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Key Points Alcoholic liver disease (ALD) is characterized by a complex spectrum of histological lesions, ranging from steatosis to cirrhosis Alcoholic hepatitis is a specific entity, which is associated with a fast progression to cirrhosis and with liver failure and a poor outcome in its most severe form ALD is characterized by oxidative stress, disturbance of hepatocyte metabolism, liver inflammation, modifications in the regeneration process and translocation of bacterial products from the gut microbiota into the portal blood stream Because animal models do not reproduce the complete spectrum of alcohol-induced hepatic lesions, translational research based on human samples is crucial to identify new treatment options The best-documented treatment for severe alcoholic hepatitis is corticosteroids, but this treatment is not ideal and 40% of patients still die after a short period of time The future evaluation of new strategies in severe alcoholic hepatitis should focus not only upon survival, but also on surrogate markers of outcome, with a specific plan of development Alcoholic liver disease is characterized by a complex spectrum of histological lesions, ranging from steatosis to cirrhosis. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways. The need to adapt the design of future studies to the histological lesions of the disease is also highlighted. Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.

Six months of abstinence is typically required before transplantation for alcoholic liver disease. In this study, early liver transplantation improved the 6-month survival rate among selected patients with severe alcoholic hepatitis (77%, vs. 23% without transplantation). Liver transplantation for alcoholic liver disease has a favorable outcome but remains controversial. 1 , 2 Reluctance to perform transplantation in patients with alcoholism is often based on the view that they are responsible for their illness and are likely to resume alcohol use after transplantation. 3 To select the most appropriate patients with severe forms of alcoholic liver disease for transplantation, most programs require a 6-month abstinence period before patients can be considered. Nevertheless, data regarding the 6-month rule as a predictor of long-term sobriety are controversial. 4 Despite the frequent use of the rule, the United Network for Organ Sharing and the . . .

ObjectiveIn alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in-depth molecular translational studies.DesignWe studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy.ResultsLivers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor α and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes.ConclusionsAH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH.

INTRODUCTION:Severe alcohol-related hepatitis (AH) is associated with an increased risk of infection, but the impact of pneumonia has not been specifically analyzed in a specific cohort.METHODS:All patients admitted for severe AH between 2002 and 2020 were prospectively included. Systematic screening for infection was performed at admission and renewed in the case of clinical suspicion.RESULTS:We included 614 patients (60.4% men, mean age 49.9 years, median model for end-stage liver disease [MELD] 25.2, bilirubin 18.1 mg/dL), 202 (32.9%) with infections at admission (73 lung infections). Encephalopathy (P = 0.006), MELD score (P = 0.0002), and tobacco exposure (past vs never smokers: P = 0.002 or active vs past smokers: P = 0.005) were associated with lung infection at admission on multivariate analysis. Factors independently associated with death before steroid initiation were encephalopathy (P = 0.003), MELD score (P = 0.05), and especially lung infection (P < 0.0001). Thus, patients with a lung infection had a lower probability of receiving steroids than those with other infections and noninfected patients: 54.8 vs 88.4 vs 98.1% (P < 0.0001). One hundred forty-six of the 558 patients who received corticosteroids developed infection, including 57 (39.04%) pneumonias. The risk of respiratory and nonrespiratory infection was higher in nonresponders to steroids (Lille score ≥0.45) than in responders: 13% vs 7.6%, P = 0.03 and 27.9% vs 10.6%, P < 0.001, respectively. The variables independently associated with 3-month mortality after steroid initiation were lung infection (P = 0.004), nonresponse to steroids (P < 0.0001), MELD score (P = 0.0003), ascites (P = 0.003), and encephalopathy (P = 0.018), whereas nonrespiratory infections were not (P = 0.91).DISCUSSION:Lung infection is frequent during severe AH and influences mortality at admission and after steroid initiation. These results emphasize the need for specific management of lung infection during the course of AH.

Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies. Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD. Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual's drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.

Nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are the leading causes of chronic liver disease worldwide. NAFLD and ALD share pathophysiological, histological and genetic features and both alcohol and metabolic dysfunction coexist as aetiological factors in many patients with hepatic steatosis. A diagnosis of NAFLD requires the exclusion of significant alcohol consumption and other causes of liver disease. However, data suggest that significant alcohol consumption is often under-reported in patients classified as having NAFLD and that alcohol and metabolic factors interact to exacerbate the progression of liver disease. In this Review, we analyse existing data on the interaction between alcohol consumption and metabolic syndrome as well as the overlapping features and differences in the pathogenesis of ALD and NAFLD. We also discuss the clinical implications of the coexistence of alcohol consumption, of any degree, in patients with evidence of metabolic derangement as well as the use of alcohol biomarkers to detect alcohol intake. Finally, we summarize the evolving nomenclature of fatty liver disease and describe a recent proposal to classify patients at the intersection of NAFLD and ALD. We propose that, regardless of the presumed aetiology, patients with fatty liver disease should be evaluated for both metabolic syndrome and alcohol consumption to enable better prognostication and a personalized medicine approach.In this Review, Arrese and colleagues discuss the intersection of nonalcoholic fatty liver disease and alcohol-related liver disease, including their pathophysiology, clinical management and suggestions for future research.

To validate cancer screening programs, experts recommend estimating effects on case fatality rates (CFRs) and cancer‐specific mortality. This study evaluates hepatocellular carcinoma (HCC) screening in patients with cirrhosis for those outcomes using a modeling approach. We designed a Markov model to assess 10‐year HCC‐CFR, HCC‐related, and overall mortality per 100,000 screened patients with compensated cirrhosis. The model evaluates different HCC surveillance intervals (none, annual [12 months], semiannual [6 months], or quarterly [3 months]) and imaging modalities (ultrasound [US] or magnetic resonance imaging [MRI]) in various annual incidences (0.2%, 0.4%, or 1.5%). Compared to no surveillance, 6‐month US reduced the 10‐year HCC‐CFR from 77% to 46%. With annual incidences of 0.2%, 0.4%, and 1.5%, the model predicted 281, 565, and 2059 fewer HCC‐related deaths, respectively, and 187, 374, and 1356 fewer total deaths per 100,000 screened patients, respectively. Combining alpha‐fetoprotein screening to 6‐month US led to 32, 63, and 230 fewer HCC‐related deaths per 100,000 screened patients for annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6‐month US, 3‐month US reduced cancer‐related mortality by 14%, predicting 61, 123, and 446 fewer HCC‐related deaths per 100,000 screened patients with annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6‐month US, 6‐month MRI (−17%) and 12‐month MRI (−6%) reduced HCC‐related mortality. Compared to 6‐month US, overall mortality reductions ranged from −0.1% to −1.3% when using 3‐month US or MRI. A US surveillance interval of 6 months improves HCC‐related and overall mortality compared to no surveillance. A shorter US interval or using MRI could reduce HCC‐CFR and HCC‐related mortality, with a modest effect on overall mortality.

Objectives The purpose of this study was to evaluate a three-material decomposition algorithm for hepatic fat quantification using a dual-layer computed tomography (DL-CT) and MRI as reference standard on a large patient cohort. Method A total of 104 patients were retrospectively included in our study, i.e., each patient had an MRI exam and a DL-CT exam in our institution within a maximum of 31 days. Four regions of interest (ROIs) were positioned blindly and similarly in the liver, by two independent readers on DL-CT and MRI images. For DL-CT exams, all imaging phases were included. Fat fraction agreement between CT and MRI was performed using intraclass correlation coefficients (ICC), determination coefficients R 2 , and Bland–Altman plots. Diagnostic performance was determined using sensitivity, specificity, and positive and negative predictive values. The cutoff for steatosis was 5%. Results Correlation between MRI and CT data was excellent for all perfusion phases with ICC calculated at 0.99 for each phase. Determination coefficients R 2 were also good for all perfusion phases (about 0.95 for all phases). Performance of DL-CT in the diagnosis of hepatic steatosis was good with sensitivity between 89 and 91% and specificity ranging from 75 to 80%, depending on the perfusion phase. The positive predictive value was ranging from 78 to 93% and the negative predictive value from 82 to 86%. Conclusion Multi-material decomposition in DL-CT allows quantification of hepatic fat fraction with a good correlation to MRI data. Clinical relevance statement The use of DL-CT allows for detection of hepatic steatosis. This is especially interesting as an opportunistic finding CT performed for other reasons, as early detection can help prevent or slowdown the development of liver metabolic disease. Key Points • Hepatic fat fractions provided by the dual-layer CT algorithm is strongly correlated with that measured on MRI. • Dual-layer CT is accurate to detect hepatic steatosis ≥ 5%. • Dual-layer CT allows opportunistic detection of steatosis, on CT scan performed for various indications.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality 1 – 3 . Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice 4 , but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin—a two-subunit exotoxin that is secreted by Enterococcus faecalis 5 , 6 —as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis . The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis . We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis , which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis. In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.