Loss of solute carrier family 38 member 4 (SLC38A4) as a driver for the pathogenesis of severe alcoholic hepatitis

term prognosis.Molecular mechanisms underlying AFD are unknown and histological pattern has been scarcely studied.Our aim was to unveil the histological and transcriptional characteristics of AFD in this series.Method: liver biopsies from 16 patients with AFD and 20 patients with AH diagnosed in the same period, were obtained.Results from RNA sequencing were analyzed with IPA, GO and RA platforms.Moreover, liver biopsies were reviewed by two pathologists to describe steatosis, steatohepatitis, degree of inflammation and fibrosis.Results: compared to patients with AH, patients with AFD presented with a lower proportion of ascites and had higher levels of transaminases, cholesterol and triglycerides.Bilirubin levels were similar but MELD score was lower in patients with AFD.RNA sequencing analysis revealed that patients with AFD and AH have a differential gene expression pattern.On PCA analysis using gene expression, AFD patients clustered apart from AH patients.Moreover, the analysis of the deregulated gene expression showed that AFD patients have a significant upregulation of pathways associated with lipid metabolism, such as cholesterol and triglycerides biosynthesis, stearate and retinol biosynthesis, mitochondrial function and cell cycle, and a downregulation of pathways related to hepatic fibrosis such as wound healing signaling, integrin signaling and extracellular matrix deposition.Genes involved in senescence, autophagy and inflammation are also downregulated.Half of the cases (n = 8) had predominant microvesicular steatosis, six (37.5%) had a mixed pattern of micro and macrovesicular steatosis and the remaining two cases (12.5%) showed microvesicular steatosis (≥40%) with focally associated steatohepatitis.Fibrosis was uncommon, especially in the cases of predominant microvesicular steatosis.Figure: heatmap of the top upregulated (red) and downregulated (blue) genes in liver biopsies with AFD (green bar) and AH (orange bar).Conclusion: AFD displays a specific gene signature differentiated from that of AH.Genetic functional pathways associated with lipid metabolism and mitochondrial function are upregulated in patients with AFD.In contrast, there is a downregulation of pathways associated with inflammation, fibrosis and senescence.Histological findings are consistent with genetic profile, with a predominant pattern of steatosis, with scarce fibrosis and steatohepatitis.