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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.

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.Global alcohol consumption has increased in the past two decades and is projected to increase further. In this Review, Loomba and colleagues discuss the global epidemiology of alcohol-associated cirrhosis and hepatocellular carcinoma, including risk factors, trends and projections.

Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1–2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7–28·0) for the nivolumab group and 13·4 months (5·7–25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9–18·4) with nivolumab and 14·7 months (11·9–17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72–1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

In a randomized trial of patients with primary biliary cholangitis, bezafibrate and ursodeoxycholic acid resulted in a higher rate of complete biochemical response than ursodeoxycholic acid alone. Bezafibrate was associated with increases in creatinine and myalgias.

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.

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment. Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.

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 . . .

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGF β 1 is a key upstream transcriptome regulator in AH and induces the use of HNF4 α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4 α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4 α -dependent gene expression. We conclude that targeting TGF β 1 and epigenetic drivers that modulate HNF4 α -dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH. Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628). Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively). In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.