Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC), which is the predominant liver cancer type in Southeast Asia. Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide. HBV promotes HCC development through direct and indirect mechanisms. HBV DNA integrates into the host genome during the initial stages of tumorigenesis, causing insertional mutagenesis of cancer-related genes and genomic instability. Extrachromosomal circular DNA (ecDNA) is formed, which is efficiently amplified in large quantities to express viral genes and host oncogenes. Moreover, virus-associated proteins, such as the regulatory HBV X (HBx) protein and/or the modified preS/S envelope protein, alter the expression of genes associated with multiple functions in host cells. In this review, we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis. In addition to summarizing the specific mechanism of HBV-related tumorigenesis, the concerns and perspectives for future study are discussed.
The critical shortage of liver transplant donors necessitates innovative solutions, with xenotransplantation emerging as a promising alternative. Despite significant ethical, scientific, and practical challenges, recent advancements in liver xenotransplantation, particularly using pigs as donors for non-human primates (NHPs), have extended graft survival duration. However, life-threatening issues such as thrombocytopenia and coagulation disorders persist, limiting survival to under a month. Advances in genetic engineering have enabled the modification of pig genomes to match the human immune system better, targeting genes responsible for immune rejection and increasing compatibility. While these breakthroughs enhance the potential for human transplantation, the challenges of immune rejection and long-term functionality remain substantial. This review highlights recent progress in liver xenotransplantation from pigs to NHPs and explores the implications for potential human clinical application.
Background and aims: Liver fibrosis is a prevalent pathological stage of various chronic liver diseases and has the potential to progress to liver cirrhosis and hepatocellular carcinoma. However, experimental models for in vivo research are limited. Unexpectedly, increased liver inflammation and fibrosis were previously observed in mice treated with aluminum adjuvant (commercial Imject Alum, a mixture of Al(OH)3 and Mg(OH)2). Our study aimed to reveal the pathogenesis and pathological features of Imject Alum-induced liver injury and evaluate its potential as an experimental model of fibrotic liver disease.
Methods and materials: C57BL/6J mice were randomly divided into the following four groups: (i) control group, which received phosphate-buffered saline injections on days 1, 12, 26, 40, and 54; (ii) Imject Alum (Al(OH)3 160 mg/kg) D26 group, which was administered with Imject Alum (Al(OH)3 160 mg/kg) on days 1, 12, and 26; (iii) Imject Alum (Al(OH)3 80 mg/kg) D54; and (iv) Imject Alum (Al(OH)3 160 mg/kg) D54 groups, which were treated with 80 mg/kg and 160 mg/kg of Imject Alum (Al(OH)3), respectively, on days 1, 12, 26, 40, and 54. All reagents were delivered by intraperitoneal injection. Serum biochemical parameters, liver pathology, and expression of genes related to inflammation and fibrogenesis were evaluated. Transcriptome sequencing was performed. The genetic characteristics of the Imject Alum-induced liver lesions in the existing fibrosis model and patients with cirrhosis were determined.
Results: Administration of Imject Alum (Al(OH)3 160 mg/kg) at certain points for 54 days led to extensive hepatic inflammation and fibrosis, accompanied by disturbed bile acid metabolism in mice. Moreover, Imject Alum aggravated liver inflammation and injury by activating the pyroptosis-related inflammasome pathway. Transcriptome analysis revealed that Imject Alum-induced liver lesions had differentially expressed genes that were significantly enriched in pathways related to inflammation, fibrogenesis, and multiple metabolic processes. Moreover, Imject Alum-induced liver lesions exhibited gene signatures similar to those of existing fibrosis models and patients with cirrhosis.
Conclusions: Aluminum adjuvant (Imject Alum; Al(OH)3 160 mg/kg) administration at certain points for 54 days resulted in notable liver injury, inflammation, and fibrosis. This model had similar gene expression characteristics with existing fibrosis models and liver samples from patients with cirrhosis. Overall, aluminum adjuvant (Imject Alum)-induced mouse model may be a novel approach for establishing a liver fibrosis animal model.
Background and aims: Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors (ICIs) to increased allograft rejection risk after livertransplantation (LT), a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists. This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.
Methods: This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma (HCC) between June 2019 and March 2023. The recipients were categorized into ICI (n = 35) and non-ICI (n = 86) exposure groups based on pretransplant ICI exposure. Demographics, clinical characteristics, and short-term outcomes were compared between the cohorts. Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival. Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.
Results: Recipients with or without ICI exposure exhibited comparable demographic baseline characteristics. The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups. Post-transplant infection incidence was 37.1% and 20.9% in the ICI and non-ICI groups, respectively (P = 0.064). Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group (22.9% vs. 5.8%, P = 0.015). The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group (14.3% vs. 2.3%, P = 0.034). Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality, with ICI exposure being an independent risk factor for allograft rejection. In recipients with ICI exposure, a shorter interval between ICIs and LT (washout period) was significantly associated with a higher allograft rejection risk, with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival (P = 0.0001). Moreover, in recipients with allograft rejection, the peripheral CD4+/CD8+ T cell ratio was much lower in the ICI group than in the non-ICI group.
Conclusions: Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC. A ≤21-day washout period was significantly associated with allograft rejection. Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings, confirm causality, and establish standardized clinical guidelines for ICI use before transplantation.
Background and aims: Noninvasive assessments play a crucial role in ruling out high-risk esophageal varices (HREV) in cirrhotic patients. However, the value of sound touch elastography (STE) in predicting HREV has not been comprehensively investigated. Therefore, this study aimed to establish prediction models based on liver and spleen stiffness measurements obtained by STE and provide assessment strategies and cutoff values tailored for different clinical situations.
Methods: This prospective study included cirrhotic patients who underwent esophagogastroduodenoscopy (EGD). Liver and spleen stiffness measurements by STE were performed within six months of EGD examination. Various prediction models and their corresponding cutoff values were established for different clinical situations, incorporating spleen diameter and laboratory parameters.
Results: A total of 154 cirrhotic patients were included in the study and stratified into training (n = 119) and validation (n = 35) sets. Multivariable analysis revealed platelet, spleen diameter and spleen stiffness measurement as independent predictors of HREV. The model incorporating spleen stiffness measurement, platelet, and spleen diameter demonstrated superior performance in predicting HREV, yielding an area under the receiver operating characteristic curve (AUC) of 0.878 and 0.853 in the training set and validation set, respectively. Application of this model for screening cirrhotic patients could avoid EGDs in 39.7% (27/68) and 35.3% (6/17) of patients in the training and validation sets, respectively.
Conclusions: Liver and spleen stiffness measurements obtained through STE are valuable for predicting HREV in cirrhotic patients. The developed prediction models and their corresponding cutoff values provide tailored solutions for various clinical situations, thereby effectively reducing the need for unnecessary endoscopies.
Background and aims: Primary sclerosing cholangitis (PSC) is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options. The mechanisms underlying the development and progression of PSCs remain unclear. Liver X receptor beta (LXR-β) is recognized to modulate lipid metabolism and immune response, but its specific involvement in the PSC has not been elucidated. Here, we explored the role and mechanism of LXR-β in PSC induced by 3, 5-diethoxycarbonyl-1, 4-dihydro-2, 4, 6-collidine (DDC).
Methods: CRISPR-Cas9 technology was applied to generate Abcb4 (coding MDR2, next named as Mdr2), Nr1h2 (coding LXR-β, next named as Lxrβ), and Rag2 (coding RAG2) knockout mice. DDC was used to induce PSC. Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis. Flow cytometry was used to observe immune cell subsets.
Results: We observed a declining trend in hepatic Lxrβ in the PSC model. Unexpectedly, Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis. Concomitantly, assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/- DDC mice. However, Lxrβ depletion intensified DDC-induced PSC in the Rag2-/- mice, with more abundant infiltrative inflammatory cells and more severe liver fibrosis. Compared with Rag2-/- DDC mice, Lxrβ-/-Rag2-/- DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes. Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.
Conclusion: This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.