World Journal of Hepatology最新文献

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abundantly expressed by hepatocytes and regulates the uptake of low-density lipoprotein by these parenchymal cells. Little research has been conducted on PCSK9 expression in non-hepatocyte liver cells.

Aim: To investigate PCSK9 levels in the supernatant of different liver cells and its regulation in hepatic stellate cells (HSCs).

Methods: PCSK9 levels were measured in the cell culture medium of primary human hepatocytes, HepG2 and Huh7 cells, primary human HSCs, the HSC cell line LX-2, primary human Kupffer cells, and primary human sinusoidal endothelial cells. The effects of cytokines, adipokines, lipopolysaccharide, transforming growth factor beta (TGF-β) and ligands of nuclear receptors on PCSK9 levels in LX-2 cells during 24 hours of culture were determined using enzyme-linked immunosorbent assay.

Results: Primary human hepatocytes, HepG2, Huh7, HSCs, and LX-2 cells secreted significant levels of PCSK9. There were low levels of PCSK9 in the supernatant of Kupffer cells and sinusoidal endothelial cells. Interleukin-6 reduced PCSK9 in LX-2 cells to 86% of controls and lipopolysaccharide increased it by 7%, whereas tumor necrosis factor, as well as exogenous adiponectin and leptin had no effect. Chemerin-156, but not chemerin-155 or chemerin-157 isoform overexpressed in LX-2 cells, reduced PCSK9 to 84% of the controls. TGF-β reduced PCSK9 in LX-2 cell culture media to 68% of controls and lowered its cellular level. Activation of liver X receptor but not farnesoid X receptor or peroxisome proliferator-activated receptor gamma, reduced PCSK9 levels by 42% in LX-2 cell culture medium.

Conclusion: Profibrotic TGF-β and the antifibrotic liver X receptor ligand both reduced PCSK9 in LX-2 medium, showing that PCSK9 is not a marker of HSC activation.

Background: The model for end-stage liver disease (MELD) score helps assess the severity of liver disease and can predict survival after liver transplant. The Charlson comorbidity index (CCI) is frequently employed to forecast the 10-year survival probability of patients with multiple health conditions. We employed the CCI to evaluate the impact of comorbid health conditions on patients and assess its predictive capability regarding health complications and mortality following living donor liver transplantation (LDLT).

Aim: To understand the prevalence of extrahepatic comorbidities in our cohort of LDLT patients with modified CCI (mCCI) and to analyze the utility of mCCI as a predictor of morbidity and mortality following LDLT.

Methods: After obtaining institutional ethics committee approval, a retrospective analysis was conducted on 497 adult patients who underwent LDLT at our institute between January 2021 and December 2023.

Results: Our analysis revealed that the area under the curve (AUC) of the original CCI for predicting 90-day mortality decreased when malignancy was assigned a score of 2 in patients with hepatocellular carcinoma undergoing transplantation. Therefore, we used a mCCI. Both MELD and mCCI scores demonstrated predictive value for 90-day mortality, with AUCs of 0.60 and 0.62, respectively. Using regression coefficients, we developed a composite score defined as: Combined score = [mCCI + (MELD/10)]. This composite metric improved predictive accuracy, yielding an AUC of 0.70 for 90-day mortality prediction. Patients with a CCI > 3 and a MELD > 21 had a significantly higher 90-day mortality rate than others (12.5% vs 5.7%; P = 0.02).

Conclusion: The mCCI was independent of decompensation and overall disease severity. Combining MELD and CCI scores enhanced the discriminatory power for predicting morbidity and 90-day mortality.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as non-alcoholic fatty liver disease, is a major cause of end-stage liver disease worldwide. Numerous studies have demonstrated that the liver is predominantly influenced by environmental and lifestyle risk factors that lead to obesity and diabetes, excessive alcohol consumption, and exposure to environmental pollutants. Microplastics (MPs) are a significant global concern, having been detected in human blood, lungs, kidneys, and liver, and may have deleterious effects on these tissues. Although the effects of MP exposure on the liver have only been partially elucidated, further research is necessary to integrate the direct and extrahepatic effects of MPs on the pathogenesis of MASLD. This review offers a comprehensive analysis of the impact of MPs on hepatic metabolism, including their effects on mitochondrial homeostasis and the endocrine system, with potential implications for the progression of MASLD.

Background: Steatotic liver disease (SLD) including metabolic dysfunction-associated SLD is the most prevalent chronic liver disease worldwide and is strongly associated with metabolic dysfunction as well as chronic hepatitis C (CHC).

Aim: To compare the characteristics of patients with CHC virus infection and the treatment with direct-acting antivirals (DAAs), considering the presence of SLD comorbidity.

Methods: The study included all consecutive hepatitis C virus-infected patients treated with pangenotypic DAA regimens at a single tertiary hepatology center in 2018-2024. SLD was diagnosed via abdominal ultrasound.

Results: Among 688 patients included in the study, 290 (42.2%) had comorbid SLD. The highest prevalence (62.3%) was observed in patients infected with genotype 3. The SLD group was predominantly male (62.8%), in contrast to the non-SLD group, where women predominated. Patients with SLD were significantly older (P = 0.0007), had a higher body mass index (P < 0.0001), and more frequently presented with diabetes (P = 0.01), obesity (P < 0.0001), hyperlipidemia (P = 0.004), and a history of alcohol abuse (P < 0.0001). They also had more advanced liver disease as indicated by a higher rate of cirrhosis (35.5% vs 12% in the non-SLD group, P < 0.0001), elevated aminotransferase activity (P < 0.0001), bilirubin concentration (P < 0.0001), and international normalized ratio values (P = 0.0001), and lower albumin concentration (P = 0.0028). While most patients in both groups completed treatment as planned, adverse events, including severe events and deaths, were more frequent in the SLD group. A sustained virologic response was achieved in 97.6% of the overall population but was significantly lower among patients with SLD compared to the non-SLD group (95.6% vs 99.0%, P = 0.0081). However, logistic regression analysis did not identify SLD as an independent predictor of treatment failure.

Conclusion: Comorbid SLD was common among CHC patients treated with DAAs and was associated with adverse baseline characteristics, including older age, higher body mass index, greater comorbidity burden, and more advanced liver disease. Although SLD patients achieved slightly lower rates of sustained virologic response, SLD itself was not an independent predictor of treatment failure. These findings suggest that poorer treatment outcomes in this subgroup are largely attributable to coexisting risk factors rather than SLD per se, highlighting the need for comprehensive management of metabolic and liver-related comorbidities to optimize antiviral therapy outcomes.

Background: Glucocorticoids (GC) are the cornerstone in the treatment of severe alcohol-associated hepatitis (SAH) but may be associated with adverse events.

Case summary: We report a prospective series of patients with SAH who were treated with GC and developed de novo arthropathy within 2 weeks of GC cessation. Five patients were included in this series, three of whom were women. All patients underwent ultrasound evaluation and were referred to the Rheumatology Clinics. Final diagnoses were: Arthralgia associated with GC cessation (n = 3), polymyalgia rheumatica (n = 1) and psoriatic arthritis (n = 1). Joint soreness was the main symptom, whereas arthritis occurred rarely. Patients with arthralgia associated with GC cessation required longer regimes of GC and tapering strategies but remained free of symptoms and specific treatment in the long term.

Conclusion: De novo arthropathy may occur following GC for SAH. Close monitoring and tapering regimes are advised.

Metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic steatohepatitis (ASH) are severe forms of chronic liver disease, characterized by inflammation, oxidative stress, lipid dysregulation, and fibrosis. Epigenetic changes, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and lactylation of histones, dynamically regulate gene expression by altering the chromatin structure. Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases. Lactylation which is a novel post-translational modification (PTM) of histone, has been observed as a crucial contributor to liver physiology as well as pathobiology. This modification, characterized by the addition of lactate to lysine residues on histones, influences gene expression and cellular metabolism in the liver. Intriguingly, elevated lactate levels in the liver, resulting from either chronic alcohol consumption or a high-fat/fructose-rich diet, may promote histone lactylation, particularly at histone 3 at lysine 18 (H3K18), which facilitates the transcription of pro-inflammatory and fibrogenic genes. This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways, resulting in further liver damage. This review aims to elucidate the role of histone lactylation in MASH. Although a direct demonstration of histone lactylation in ASH has not yet been reported, the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis. Finally, we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.

Metabolic dysfunction-associated steatotic liver disease is a multifaceted disease associated with obesity, insulin resistance (IR), type 2 diabetes mellitus - in a word, metabolic syndrome - which has been extensively studied because it is related to an alteration of the normal metabolism of glucose and lipids, ultimately leading to triglyceride accumulation within hepatocytes. This lipid overload triggers an inflammatory status, also influenced by gut-liver axis dysfunction, with gut dysbiosis, which alters intestinal permeability, causing inflammation and IR in a vicious circle. Several approaches have been attempted to treat this condition and stop its possible evolution towards increasingly serious stages, but the first step is always lifestyle modification. The Mediterranean diet seems to be the most reliable for affecting liver steatosis, probably thanks to extra virgin olive oil, a healthy food with a high content of monounsaturated fatty acids and variable concentrations of phenols (oleocanthal) and phenolic alcohols, such as hydroxytyrosol and tyrosol. This review investigates the mechanisms underlying the bidirectional and synergistic relationships among metabolic dysfunction-associated steatotic liver disease, IR, and the gut-liver axis, specifically focusing on the role of extra virgin olive oil as one of the main antioxidant components of the Mediterranean diet.

Background: Inhibition of liver fibrosis plays a crucial role in curbing the advancement of chronic disease to cirrhosis and even liver cancer. However, modern medicine currently lacks direct anti-fibrotic drugs. He-He-Shu-Yang formula (HHSY) is a renowned Chinese medicine for the treatment of liver fibrosis. However, its mechanism of action has not been fully unraveled.

Aim: To explore the efficacy and mechanism of action of HHSY through in vitro and in vivo experiments.

Methods: A liver fibrosis rat model (carbon tetrachloride-induced) was treated with low- or high-dose HHSY (10.42 g/kg or 20.84 g/kg) or with colchicine (1 mg/kg) for 9 weeks. In vitro, LX-2 human hepatic stellate cells (HSCs) were activated using transforming growth factor-β1 and subsequently treated with HHSY-containing serum or a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) inhibitor. Through high-performance liquid chromatography, histopathology (hematoxylin and eosin, Masson), immunohistochemistry, western blot, and quantitative reverse transcription polymerase chain reaction analyses, we demonstrated that HHSY inhibited HSC activation and suppressed the NOX4/reactive oxygen species (ROS)/nucleotide binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) pathway.

Results: In vivo, HHSY improved liver function and alleviated liver pathology, including reducing inflammatory cell infiltration, and liver fibrosis in carbon tetrachloride rats. with more significant effects at higher doses. Immunohistochemistry revealed that HHSY could decrease alpha-smooth muscle actin, NOX4, and NLRP3 expression, as well as serum ROS levels (O₂ ^- and H₂O₂, P < 0.05). Western blot analysis confirmed HHSY also reduced NLRP3 protein levels (P < 0.05). In vitro, HHSY at 1.25% or 2.5% reduced the levels of ACTA2 mRNA, NOX4 protein and NOX4 mRNA, ROS production, and NLRP3 and IL-1β mRNA in activated LX-2 cells (P < 0.05).

Conclusion: HHSY effectively treats liver fibrosis, likely by inhibiting HSC activation through the NOX4/ROS/NLRP3 pathway. This underscores HHSY's clinical relevance as a potential therapeutic option for liver fibrosis.

Background: Xietu Hemu prescription (XHP), a Chinese patent formula, is optimized based on the theory of "phlegm-dampness" and has been clinically validated to effectively combat metabolic dysfunction-associated steatotic liver disease (MASLD). It notably reduces visceral fat and body mass index. However, the molecular mechanisms underlying its regulation of lipid metabolism homeostasis remain unexplored.

Aim: To elucidate the mechanisms by which XHP inhibits adipocyte differentiation and maintains lipid metabolism homeostasis.

Methods: The therapeutic efficacy of XHP in metabolic-related disorders was analyzed using HepG2 cells and 3T3-L1 cells, along with transcriptomics to assess gene expression alterations during white adipogenesis. The primary metabolites of XHP were identified through ultra-performance liquid chromatography, and metabolic pathways were examined via serum metabolomics. Network analysis was employed to predict therapeutic targets. The accumulation of lipid droplets and the expression of associated proteins were confirmed using oil red O staining and Western blotting, respectively. Molecular docking was utilized to identify core targets and signaling pathways, which were substantiated through immunofluorescence and siRNA interference.

Results: XHP-containing serum (XHPS) significantly inhibited the transformation of normal HepG2 cells into fatty liver cells. Concurrently, the treatment suppressed the differentiation of 3T3-L1 cells, reduced lipid droplet accumulation and total cholesterol/triglyceride levels, and downregulated the expression of PPARγ, C/EBPα, and FABP4. Through transcriptomics and network pharmacological intersectionality analyses, 24 core targets were identified, predominantly enriched in the AMPK signaling pathway. Molecular docking validated the strong binding affinity of XHP metabolites to targets such as leptin (-11.3 kcal/mol) and ADIPOQ (-9.4 kcal/mol). ELISA results indicated that XHPS augmented leptin autocrine secretion, thereby activating the AMPK signaling pathway (P < 0.05). Conversely, LEPR knockdown negated this effect (P < 0.05).

Conclusion: XHP effectively inhibits adipogenesis and enhances lipid metabolism homeostasis through the LEP/AMPK/PPARγ pathway, presenting a promising multi-target therapeutic strategy for MASLD by mitigating lipotoxicity.

Background: About 35%-50% of patients with hepatocellular cancer (HCC) present with portal venous tumor thrombosis (PVTT). Stereotactic body radiation therapy (SBRT) offers a promising approach for locoregional treatment in patients with HCC with PVTT. This study aimed to report the clinical characteristics and early outcomes of patients with unresectable HCC and PVTT treated with SBRT.

Aim: To report the clinical characteristics and early outcomes of patients with unresectable HCC and PVTT treated with SBRT.

Methods: This retrospective, single-institution study included adult HCC patients with PVTT treated between March 2020 and December 2023. Eligibility criteria included Child-Pugh A-B liver function, serum bilirubin < 3 mg/dL, Eastern Co-operative Oncology Group performance status 0-2, a normal liver volume > 700 cc, and a tumor-lumen distance > 5 mm. SBRT dose and fractionation were determined based on tumor volume and organ-at-risk constraints. Baseline clinical and dosimetric parameters were recorded. Survival analysis was performed using Kaplan-Meier curves, response was assessed at 3 months post-SBRT using the Revised Response Evaluation Criteria in Solid Tumors 1.1 criteria, and toxicity was graded per Common Terminology Criteria for Adverse Events 4.0.

Results: Thirty patients (median age: 65 years, 90% male) were included. Sixteen (53.3%) were Child-Pugh A, and fourteen (46.6%) were Child-Pugh B. Sixty percent had VP4 disease. SBRT doses ranged from 30-50 Gy in 5-6 fractions. The median tumor diameter was 6.1 cm, and the median follow-up was 15 months. The overall response rate was 83.3%, with a median overall survival of 13 months and progression-free survival of 10.2 months. No grade 4 toxicities were observed.

Conclusion: SBRT has the potential to be an effective modality for locoregional control in patients with unresectable HCC with PVTT.