Hepatology Communications最新文献

Background: Immune checkpoint inhibitors combined with antiangiogenic therapy have become the standard of care for advanced HCC, albeit with limited therapeutic benefit. Our previous studies demonstrated the immunomodulatory and antitumor effects of polyIC, a synthetic dsRNA. Here, we compared the efficacy of anti-programmed death ligand 1 (αPD-L1) plus polyIC versus αPD-L1 plus anti-vascular endothelial growth factor (αVEGF) in mouse tumor models.

Methods: We established a primary liver tumor model using hydrodynamic tail vein injection of Ras/Myc oncogenes and a metastasized tumor model via intrasplenic injection of colon cancer cells. Flow cytometry and gene expression analysis were performed to assess immune profiles across treatment groups. Key factors contributing to antitumor efficacy were explored.

Results: In both models, αPD-L1 plus polyIC demonstrated superior antitumor effects relative to αPD-L1 plus αVEGF. Unlike αVEGF, polyIC enhanced the immune response to αPD-L1 by increasing T cell infiltration, T effector memory CD8+ T cells, CD8+ to CD4+ T cell ratio, and CD8+ T cell function. This combination also promoted apoptosis in tumors and the accumulation of conventional dendritic cells and invariant natural killer T cells. In addition, αPD-L1 plus polyIC treatment led to upregulation of cytokines and chemokines, with CCL5 blockade partially reducing the CD8+ to CD4+ T cell ratio and attenuating polyIC-driven antitumor effects.

Conclusions: This preclinical study identifies polyIC as an efficacious adjuvant of αPD-L1 treatment in liver cancer, providing a better strategy to improve immunotherapy outcomes.

Background: Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established.

Methods: Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks.

Results: We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function.

Conclusions: KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.

Background: The urea cycle and pyrimidine synthesis occur mainly in the liver and undergo opposite changes during hepatocarcinogenesis. Argininosuccinate synthase 1 (ASS1) and carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are key enzymes in the urea cycle and pyrimidine synthesis, respectively, and compete for the common substrate, aspartate. Moreover, ASS1 is lowly expressed in certain cancers, while CAD is highly expressed. However, the role of ASS1 and CAD in liver cancer still remains unclear.

Methods: ASS1 and CAD expression in liver cancer were detected by tissue microarrays. Overexpression of ASS1 and CAD was achieved via lentivirus methods. All in vitro experiments were conducted in cells. The interactions of ASS1 and CAD were detected by co-immunoprecipitation (Co-IP) and GST-pull down. The in vivo study was conducted in a BALB/c nude mouse model. Intracellular metabolites were detected by LC-MS/MS.

Results: ASS1 was lowly expressed in liver cancer, while CAD was highly expressed. In patients with recurrent liver cancer, ASS1 and CAD were significantly negatively correlated. Moreover, liver cancer patients with low ASS1 expression and high CAD expression had a poor prognosis. ASS1 and CAD interacted directly and promoted CAD ubiquitination through STUB1. In addition, Overexpression of CAD attenuated the tumor-suppressive effect of ASS1 in liver cancer cells. Pyrimidine supplementation enhanced the growth of liver cancer cells with ASS1 overexpression.

Conclusions: ASS1 deficiency causes an imbalance in the urea cycle and pyrimidine synthesis in liver cancer. ASS1 directly controls the ubiquitination of CAD via STUB1, rather than just competing with aspartate, thereby suppressing liver cancer. Thus, ASS1 has potential as a druggable target in liver cancer.

Background: Sarcopenia, assessed by psoas muscle CT or MRI, predicts adverse outcomes in adults with advanced chronic liver disease (CLD). However, these radiologic techniques are understudied in children. Ultrasound (US) measures of leg muscle quality and quantity potentially offer a novel, safe, and practical means to assess sarcopenia in pediatric patients.

Methods: We prospectively enrolled pediatric patients (age ≤18) with and without CLD. US of the rectus femoris muscle was performed in triplicate for cross-sectional area (CSA), muscle thickness (MT), echogenic intensity (EI), and fascicle length (FL, calculated). Muscle measures were assessed for intra-rater reliability by intraclass correlation coefficients (ICC) and association with CLD, PELD/MELD, and body mass index (BMI) z-score using logistic regression, linear regression, and Pearson correlation, respectively.

Results: Among 156 participants (N=69 CLD, N=85 healthy), reliability was excellent for CSA, MT, and EI, with ICC ranging from 0.946 (95% CI 0.929-0.959) for EI-right to 0.998 (95% CI 0.998-0.999) for CSA-left, and good for FL (right 0.823, 95% CI 0.769-0.866; left 0.768, 95% CI 0.698-0.825). In age-adjusted and sex-adjusted logistic regression, CLD likelihood decreased with increasing MT and FL (per unit increase: OR=0.82, 95% CI 0.71-0.96; OR=0.99, 95% CI 0.97-0.99) and CLD likelihood increased with increasing EI (OR=1.04, 95% CI 1.01-1.08) for right-side measures (but not left-side). Among CLD, all muscle measures, except EI, were positively correlated with BMI z-score and negatively associated with PELD/MELD score after age-adjustment and sex-adjustment.

Conclusions: Pediatric ultrasound of the rectus femoris muscle demonstrates excellent intra-rater reliability, correlates with measures of malnutrition (BMI) and distinguishes CLD from healthy participants. This may offer a novel tool for assessing sarcopenia and liver disease severity in pediatric CLD.

Background: Strategies to identify patients with early alcohol-associated liver disease (ALD), prior to the development of liver-related decompensated events, and promote alcohol therapy engagement in these patients are urgently needed to stem the rising tide of mortality associated with ALD.

Methods: We compared the rate of incident liver-related decompensating events in hospitalized patients with alcohol use disorder (AUD) seen either by an integrated hepatology and addiction care approach or addiction care alone at 2 academic medical centers. Cox proportional hazards regression model and a Kaplan-Meier analysis were used.

Findings: An integrated approach of hepatology and addiction care is associated with a reduced likelihood of future liver-related decompensating events in hospitalized patients with AUD. This finding correlated with an increased uptake of medical alcohol therapy and a reduced likelihood of an alcohol-associated readmission. Integrated hepatology and addiction care for hospitalized AUD patients may help reduce the progression of ALD.

Background: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by biliary fibroinflammation. TGFβ-activated cholangiocytes release signals that recruit immune cells and activate myofibroblasts, promoting inflammation and extracellular matrix (ECM) deposition. TGFβ also regulates stearoyl-CoA desaturase (SCD), an enzyme involved in lipid signaling. Yet, the role of SCD or its inhibitor, Aramchol, in biliary fibroinflammation had not been studied.

Methods and results: Mdr2-/- with established biliary fibrosis and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were treated with Aramchol meglumine (12.5 mg/kg/day). Hepatic fibrosis was assessed by qPCR, Picrosirius red staining, immunofluorescence, and hydroxyproline content. Human H69 or murine large cholangiocyte cell lines stimulated with TGFβ, as well as PSC-derived cholangiocytes (PSC-C), were treated with Aramchol or SCD siRNA. RNA-seq, fibroinflammatory marker expression, peroxisome proliferator-activated receptor (PPAR) activity, and targeted fatty acid profiling were performed. Aramchol treatment significantly reduced hepatic ECM gene expression, inflammatory cytokines (Il6,Tnfa), collagen content, and myofibroblast activation (aSMA staining) in both mouse models. In TGFβ-stimulated H69 cells, Aramchol suppressed hepatic fibrosis pathways and enhanced PPAR signaling. Aramchol also reduced the expression of fibrotic markers, myofibroblast-activating mediators (VEGFA and PDGFB), and IL6, mirroring the effects of SCD knockdown. In PSC-C, Aramchol significantly downregulated SCD, VEGFA and IL6. Conversely, PPARα and -γ activity and fatty acid agonist, linoleic acid levels were increased in cholangiocyte cell lines.

Conclusions: Aramchol attenuates and prevents biliary fibrosis in mouse models of cholestatic liver disease by inhibiting TGFβ-induced fibroinflammatory mediators and activating PPARa/γ in cholangiocytes. These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC.

Background: Post-reperfusion syndrome (PRS) is a critical hemodynamic complication during liver transplantation, characterized by a significant drop in mean arterial pressure and associated with increased morbidity and mortality, systemic inflammation, and ischemia-reperfusion injury. Ascorbic acid (AA), with its antioxidant and anti-inflammatory properties, has been proposed as a potential therapeutic intervention.

Methods: A single-center, double-blind, randomized controlled trial was conducted at the Hospital Universitario Ramón y Cajal, Madrid. Patients undergoing liver transplantation were randomly assigned to receive either 1500 mg of intravenous AA during the anhepatic phase (vitamin C-treated group) or 0.9% saline as a placebo (control group). The primary endpoint was PRS incidence. The secondary outcomes included inflammatory cytokine levels, postoperative renal function, and patient/graft survival.

Results: Thirty-nine patients were randomized (20 controls and 19 AA-treated patients). The incidence of PRS was 30% in the control group and 10.5% in the AA group (p=0.235). Postoperative renal failure occurred more frequently in the AA group (68.4%) than in the control group (35%) (p=0.037). Four AA-treated patients (21.1%) required re-transplantation. No significant differences in cytokine levels were observed between the groups, although increases in IL-6, IL-8, and IL-10 levels were noted in patients with PRS, suggesting a stronger inflammatory response.

Conclusions: AA supplementation demonstrated a noticeable trend toward reducing PRS during liver transplantation, although this was not statistically significant. An increase in renal failure and the need for re-transplantation were observed in the AA-treated group. Although the study suggests potential benefits, its small sample size limits the conclusions, pointing to the need for larger multicenter trials to determine the optimal dosage and timing.

Background: The Barcelona Clinic Liver Cancer staging system considers, among patients with HCC, "ideal candidates" (ICs) for hepatic resection (HR) those with a single lesion, normal bilirubin, and without clinically significant portal hypertension (CSPH). We compared the outcome of HR between ICs and non-ICs.

Methods: Retrospective analysis was conducted on Child-Pugh A patients. CSPH was defined by the presence of gastroesophageal varices and/or platelet count <100,000/mm3. Hyperbilirubinemia was accepted up to 2 mg/dL. The selected 1057 patients were distributed in 3 calendar periods (2000-2022).

Results: In all calendar periods, non-ICs were more prevalent than ICs. Among non-ICs, the proportion of patients with isolated CSPH did not change over time (from 22.6% to 30.3%; p=0.359), while patients with multinodular HCC (mHCC) increased (from 35.5% to 50.2%; p=0.042). Patients with hyperbilirubinemia decreased (from 20.4% to 10.1%; p=0.036), likewise those with hyperbilirubinemia+CSPH (from 21.5% to 9.4%; p=0.005). Over a median follow-up of 41.0 months, median overall survival was higher in ICs compared to non-ICs (104.9 vs. 75.3 months; p<0.001). However, compared to ICs, median overall survival did not differ in patients with isolated CSPH (93.1 mo; p=0.432) or isolated hyperbilirubinemia (86.0 mo; p=0.356), while it was lower in those with hyperbilirubinemia+CSPH (60.0 mo; p<0.001) or mHCC (61.9 mo; p<0.001). Compared to ICs, only hyperbilirubinemia+CSPH patients showed a higher perioperative mortality.

Conclusions: In real-world practice, among resected patients, the proportion of non-ICs has remained constantly higher than that of non-ICs since 2000. HR can be offered to Child-Pugh A patients with CSPH or modest hyperbilirubinemia without compromising its outcome. For patients with 2 of these features or mHCC, which generate a poorer prognosis, studies comparing HR versus non-surgical therapies are warranted.