Hepatology : Official Journal of the American Association for the Study of Liver Diseases

BACKGROUND AND AIMS: Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis. APPROACH AND RESULTS: Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays...

BACKGROUND AND AIMS: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown. APPROACH AND RESULTS: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers...

BACKGROUND AND AIMS: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH), however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. APPROACH AND RESULTS: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0...

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) is a common complication of liver disease defined by abnormal oxygenation and intrapulmonary vascular dilatation, treated with liver transplantation. Little is known about changes in HPS physiological parameters over time. We sought to describe baseline clinical and physiological characteristics in HPS and their relationships, temporal changes in physiological parameters before and after transplant, and predictors of changes in oxygenation...

BACKGROUND AIMS: The multisociety consensus nomenclature has renamed non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD) with various sub-classifications. There is paucity of data regarding how the new nomenclature modifies our understanding of disease prevalence and patient phenotypes. APPROACH RESULTS: Using the National Health and Nutrition Examination Survey from 1/2017-3/2020, we included all participants aged≥18 with complete vibration-controlled transient elastography measures...

Hepatoblastoma (HB) is the main paediatric liver cancer, but it is a very rare disease. Despite significant improvements in the treatment of children diagnosed with HB, limited treatment options exist for patients with advanced tumours. Besides, survivors generally have long-term adverse effects derived from treatment such as ototoxicity, cardiotoxicity, delayed growth, and secondary tumours. Accordingly, there is an urgent need to define new and efficient therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumour's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in paediatric cancers are lacking because of paucity of data...

BACKGROUND AIMS: Inherited short telomeres are associated with risk of liver disease, whereas longer telomeres predispose to cancer. The association between telomere length and risk of hepatocellular carcinoma and cholangiocarcinoma remains unknown. APPROACH RESULTS: We measured leukocyte telomere length using multiplex PCR in 63,272 individuals from the Danish general population. Telomere length and plasma alanine transaminase concentration were not associated (β = 4 ×10⁻⁶, p-value = 0...

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Obesity is highly prevalent in hepatology clinics and has significant impact in chronic liver disease and patient management. Hepatologists and gastroenterologist need to be actively engaged in the management of obesity. This review provides a detailed approach to this challenging comorbidity.

The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest...

BACKGROUND AND AIMS: Scirrhous hepatocellular carcinoma (SHCC) is one of the unique subtypes of hepatocellular carcinoma (HCC), characterized by abundant fibrous stroma in tumor microenvironment. However, it remains unclear about the molecular traits of SHCC, which is essential to develop specialized therapeutic approaches for SHCC. APPROACH RESULTS: We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients, to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC...

Cell death and inflammation play critical roles in chronic tissue damage caused by cholestatic liver injury leading to fibrosis and cirrhosis. Liver cirrhosis is often associated with kidney damage that is a severe complication with poor prognosis. Interferon regulatory factor 3 (IRF3) is known to regulate apoptosis and inflammation, but its role in cholestasis remains obscure. In this study, we discovered increased IRF3 phosphorylation (p-IRF3) in the liver of patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)...

BACKGROUND AND AIMS: The fitness and viability of a tumor ecosystem are influenced by the spatial organization of its cells. We aimed to study the structure, architecture, and cell-cell dynamics of the heterogenous liver cancer tumor microenvironment using spatially resolved multiplexed imaging. APPROACH AND RESULTS: We performed co-detection by indexing (CODEX) multiplexed immunofluorescence imaging on 68 hepatocellular carcinoma (HCC) biopsies from Thai patients (TIGER-LC) as a discovery cohort, and then validated the results in an additional 190 HCC biopsies from Chinese patients (LCI)...

BACKGROUND AIM: Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume reducing therapy. APPROACH RESULTS: In this prospective cohort study, we included PLD patients from European treatment centers...

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