Hepatology Communications最新文献

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Bacterial infections in patients with cirrhosis lead to a 4-fold increase in mortality. Immune dysfunction in cirrhosis further increases the risk of bacterial infections, in addition to alterations in the gut microbiome, which increase the risk of pathogenic bacteria. High rates of empiric antibiotic use contribute to increased incidence of multidrug-resistant organisms and further increases in mortality. Despite continous advances in the field, major unknowns regarding interactions between the immune system and the gut microbiome and strategies to reduce infection risk and improve mortality deserve further investigation. Here, we highlight the unknowns in these major research areas and make a proposal for a research agenda to move toward improving disease progression and outcomes in patients with cirrhosis and infections.

Background: Transarterial chemoembolization (TACE) is the first-line treatment for patients with advanced HCC, but there are limited studies on the microenvironment alterations caused by TACE.

Methods: Six fresh HBV-related HCC specimens with or without TACE intervention were used to perform single-cell RNA sequencing. The 757 bulk samples from 3 large-scale multicenter cohorts were applied for comprehensive analysis. The biological functions of the biomarkers were further validated by phenotypic experiments.

Results: Using single-cell RNA sequencing analysis, we delineated the global cell atlas of post-TACE and demonstrated elevated tumor heterogeneity and an enhanced proinflammatory microenvironment induced by TACE. Cell-cell communication analysis revealed that markedly elevated interactions between NABP1+ malignant hepatocytes, neutrophils, and CD8+ T cells after TACE might accelerate the shift from CD8+ effector memory T cells to CD8+ effector T cells. This result was substantiated by the developmental trajectory between the 2 and dramatically decreased resident scores along the pseudotemporal trajectory. Integrating bulk data, we further found that the increased estimated proportion of NABP1+ malignant hepatocytes was related to poor TACE response and dismal prognosis, and its biomarker role could be replaced by NABP1. In vitro, multiple biological experiments consistently verified that NABP1 knockdown significantly inhibited the proliferation and migration of HCC cells.

Conclusions: Based on our depicted global map of post-TACE, we confirmed that the enhanced interactions within the microenvironment after TACE may be the culprits for postoperative progression. NABP1 may become an attractive tool for the early identification of patients sensitive to first-line TACE in clinical practice.

Background: Hospitalized patients with end-stage liver disease are at risk of malnutrition, reduced body function, and cognitive impairment due to HE. This combination may have an impact on in-hospital falls and mortality. The purpose of this study was to identify factors associated with the risk of falls and to analyze the consequences regarding in-hospital mortality.

Methods: We performed a retrospective analysis of patients hospitalized with liver cirrhosis between 2017 and 2019 at the Department of Gastroenterology at the University Hospital Frankfurt. Clinical data, laboratory work, and follow-up data were analyzed. Factors associated with the risk of falls and in-hospital mortality were calculated using a mixed effect poisson regression model and competing risk time-to-event analyses.

Results: Falls occurred with an incidence of 4% (80/1985), including 44 injurious falls with an incidence rate of 0.00005/100 patient-days (95% CI: 0.00001-0.00022). In the multivariate analysis malnutrition (incidence risk ratio: 1.77, 95% CI: 1.04-3.04) and implanted TIPS (incidence risk ratio: 20.09, 95% CI: 10.1-40.1) were independently associated with the risk of falling. In a total of 21/80 (26.25%) hospitalizations, patients with a documented fall died during their hospital stay versus 160/1905 (8.4%) deaths in hospitalizations without in-hospital fall. Multivariable analysis revealed as significant clinical predictors for in-hospital mortality a Nutritional Risk Screening ≥2 (HR 1.79, 95% CI: 1.32-2.4), a falling incident during hospitalization (HR 3.50, 95% CI: 2.04-6.0), high MELD, and admission for infections.

Conclusions: Malnutrition and TIPS are associated with falls in hospitalized patients with liver cirrhosis. The in-hospital mortality rate of patients with cirrhosis with falls is high. Specific attention and measures to ameliorate these risks are warranted.

Background: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions.

Methods: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens.

Results: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner.

Conclusions: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.

Background: To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls.

Methods: In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis.

Results: Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005).

Conclusions: LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients.