specific mechanisms, optimized H₂S donors, and combination therapies for NAFLD treatment.

Background: Liver enzyme abnormalities are early indicators of hepatic dysfunction and are increasingly observed in individuals with non-communicable diseases (NCDs). Globally, liver diseases cause approximately 2 million deaths every year (≈4% of all deaths). In Rwanda, data on liver health and its gender-based stratification among adults with NCDs are scarce. This study assessed the prevalence and gender-specific patterns of liver enzyme abnormalities in this population to inform targeted interventions.

Methods: A descriptive cross-sectional study was conducted at the NCD outpatient clinic of the University Teaching Hospital of Butare (CHUB), involving 185 adult patients with documented NCDs. A structured and pretested questionnaire was used to collect sociodemographic, behavioral, and clinical data. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) were measured using the HumaLyzer 3500 semi-automated analyzer. Gender-stratified analyses were performed to assess prevalence and clustering of liver enzyme abnormalities.

Results: Out of the 185 participants, liver enzyme abnormalities were observed in 51 (27.6%), with isolated GGT elevation being the most common pattern (18, 9.7%). Females exhibited significantly higher De Ritis ratios with median = 1.04, interquartile range (IQR) = 0.83-1.4, p = 0.019. Females showed relatively elevated GGT levels, possibly linked to non-alcoholic fatty liver disease or environmental exposures.

Conclusion: Liver enzyme abnormalities are prevalent among older Rwandan adults with NCDs, with gender and occupational disparities. These findings underscore the need to integrate liver health into NCD care strategies in Rwanda.

Background and purpose: Metabolic dysfunction-associated steatotic liver disease (MASLD), affecting between 20% and 30% of adults around the world, represents a growing public health burden characterized by hepatic steatosis concurrent with cardiometabolic risk factors. Despite two decades of research into its pathophysiology - spanning insulin resistance, gut-liver axis dysregulation, and genetic/epigenetic mechanisms - the vast body of literature has not yet been systematically mapped. A comprehensive bibliometric analysis mapping the field's evolution, collaborative networks, and knowledge gaps remains lacking. Therefore, a 20-year bibliometric analysis (2005-2024) on the mechanism of MASLD was conducted.

Patients and methods: Publications on the mechanisms of MASLD were retrieved from the Web of Science Core Collection. The search period spanned from January 1st, 2005 to December 31st, 2024. Data were analyzed with CiteSpace (v6.3.R1) and VOSviewer (v1.6.20) to assess publication trends, country/institution contributions, journal influence, author networks, keyword clusters, and reference co-citations.

Results: China (40.75% of publications, n=4368) and the USA (21.18%, n=2270) dominate research output, with the Chinese Ministry of Education, Shanghai Jiao Tong University, and Harvard University as top institutions. International collaboration is prominent, particularly between China and the USA. International Journal of Molecular Sciences, Nutrients, and high-impact journals (Journal of Hepatology, IF=33.0) are key publication venues. Keyword analysis identifies five major research clusters: (1) lipid metabolism/mitochondrial dysfunction, (2) dietary factors/exercise, (3) inflammation/fibrosis, (4) metabolic comorbidities, and (5) gut-liver axis dysregulation. Temporal trends reveal a shift from insulin resistance/oxidative stress toward microbiota and molecular drivers (eg, WDR6-PPP1CB). Influential authors include Nobili Valerio (most productive) and Gerald I. Shulman (most cited; n=7703). Reference bursts highlight seminal works on disease burden (Younossi 2016) and pathogenesis (Powell 2021, Friedman 2018).

Conclusion: This first comprehensive bibliometric analysis of MASLD mechanisms highlights dynamic growth, interdisciplinary collaboration, and evolving research hotspot. Persistent challenges include mechanistic heterogeneity, early diagnostic tools, and targeted therapies. In conclusion, this analysis provides a foundational roadmap for researchers and policymakers, highlighting the imperative to translate mechanistic insights into precision diagnostics and therapies to mitigate the growing global burden of MASLD.

Introduction: Xenotransplantation has advanced through porcine genetic modifications to enhance graft survival and immunological compatibility. More recently, generating of exogenic organs from recipient-derived stem cells via blastocyst complementation has emerged as a promising strategy to achieve graft-specific tolerance and reduce dependence on long-term immunosuppression. However, ischemia-reperfusion-injury (IRI) during organ donation and transplantation activates inflammatory and innate immune pathways that compromise graft function and survival. To better understand the immunological response following interspecies transplantation, we compared xeno-adaptive and acute inflammatory responses between mouse-to-rat heterotopic liver transplants and rat allotransplants. This model will serve as baseline parameters for future studies of anti-inflammatory mechanisms to mitigate IRI, especially while testing exogenic livers.

Methods: Livers from retired breeder male C57BL/6 mice were heterotopically transplanted into retired breeder male Lewis rats. After 90 minutes of reperfusion, transplanted liver, recipient blood and spleen were recovered for immune and inflammatory analyses. As a control to xenografts, Sprague Dawley donor livers were transplanted into Lewis recipients to represent a clinically relevant allotransplant model. Plasma cytokine and chemokine levels were quantified, and mixed leukocyte reactions (MLR) were performed to assess CD4⁺ and CD8⁺ T cell proliferation.

Results: Xenografts exhibited elevated plasma levels of IL-2 (p = 0.04), IL-10 (p < 0.01), IL-13 (p = 0.01), IL-17A (p < 0.01) TNF-a (p < 0.05), and RANTES (p < 0.05) compared with naïve controls. Although xenografts demonstrated higher levels after transplant, they were not statistically distinct to allotransplant results. MLR assays revealed significantly increased CD8⁺ T cell proliferation (p = 0.01) when rat splenocytes were stimulated with mouse non-parenchymal liver cells, whereas CD4⁺ T cell proliferation was not significant in either model.

Discussion: Although xenograft induced heightened inflammatory and adaptive responses, these were comparable to allotransplants. For successful exogenic organ transplantation without maintenance immunosuppression, future strategies must focus on mitigating reperfusion-induced systemic inflammation to improve graft tolerance and survival.

Background: Recent studies suggest that impaired mitophagy leading to epithelial-mesenchymal transition (EMT) in hepatocytes plays a major role in the progression of hepatic fibrosis (HF). The authors' previous study demonstrated that aldose reductase (AR) promotes radiation-induced EMT in alveolar epithelial cells. This study aims to examine whether AR influences EMT in hepatocytes by regulating defective mitophagy.

Methods: Some histological techniques, including HE staining, Masson's trichrome staining, immunohistochemistry, and transmission electron microscopy, were employed to validate the model and examine mitochondrial injury. Subsequently, EMT was induced in hepatocytes through TGF-β1 treatment. Then experiments such as siRNA-mediated gene silencing, AR inhibition, and AR overexpression were performed. Finally, the activation status of AKT and mTOR, as well as the expression levels of proteins associated with mitophagy and EMT, were evaluated using RT-qPCR, immunofluorescence staining, and Western blotting.

Results: AR knockout significantly reduced AKT and mTOR phosphorylation In vivo but increased the expression of Pink1 and Parkin in CCl₄-exposed liver tissues. This was associated with an increased LC3 II/I expression ratio, decreased p62 expression, reduced mitochondrial damage, enhanced E-cadherin expression, and diminished Snail, α-SMA, and vimentin expression, which collectively alleviated HF. In vitro experiments revealed that AR knockdown significantly attenuated the activation of the TGF-β1-induced AKT/mTOR pathway, restored mitochondrial autophagy function, decreased ROS levels, increased mitochondrial membrane potential (MMP) and ATP production, and reversed EMT in hepatocytes via siRNA or pharmacological inhibition. Conversely, AR overexpression exacerbated the activation of the TGF-β1-induced AKT/mTOR pathway, impaired mitophagy efficiency, increased ROS levels, decreased MMP and ATP levels, and facilitated EMT process.

Conclusion: The study findings demonstrated that AR facilitates EMT in hepatocytes and plays a major role in enhancing HF. This process may be linked to AR-induced activation of the AKT/mTOR. Consequently, this activation suppresses the expression of Pink1 and Parkin, ultimately reducing the risk of mitophagy in hepatocytes.

Background: The known major causes of chronic liver diseases (CLDs) include, hepatitis B virus (HBV) and hepatitis C virus (HCV); however, there is scarcity of data regarding their seroprevalence in Tanzania. We aimed to evaluate the seroprevalence of HBsAg and anti-HCV and their predictors among patients with CLDs. Additionally, we also described the clinical patterns of the patients.

Methods: A cross-sectional analytical study design was carried at the two referral public hospitals in Dodoma region; Dodoma referral regional hospital (DRRH) and Benjamin Mkapa hospital (BMH) among 118 patients with CLDs. Rapid test immunochromatography was used to test for HBsAg whereas anti-HCV antibody positivity was tested using lateral flow chromatographic immunoassay. Multivariable binary logistic regression was used to evaluate the predictors of HbsAg positive results, and statistical significance was set at p˂0.05.

Results: The seroprevalence of HBsAg and anti-HCV antibody was 28% (33/118) and 3.4% (4/118), respectively. Having a chronic illness (AOR = 2.3, 95% CI = 1.76-7.19, p = 0.041), raised level of alanine transaminase (ALT) (AOR = 3.6, 95% CI = 1.74-8.21, p = 0.025), increased AST/ALT ratio (AOR = 2.9, 95% CI = 2.57-11.57, p = 0.039), and increased level of total bilirubin (AOR = 5.1, 95% CI = 1.09-24.39, p = 0.039) remained the predictors of HBsAg positivity.

Conclusion: This study reports that almost one-third of the study subjects had positive HbsAg, and the positivity of anti-HCV antibody was quite low. The positivity of HbsAg was associated with having chronic illness, increased levels of ALT, total bilirubin, and AST/ALT ratio. Therefore, emphasis should be made to maximize the screening practices for individuals with such predictors due to high possibility of being infected with HBV.

Purpose: Hepatic encephalopathy (HE), one of the more important cerebral complications attributable to acute liver failure and more severe forms, has traditionally been associated with hyperammonemia. However, recent studies implicate gut microbiota-derived metabolites in HE pathogenesis through systemic inflammation and neurotoxicity. Despite this, the integrated molecular mechanisms linking these metabolites to HE remains poorly described. This study addresses this gap by employing a bioinformatics-based systems biology approach to identify interactions between gut metabolites and host genes, thereby identifying novel diagnostic and therapeutic targets.

Methods: Differentially expressed genes (DEGs) from peripheral (GSE184200: CD4⁺ T lymphocytes) and central (GSE57193: fusiform gyrus) tissues of HE patients were analyzed using GEO2R. Genes associated with five gut microbiota-derived metabolites including choline metabolites, lipid metabolites, short-chain fatty acids, tryptophan catabolites, and secondary bile acids were extracted from GeneCards. Overlapping genes between HE-related genes and gut-derived metabolites were then subjected to multi-level enrichment analyses (pathway, phenotype, cell type, and cellular component), and miRNA/drug prediction using Enrichr and ToppGene.

Results: We identified nine hub genes related to gut-systemic interactions and 29 hub genes associated with gut-brain interactions in the context of HE. The most significantly impaired pathways were signaling by interleukin 24 and TP53, as well as oxidative stress, which were affected by gut metabolites and peripheral HE-related genes. Similarly, mitochondrial fatty acid β-oxidation, neuroinflammation, and glutamate tone were significantly altered by gut metabolites and central HE-related genes. Additionally, we predicted 18 miRNAs and 13 potential drugs that target both gut microbiota metabolites and HE.

Conclusion: This study offers the first systems-level framework connecting gut-derived metabolites to HE through gene networks, challenging the ammonia-centric viewpoint. The predicted miRNAs and drugs offer translational potential for precision medicine in HE. Experimental validation of these targets is required to advance therapeutic strategies.

Purpose: Liver stiffness (LS) assesses liver fibrosis, while spleen stiffness (SS) is a promising marker for portal hypertension (PH), reflecting blood flow and vascular resistance. However, the response of LS and SS to vasoactive drugs is unclear. This study evaluates the effects of various PH-lowering drugs on LS and SS in a rat cirrhosis model.

Patients and methods: In this study, cirrhosis was induced in 43 male Wistar rats (8 weeks old) via intraperitoneal thioacetamide (TAA) injections (200 mg/kg, twice weekly for six weeks). Rats were divided into six groups: control (sodium chloride), metoprolol, udenafil, enalapril, terlipressin, and carvedilol. LS and SS were measured using μFibroscan. Mean arterial pressure (MAP), heart rate (HR), and portal vein pressure (PVP) were continuously monitored. Drugs were administered systemically, with data collected at 0, 15, and 30 minutes.

Results: TAA-treated rats exhibited significantly higher LS and SS compared to controls (22.1 vs 4.2 kPa and 53.7 vs 27.7 kPa; P < 0.001). Changes in LS and SS correlated with PVP (r = 0.670 for LS and r = 0.867 for SS; P < 0.01). Metoprolol, udenafil, enalapril, and carvedilol significantly reduced PVP (22-34%, P < 0.05), accompanied by decreases in LS and SS (13-37%, P < 0.05). Terlipressin did not reduce LS or SS, likely due to opposing effects of increased MAP and reduced PVP.

Conclusion: In conclusion, combined LS and SS measurements may provide valuable non-invasive insights into patient responses and adherence to PH-lowering therapies.

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over 30% of the global population. It is a multisystem condition with a strong association with cardiovascular disease (CVD), the leading cause of mortality worldwide. Key shared mechanisms, including insulin resistance, systemic inflammation, oxidative stress, and genetic predisposition, couple MAFLD with increased risks of coronary artery disease, ischemic heart disease, and heart failure. Early detection via non-invasive imaging and biomarkers is crucial for effective risk stratification. Management strategies emphasize lifestyle modifications and the development of targeted pharmacotherapies addressing metabolic and inflammatory pathways. Understanding the interconnected pathogenic mechanisms facilitates personalized interventions to reduce morbidity and improve long-term outcomes. A multidisciplinary approach remains essential to prevent and manage the cardiovascular implications of MAFLD.

Purpose: Metabolic dysfunction-associated fatty liver disease (MAFLD) is considered a major global health concern. Considering the preliminary trend of hepatoprotective function of Liv.52 DS, the present study was conducted to explore its role in MAFLD.

Patients and methods: This randomized, double-blind, placebo-controlled, prospective, multicenter study was performed at four tertiary care hospitals in India. A total of 52 randomized subjects were administered either Liv.52 DS or placebo tablets twice daily for six months. Liver Stiffness Measurement (LSM) and Controlled Attenuated Parameter (CAP) values were compared at baseline and 6 months. After completion of the study, data from 47 subjects were available for analysis (31 in the Liv.52 DS group and 16 in the placebo group).

Results: The mean LSM score, was reduced from 7.3 to 6.0 (Change From Baseline = 17.5%) in the active group with statistically significance (p = 0.007) compared to placebo group with LSM score reduction from 7.5 to 6.9 (CFB = 7.29%). A shift in the mean value from fibrosis (>6.0 kPa) to almost no significant fibrosis (<6.0 kPa), as per the Indian National Association for the Study of the Liver (INASL) cutoff, was achieved in the Liv.52 DS Group. Improvement was also observed in CAP values with Liv.52 DS, where 71% of the subjects showed an overall improvement in steatosis grade. The other liver markers like alanine transaminase (ALT) and aspartate aminotransferase (AST) were within the normal range. There were no cases of nephrotoxicity (common concern for herbal formulation), and no drug-related adverse events were reported.

Conclusion: A significant improvement in LSM and improvement in CAP was observed after 6 months of treatment with Liv.52 DS using fibroscan. This suggests that Liv.52 DS should be further explored for its potential role in the treatment of unmet medical needs in MAFLD patients.