Histological characteristics in patients admitted to the hospital with alcoholic hepatitis complicated by acute-on-chronic liver failure.

OBJECTIVES: Alcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics. METHODS: Prospective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared. RESULTS: 184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated. CONCLUSIONS: In this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections.

Alcoholic Foamy Degeneration, an Entity Resembling Alcohol-Associated Hepatitis: Diagnosis, Prognosis, and Molecular Profiling.

BACKGROUND & AIMS: Alcoholic foamy degeneration (AFD) is a condition with similar clinical presentation to alcohol-associated hepatitis (AH), but with a specific histologic pattern. Information regarding the prevalence and prognosis of AFD is scarce and there are no tools for a noninvasive diagnosis. METHODS: A cohort of patients admitted to the Hospital Clinic of Barcelona for clinical suspicion of AH who underwent liver biopsy was included. Patients were classified as AFD, AH, or other findings, according to histology. Clinical features, histology, and genetic expression of liver biopsy specimens were analyzed. The accuracy of National Institute on Alcohol Abuse and Alcoholism criteria and laboratory parameters for differential diagnosis were investigated. RESULTS: Of 230 patients with a suspicion of AH, 18 (8%) met histologic criteria for AFD, 184 (80%) had definite AH, and 28 (12%) had other findings. In patients with AFD, massive steatosis was more frequent and the fibrosis stage was lower. AFD was characterized by down-regulation of liver fibrosis and inflammation genes and up-regulation of lipid metabolism and mitochondrial function genes. Patients with AFD had markedly better long-term survival (100% vs 57% in AFD vs AH; P = .002) despite not receiving corticosteroid treatment, even in a model for end-stage liver disease-matched sensitivity analysis. Serum triglyceride levels had an area under the receiver operating characteristic of 0.886 (95% CI, 0.807-0.964) for the diagnosis of AFD, whereas the National Institute on Alcohol Abuse and Alcoholism criteria performed poorly. A 1-step algorithm using triglyceride levels of 225 mg/dL (sensitivity, 0.77; specificity, 0.90; and Youden index, 0.67) is proposed for differential diagnosis. CONCLUSIONS: AFD in the setting of suspicion of AH is not uncommon. A differential diagnosis is important because prognosis and treatment differ largely. Triglyceride levels successfully identify most patients with AFD and may be helpful in decision making.

Portal Venous Thrombosis in Alcoholic Hepatitis: A Relatively Unknown Association.

Portal venous thrombosis (PVT) is a rare diagnosis in the general population. However, it is seen in patients with liver cirrhosis with an estimated prevalence ranging from 0.6% to 26%. Literature reports that about one-third of PVT cases have an unknown etiology. Identifying the precipitating factors implicated in the development of PVT is imperative as it may help guide therapy. Although the association between liver cirrhosis and PVT has been well established in current literature, there continues to be a relative lack of awareness of alcoholic hepatitis (AH) as a risk factor for PVT. Identifying AH as a trigger for thrombosis can help avoid extended anticoagulation and its complications. In the following case report and brief review, we discuss an uncommon case of a 33-year-old male who came to the hospital emergency department with complaints of nauseousness, abdominal discomfort, and yellow discoloration. Lab investigations showed transaminitis. The diagnosis of AH was established, and an abdominal duplex ultrasound revealed PVT. Heparin drip was started as a part of treatment, which improved his abdominal discomfort. He was eventually discharged on apixaban 5 mg twice daily for 3 months and a repeat abdominal duplex ultrasound in 3 months to check for the resolution of the PVT.

Fibrinogen-like protein 2 regulates macrophage glycolytic reprogramming by directly targeting PKM2 and exacerbates alcoholic liver injury.

BACKGROUND & AIMS: Switching of the macrophage activation phenotype affects the pathogenesis of alcoholic liver diseases, and metabolic reprogramming can provide the energy demand for macrophage phenotypes shift. However, the molecular mechanism by which immune metabolism regulates the activation of proinflammatory macrophages remains unclear. APPROACH: Expression of Fgl2 was examined in patients with alcoholic hepatitis and healthy controls. Mice were fed with a Lieber-DeCarli diet. Livers from mice were used to observe liver injury and macrophage activation. Fgl2 overexpressing THP-1 cell was used to find interacting partners through immunoprecipitation plus mass spectrometry. Naive bone marrow derived macrophages stimulated with LPS and ethanol were used for cell experiments. RESULTS: Expression of Fgl2 was elevated in macrophages of livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Fgl2 depletion ameliorated ethanol diet-induced hepatic steatosis and oxidative injury as well as the levels of proinflammatory cytokines. Fgl2-/- mice exhibited suppressed M1 polarization and glycolysis pathway activation. Fgl2 interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and facilitated PKM2 nuclear translocation, thus promoting glycolysis in M1 macrophages and the secretion of proinflammatory cytokines. Furthermore, Fgl2 overexpression in THP-1 cells enhances PKM2-dependent glycolysis and inflammation, which could be reversed by activation of enzymatic PKM2 using DASA58. CONCLUSIONS: Taken together, Fgl2 hastens the development of alcoholic liver injury by mediating PKM2 dependent aerobic glycolysis in proinflammatory macrophages. Strategies that inhibiting proinflammatory macrophage activation by silencing Fgl2 might be a potential therapeutic intervention for alcoholic liver injury.

New murine model of alcoholic hepatitis in obesity-induced metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) and alcoholic hepatitis (AH) are among the most prevalent liver diseases worldwide, and their coexistence is common in clinical practice. However, currently established models of MAFLD-AH coexistence do not fully replicate their pathological characteristics and require sophisticated experimental techniques. Therefore, we aimed to develop an easily replicable model that mimics obesity-induced MAFLD-AH in patients. Our goal was to establish a murine model that replicates MAFLD and AH coexistence, resulting in significant liver injury and inflammation. To this end, we administered a single ethanol gavage dose to ob/ob mice on a chow diet. The administration of a single dose of ethanol led to elevated serum transaminase levels, increased liver steatosis, and apoptosis in ob/ob mice. Furthermore, ethanol binge caused a significant increase in oxidative stress in ob/ob mice, as measured via 4-hydroxynonenal. Importantly, the single dose of ethanol also markedly exacerbated liver neutrophil infiltration and upregulated the hepatic mRNA expression of several chemokines and neutrophil-related proteins, including Cxcl1, Cxcl2, and Lcn2. Whole-liver transcriptomic analysis revealed that ethanol-induced changes in gene expression profile shared similar features with AH and MAFLD. In ob/ob mice, a single dose of ethanol binge caused significant liver injury and neutrophil infiltration. This easy-to-replicate murine model successfully mimics the pathological and clinical features of patients with coexisting MAFLD and AH and closely resembles the transcriptional regulation seen in human disease.

Persistent mTORC1 activation due to loss of liver tuberous sclerosis complex 1 promotes liver injury in alcoholic hepatitis.

BACKGROUND AND AIMS: The aim of the study was to investigate the role and mechanisms of tuberous sclerosis complex 1 (TSC1) and mechanistic target of rapamycin complex 1 (mTORC1) in alcohol-associated liver disease. APPROACH AND RESULTS: Liver-specific Tsc1 knockout (L- Tsc1 KO) mice and their matched wild-type mice were subjected to Gao-binge alcohol. Human alcoholic hepatitis (AH) samples were also used for immunohistochemistry staining, western blot, and quantitative real-time PCR (q-PCR) analysis. Human AH and Gao-binge alcohol-fed mice had decreased hepatic TSC1 and increased mTORC1 activation. Gao-binge alcohol markedly increased liver/body weight ratio and serum alanine aminotransferase levels in L- Tsc1 KO mice compared with Gao-binge alcohol-fed wild-type mice. Results from immunohistochemistry staining, western blot, and q-PCR analysis revealed that human AH and Gao-binge alcohol-fed L- Tsc1 KO mouse livers had significantly increased hepatic progenitor cells, macrophages, and neutrophils but decreased HNF4α-positive cells. Gao-binge alcohol-fed L- Tsc1 KO mice also developed severe inflammation and liver fibrosis. Deleting Tsc1 in cholangiocytes but not in hepatocytes promoted cholangiocyte proliferation and aggravated alcohol-induced ductular reactions, fibrosis, inflammation, and liver injury. Pharmacological inhibition of mTORC1 partially reversed hepatomegaly, ductular reaction, fibrosis, inflammatory cell infiltration, and liver injury in alcohol-fed L- Tsc1 KO mice. CONCLUSIONS: Our findings indicate that persistent activation of mTORC1 due to the loss of cholangiocyte TSC1 promotes liver cell repopulation, ductular reaction, inflammation, fibrosis, and liver injury in Gao-binge alcohol-fed L- Tsc1 KO mice, which phenocopy the pathogenesis of human AH.

Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.

BACKGROUND AND AIMS: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). APPROACH AND RESULTS: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis. CONCLUSIONS: Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies.

Emergence of highly profibrotic and proinflammatory Lrat+Fbln2+ HSC subpopulation in alcoholic hepatitis.

BACKGROUND AND AIMS: Relative roles of HSCs and portal fibroblasts in alcoholic hepatitis (AH) are unknown. We aimed to identify subpopulations of collagen type 1 alpha 1 (Col1a1)-expressing cells in a mouse AH model by single-cell RNA sequencing (scRNA-seq) and filtering the cells with the HSC (lecithin retinol acyltransferase [Lrat]) and portal fibroblast (Thy-1 cell surface antigen [Thy1] and fibulin 2 [Fbln2]) markers and vitamin A (VitA) storage. APPROACH AND RESULTS: Col1a1-green fluorescent protein (GFP) mice underwent AH, CCl 4 , and bile duct ligation (BDL) procedures to have comparable F1-F2 liver fibrosis. Col1a1-expressing cells were sorted via FACS by VitA autofluorescence and GFP for single-cell RNA sequencing. In AH, approximately 80% of Lrat+Thy1-Fbln2- activated HSCs were VitA-depleted (vs. ~13% in BDL and CCl 4 ). Supervised clustering identified a subset co-expressing Lrat and Fbln2 (Lrat+Fbln2+), which expanded 44-fold, 17-fold, and 1.3-fold in AH, BDL, and CCl 4 . Lrat+Fbln2+ cells had 3-15-times inductions of profibrotic, myofibroblastic, and immunoregulatory genes versus Lrat+Fbln2- cells, but 2-4-times repressed HSC-selective genes. AH activated HSCs had up-regulated inflammatory (chemokine [C-X-C motif] ligand 2 [Cxcl2], chemokine [C-C motif] ligand 2), antimicrobial (Il-33, Zc3h12a), and antigen presentation (H2-Q6, H2-T23) genes versus BDL and CCl 4 . Computational deconvolution of AH versus normal human bulk-liver RNA-sequencing data supported an expansion of LRAT+FBLN2+ cells in AH; AH patient liver immunohistochemistry showed FBLN2 staining along fibrotic septa enriched with LRAT+ cells; and in situ hybridization confirmed co-expression of FBLN2 with CXCL2 and/or human leukocyte antigen E in patient AH. Finally, HSC tracing in Lrat-Cre;Rosa26mTmG mice detected GFP+FBLN2+ cells in AH. CONCLUSION: A highly profibrotic, inflammatory, and immunoregulatory Lrat+Fbln2+ subpopulation emerges from HSCs in AH and may contribute to the inflammatory and immunoreactive nature of AH.

Alcohol-related liver disease in medical practice.

The Czech Republic is still one of the European countries with above-average alcohol consumption. Excessive consumption has a dual effect - it affects the soul and body, leads to the development of alcohol dependence, withdrawal symptoms, psychosocial problems, significantly contributes to the damage of multiple organs. The "tolerable" dose is up to 20 g of pure alcohol per day for women and 30 g of alcohol per day for men. Regular use of higher doses leads to liver damage of varying severity. The first stage of damage is clinically insignificant steatosis, which progresses to steatohepatitis and liver fibrosis as abuse continues. The end stage is irreversible liver cirrhosis. Alcoholic hepatitis is also a serious condition. The basic therapeutic measure is absolute abstinence. The treatment of these patients is long, complicated and a multidisciplinary approach seems to be the most effective. The only treatment modality in patients with liver cirrhosis and long-term abstinence is liver transplantation.

Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis.

Alcohol-associated liver disease is a global health care burden, with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) being two clinical manifestations with poor prognosis. The limited efficacy of standard of care for AC and AH highlights a need for therapeutic targets and strategies. The current study aimed to address this need through the identification of hepatic proteome and phosphoproteome signatures of AC and AH. Proteomic and phosphoproteomic analyses were conducted on explant liver tissue (test cohort) and liver biopsies (validation cohort) from patients with AH. Changes in protein expression across AH severity and similarities and differences in AH and AC hepatic proteome were analyzed. Significant alterations in multiple proteins involved in various biological processes were observed in both AC and AH, including elevated expression of transcription factors involved in fibrogenesis (eg, Yes1-associated transcriptional regulator). Another finding was elevated levels of hepatic albumin (ALBU) concomitant with diminished ALBU phosphorylation, which may prevent ALBU release, leading to hypoalbuminemia. Furthermore, altered expression of proteins related to neutrophil function and chemotaxis, including elevated myeloperoxidase, cathelicidin antimicrobial peptide, complement C3, and complement C5 were observed in early AH, which declined at later stages. Finally, a loss in expression of mitochondria proteins, including enzymes responsible for the synthesis of cardiolipin was observed. The current study identified hepatic protein signatures of AC and AH as well as AH severity, which may facilitate the development of therapeutic strategies.

The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats.

The present study was to investigate the therapeutical effects and mechanisms of Asiatic acid from Potentilla chinensis against alcoholic hepatitis. Rats were intragastrically fed with alcohol for 12 weeks to induce alcoholic hepatitis and then treated with various drugs for further 12 weeks. The results showed that Asiatic acid significantly alleviated liver injury caused by alcohol in rats, as evidenced by the improved histological changes and the lower levels of AST, ALT, and TBIL. Besides, Asiatic acid significantly enhanced the activity of ADH and ALDH, promoting alcohol metabolism. Asiatic acid suppressed CYP2E1 activity and NADP+/NADPH ratio, resulting in low ROS production. Further study revealed that Asiatic acid markedly reduced hepatocyte apoptosis by regulating the expression levels of apoptosis-related protein. Moreover, Asiatic acid could regulate the Nrf2 and NF-κB signaling pathway, attenuating oxidative stress and inflammation as a result. Interestingly, the comprehensive analysis of transcriptomics and metabolomics indicated that Asiatic acid inhibited the gene expression of Gpat3 and thereby affected the biosynthesis of the metabolites (1-acyl-Sn-glycerol-3-phosphocholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine), regulating the glycerophospholipid metabolism pathway and ultimately ameliorating hepatocyte damage. In conclusion, this study demonstrates that Asiatic acid can ameliorate alcoholic hepatitis by modulating the NF-κB and Nrf2 signaling pathways and the glycerophospholipid metabolism pathway, which may be developed as a potential medicine for the treatment of alcoholic hepatitis.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

OBJECTIVE: Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN: Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS: Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS: Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

BACKGROUND AND AIMS: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.

Recovery and outcomes of patients denied early liver transplantation for severe alcohol-associated hepatitis.

BACKGROUND AND AIMS: Liver transplantation (LT) in alcohol-associated hepatitis (AH) remains controversial, in part because spontaneous recovery (SR) can occur. There is a paucity of data on SR in patients with severe AH who undergo LT evaluation. The purpose of this study was to determine factors associated with SR and survival in patients with severe AH who undergo LT evaluation. APPROACH AND RESULTS: This is a retrospective study of ALD patients with Model for End-Stage Liver Disease (MELD) >25 and <90 days abstinence who underwent LT evaluation at a single center between 2012 and 2018. One hundred forty-four patients (median age, 45.5 years; 68.1% male) were included. Forty-nine (34%) underwent LT and 95 (66%) patients did not undergo LT, and of those, 34 (23.6%) experienced SR. Factors associated with recovery were younger age (OR, 0.92; p = 0.004), lower index international normalized ratio (INR; 0.31; p = 0.03), and lower peak MELD (OR, 0.83; p = 0.02). Only 7 patients (20.6%) achieved a compensated state with a MELD <15 and absence of therapy for ascites or HE. Survival was improved in patients who underwent early LT when compared to SR. Survival was impaired in SR following relapse to alcohol use when compared to SR patients who abstained and LT recipients. Among all 6-month survivors of AH, alcohol use trended toward an association with mortality (HR, 2.05; p = 0.17), but only LT was associated with decreased mortality risk (HR, 0.20; p = 0.005). CONCLUSIONS: SR from AH after LT evaluation is associated with age, index INR, and lower peak MELD. Most recovered patients continue to experience end-stage complications. LT is the only factor associated with lower mortality.

Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease.

Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.

Clinical Presentation and Gene Expression of Acute Alcohol-Induced Microvesicular Steatosis Mimicking Alcoholic Hepatitis.

Acute alcoholic microvesicular steatosis (MIC) may complicate heavy alcohol intake and present as alcoholic hepatitis (AH) syndrome. However, detailed clinical, biological, and histologic data associated with MIC are scarce. We compared the clinical presentation, histologic features, and hepatic transcriptomic of patients presenting with AH due to either MIC or severe alcoholic steatohepatitis (ASH). In this case-control study, patients who drank heavily (>100 g/day) with the AH syndrome were included either in the MIC group (>50% severe microvesicular steatosis, no inflammation) or in the severe ASH group (polynuclear neutrophil infiltration, macrosteatosis, ballooned hepatocytes). All patients received standard supportive care plus steroids for those with severe ASH and were followed up for 3 months. Whole-liver transcriptome profiling was performed on liver snap-frozen biopsies. Compared to ASH (n = 24, mean age 49.3 years), patients in the MIC group (n = 12, mean age 49.1 years) had a higher reported alcohol intake (P < 0.01), lower Model for End-Stage Liver Disease score (P < 0.05), lower hepatic venous pressure gradient (P < 0.01), higher alanine aminotransferase (P < 0.02) and gamma-glutamyltransferase (P < 0.001), higher triglycerides (P < 0.001) and total cholesterol (P < 0.002), but similar bilirubin levels (P = 0.54). At histology, patients with MIC had a lower fibrotic stage compared to those with ASH (P < 0.001). A higher density of megamitochondria was seen in MIC compared to ASH (P < 0.05). During follow-up, death or transplantation occurred in 4/12 (33%) patients with MIC and 7/24 (29%) patients with severe ASH. Differential hepatic gene expression in MIC compared to ASH included down-regulation of genes related to inflammation and fibrosis and up-regulation of genes involved in lipid metabolism and mitochondrial function. Conclusion: MIC is an acute, noninflammatory, potentially severe alcoholic liver injury mimicking ASH, is associated with a lower fibrosis stage, and has a distinct gene expression profile.