Annals of hepatology最新文献

Non-alcoholic fatty liver disease (NAFLD), now recognized as metabolic dysfunction-associated steatotic liver disease (MASLD), represents a significant and escalating global health challenge. Its prevalence is intricately linked to obesity, insulin resistance, and other components of the metabolic syndrome. As our comprehension of MASLD deepens, it has become evident that this condition extends beyond the liver, embodying a complex, multi-systemic disease with hepatic manifestations that mirror the broader metabolic landscape. This comprehensive review delves into the critical interplay between the gut-liver axis and oxidative stress, elucidating their pivotal roles in the etiology and progression of MASLD. Our analysis reveals several key findings: (1) Bile acid dysregulation can trigger oxidative stress through enhanced ROS production in hepatocytes and Kupffer cells, leading to mitochondrial dysfunction and lipid peroxidation; (2) Gut microbiota dysbiosis disrupts intestinal barrier function, allowing increased translocation of endotoxins like LPS, which activate inflammatory pathways through TLR4 signaling and promote oxidative stress via NADPH oxidase activation; (3) The redox-sensitive transcription factors NF-κB and Nrf2 serve as crucial mediators in the gut-liver axis, with NF-κB regulating inflammatory responses and Nrf2 orchestrating antioxidant defenses; (4) Oxidative stress-induced damage to intestinal barrier function creates a destructive feedback loop, further exacerbating liver inflammation and disease progression. These findings highlight the complex interrelationship between gut-liver axis dysfunction and oxidative stress in MASLD pathogenesis, suggesting potential therapeutic targets for disease management.

Introduction and objectives: Deregulation of m⁶A methylation, the most prevailing RNA modification, participates in cancer pathogenesis. METTL16, an atypical methyltransferase, functions as a pro-tumorigenic factor in hepatocellular carcinoma (HCC). Here, we explored the action of METTL16 on HCC glycolysis and the associated mechanism.

Materials and methods: Expression analysis was done by quantitative PCR, immunoblotting, or immunohistochemistry. Cell sphere formation, invasiveness, apoptosis, proliferation and viability were detected by sphere formation, transwell, flow cytometry, EdU and CCK-8 assays, respectively. Xenograft studies were performed to analyze the role in vivo. Methylated RNA immunoprecipitation (MeRIP) and RIP assays were used to verify the METTL16/PFKM relationship. PFKM mRNA stability was tested by actinomycin D treatment. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to analyze the POU3F2/METTL16 relationship.

Results: In HCC, METTL16 expression was elevated, and increased levels of METTL16 transcript predicted poor HCC prognosis. METTL16 deficiency resulted in suppressed HCC cell growth, invasiveness and sphere formation. Moreover, METTL16 depletion diminished HCC cell glycolysis. Mechanistically, PFKM expression was positively associated with METTL16 expression. METTL16 mediated m6A methylation to stabilize PFKM mRNA via an IGF2BP3-dependent manner. Restored PFKM expression exerted a counteracting effect on METTL16 deficiency-mediated in vitro cell phenotype alterations and in vivo xenograft growth suppression. Furthermore, POU3F2 promoted the transcription of METTL16 in HCC cells.

Conclusions: Our findings define the crucial role of the POU3F2/METTL16/PFKM axis in HCC pathogenesis, offering the potential opportunity to combat HCC.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) includes liver disease processes from simple fatty liver to nonalcoholic steatohepatitis, which may progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). As the incidence of HCC derived from viral hepatitis decreases, MASLD has emerged as a significant health threat, driven by lifestyle changes and rising obesity rates among patients. The pathogenesis of MASLD is complex, involving factors such as insulin resistance, gut microbiota imbalance, and genetic and epigenetic factors. In recent years, the role of mitochondrial dysfunction in MASLD has gained significant attention, involving β-oxidation imbalance, oxidative stress increase, mitophagy defects, and mitochondrial DNA (mtDNA) mutations. This article reviews the pathophysiological mechanisms of mitochondrial dysfunction in MASLD, diagnostic methods, and potential therapeutic strategies. By synthesizing current research findings, the review aims to highlight the critical role of mitochondrial dysfunction as a target for future diagnostic and therapeutic interventions. This focus could pave the way for innovative clinical strategies, ultimately improving treatment options and patient prognosis in MASLD.

Hepatocellular carcinoma is among the most frequent forms of primary liver cancer and develops within a context of chronic inflammation, frequently associated with a multitude of risk factors, including viral infections, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis and liver fibrosis. The tumor microenvironment is crucial for the progression of HCC, as immune cells, tumor-associated fibroblasts and hepatic stellate cells interact to promote chronic inflammation and tumor spread. Inflammasomes, the multiprotein complexes that launch the innate immune response, emerge as important mediators in the pathogenesis of HCC. Among others, the inflammasome Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 3 (NLRP3), and absent in melanoma 2 (AIM2), exhibit a dual role in HCC background. It has been reported that they can exert oncosuppressive functions by triggering the inflammatory death of cancer cells. Vice versa, chronic activation contributes to the development of a pro-tumorigenic environment, thus supporting tumor growth. In addition, other inflammasomes such as Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 6 and 12 (NLRP6 and NLRP12, respectively) regulate HCC onset and progression, although more experimental evidence is required. This review focuses on the molecular mechanisms underpinning the inflammasome's contribution to the onset, progression and spread of HCC. Moreover, we will explore the potential therapeutic approaches currently under investigation, which aim to improve the efficacy and reduce the side effects of the treatments currently available. Targeting inflammasomes may be a promising therapeutic strategy for the treatment of HCC, offering new opportunities to improve patient prognosis.

Introduction and objectives: With increases in obesity and metabolic syndrome because of lifestyle-related factors, the prevalence of non-alcoholic fatty liver disease (NAFLD) also is increasing worldwide. In a subset of patients with NAFLD, an inflammatory process arises in the steatotic liver, known as non-alcoholic steatohepatitis, that leads to liver fibrosis and liver cirrhosis. In selected patients with obesity, bariatric surgery, and bariatric endoscopy are important therapeutic options.

Materials and methods: This prospective interventional pilot study was conducted to investigate two types of intragastric balloons (IGB). The IGBs were the Orbera and the Spatz3. Liver fibrosis changes were monitored non-invasively using point and 2D shear wave ultrasound elastography (SWE) and transient elastography that allowed for quantification of liver steatosis using the controlled attenuation parameter (CAP). Patients were followed for 12 months.

Results: Of 34 patients implanted with an IGB, 30 completed follow-up at month 12; results for one patient were excluded because of initiation of obesity pharmacotherapy. Fifteen patients received the Orbera IGB, and nineteen patients received the Spatz3 type. In month 12, total and excess weight loss was 7.88 % and 30.13 %. Elastography values decreased from baseline (3.88 kPa) to 3.61 kPa at month 12 (p 0.024). 2D SWE values decreased from baseline (5.42 kPa) to a value of 4.91 kPa at month twelve (p 0.135). Transient elastography values decreased from baseline (5.62 kPa) to a value of 4.17 kPa at month twelve (p 0.009).

Conclusions: Bariatric endoscopy in the form of IGB implantation leads to weight reduction and improvement of liver fibrosis and steatosis.

Clinicaltrials:

Gov registration: NCT04895943.

Introduction and objectives: Advanced fibrosis is a crucial stage in the progression of autoimmune hepatitis (AIH), where fibrosis can either regress or advance. This study aims to leverage machine learning (ML) models for the assessment of advanced liver fibrosis in AIH patients using routine clinical features.

Patients and methods: A total of 233 patients diagnosed with AIH and underwent liver biopsy were included in the discovery cohort. The dataset was randomly split into training and testing sets. Patients were categorized into groups with no/minimal/moderate fibrosis and advanced fibrosis. Six ML models were employed to identify the optimal model. Subsequently, the predictive capability of the best ML model was validated in an additional cohort (n = 33) and compared with conventional noninvasive fibrosis scores.

Results: Three key clinical features, including prothrombin time (PT), albumin (ALB), and ultrasound spleen thickness (UTST), were analyzed by least absolute shrinkage and selection operator (LASSO) regression. In the training set, the random forest (RF) model showed the highest diagnostic performance in predicting advanced fibrosis stage (AUC=0.951). In the testing cohort and validation cohort, the RF model maintained high accuracy (AUC = 0.863 and AUC = 0.843). Additionally, the random forest model outperformed the conventional noninvasive fibrosis scores.

Conclusions: ML models, particularly the RF model, can help improve the discrimination of advanced liver fibrosis in patients with AIH.

Introduction and objectives: Tumor-associated macrophages (TAM) can influence both cancer growth and chemoresistance, but the specific mechanisms involved in these processes in cholangiocarcinoma (CCA) are unclear.

Materials and methods: We explored the distribution of TAM in CCA samples by multiplex immunofluorescence staining and tested the effects of TAM on CCA in vitro and in vivo. We then investigated the mechanisms underlying these effects using the Luminex assay, RNA sequencing, western blotting, flow cytometry, and co-immunoprecipitation.

Results: The infiltration of TAM was strongly increased in the cholangiocarcinoma tumor microenvironment. Oncostain M (OSM) secreted by TAM increased the proliferation and chemotherapeutic resistance of CCA cells both in vitro and in vivo. The results of transcriptome sequencing analysis, Western blot analysis, and immunofluorescence staining confirmed that OSM can promote Yap nuclear translocation and its subsequent formation of complexes with SMADs to upregulate the expression of inhibitor of DNA binding 1 (ID1).

Conclusions: TAM promotes CCA progression and chemoresistance through activating OSM-Yap-ID1.

Introduction and objectives: The short-term mortality of severe alcoholic hepatitis (SAH) is high, but there are no effective treatments to improve short-term mortality other than corticosteroids. This study investigated the effects of adding rifaximin to standard treatment in patients with SAH.

Material and methods: In this randomized controlled open-label trial, patients with SAH (Maddrey's discriminant function≥32) were randomized to the rifaximin or control group. Patients were simultaneously treated with corticosteroid or pentoxifylline as standard treatment for 4 weeks. Randomization was stratified by SAH treatment.

Results: A total of 49 patients were enrolled in this study (29 in the control group and 20 in the rifaximin group). The mean Model for End-stage Liver Disease (MELD) scores were 24.4 and 27.8 in the control and rifaximin groups, respectively (P = 0.083). There were no significant differences in 6-month Liver Transplantation (LT)-free survival rate between the two groups (P = 0.698). When stratified by SAH treatment, there was no significant difference in 6-month LT-free survival rate between the control and rifaximin treatment groups (P = 0.526 in the corticosteroid group and P = 0.620 in the pentoxifylline group). There were no significant differences in the occurrence of liver-related complications between the two groups (all Ps>0.05). The MELD score was the only independent factor for 6-month LT-free survival (hazard ratio 1.360, 95 % confidence interval 1.021-1.810, P = 0.035), and rifaximin was not.

Conclusions: In patients with SAH, adding rifaximin to corticosteroid or pentoxifylline had no survival benefit and no preventive effect on the development of liver-related complications. The MELD score was the only significant factor for short-term mortality.