BACKGROUND AIMS Alcohol-related hepatitis (AH) is a severe form of alcohol-related liver disease (ALD). The cellular subpopulations that contribute to AH and dynamics remain poorly understood. This study aimed to identify key cellular subpopulations and their interactions in AH and explore key mechanisms contributing to disease pathogenesis. APPROACH RESULTS Single-cell RNA sequencing was performed starting from liver biopsies from patients with AH, early-stage ALD, and healthy individuals. Immunofluorescence was used to validate protein expression of selected markers. Liver biopsy-derived organoids were generated and exposed to a conditioned medium recapitulating AH (AH-medium) to assess serum amyloid A (SAA) secretion by ELISA. Circulating SAA levels were measured in plasma samples obtained from patients at different stages of ALD. Our analysis revealed an atlas of several cell subpopulations of AH, including hepatocytes expressing SAA, scar-associated (SA) endothelial cells, Fibulin-3+ mesenchymal cells, SA-macrophages expressing MMP19, activated CD4+ and stressed/effector CD8+ T cell subsets, and hyperactivated neutrophils expressing FPR2. Cell-communication analysis predicted a strong SAA-FPR2 interaction between hepatocyte and neutrophil subpopulations in AH. We confirmed that AH-hepatocytes secreted SAA in organoid cultures after stimulation with AH-medium. We also found out that circulating SAA levels were elevated in AH and were associated with reduced survival. CONCLUSIONS The SAA-FPR2 pathway emerges as a potential mediator of inflammation in AH, offering potential therapeutic targets for this severe disease. This study provides new insights into the cellular heterogeneity and dynamics in ALD progression, dissecting AH at a single-cell level.
Background and Aims: Accuracy of Baveno criteria for avoiding endoscopy in patients with hepatocellular carcinoma (HCC) is uncertain, and systematic upper gastrointestinal endoscopy (UGE) may not be necessary. We evaluated Baveno VI criteria performance in this population and developed an alternative non-invasive rule to exclude esophagogastric varices of any grade, rather than high-risk varices (HRV). Methods: Patients with BCLC 0-C HCC and compensated advanced chronic liver disease (cACLD) from Italian Liver Cancer (ITA.LI.CA) database, with available liver stiffness measurement (LSM), UGE, and blood tests within six months of diagnosis, were included. Independent predictors of varices identified by logistic regression were combined through grid-search to derive a rule-out strategy (SAPHE-R), validated by bootstrap-resampling and in an independent cohort (Vienna). Results: The derivation cohort comprised 598 patients (age, 69 years; male sex, 75.3%; viral etiology, 69.3%; BCLC 0/A, 77.9%; ALBI 1, 54.2%; varices, 33.4%; HRV, 11.2%). Baveno VI criteria missed 8.5% of varices and 6.0% of HRV, sparing 31.1% of UGE. Independent predictors of varices were incorporated into SAPHE-R (LSM≤16 kPa, platelet count ≥160×10⁹/L, ALBI grade 1), which missed 4.0% of varices (HRV 3.0%, spared UGE 17.6%). In the validation cohort (n=149), SAPHE-R missed 4.8% of varices (HRV 3.1%, spared UGE 14.8%). Results remained consistent in sensitivity analyses. In an exploratory analysis, no HVPG-defined CSPH was observed among SAPHE-R rule-out patients (0/22). Conclusions: Baveno VI criteria showed suboptimal performance in patients with HCC and cACLD, whereas SAPHE-R provided a reliable non-invasive strategy to rule out varices, facilitating variceal risk assessment in patients with HCC.
