Alcohol-related liver disease

Among individuals with known alcohol use disorder(AUD),the prevalence of alcoholic fatty liver disease(AFLD)is present in 25-90%of cases(1).Shroff et al.(1)report that the annual progression to cirrhosis is 3%in the presence of AFLD,10%in case of alcohol-related steatohepatitis(ASH)and 8%with any grade of pre-cirrhotic fibrosis.Alcohol-related liver disease(ALD)is the cause of 36%of cases of cirrhosis in the United States and nearly one half of cirrhosis-related deaths worldwide(1).Ethanol is a recognized carcinogen for several malignancies with the risk starting at low dose(10 gr/1 unit/day)(2).The link between alcohol consumption(AC)and hepatocellular carcinoma(HCC)is well known:various evaluations carried out by both USA and Italian groups indicate that such a correlation is present in 32%to 45%of cases(2).With the reduction of hepatitis C virus(HCV)cases,AC will become the main cause of HCC in Western countries.Furthermore,ALD and metabolic syndrome(MS)are currently the main causes of liver transplantation(LT)(3).

The importance of age for liver-related mortality in patients with metabolic-dysfunction associated steatotic liver disease

In the last four decades,the importance of non-alcoholic fatty liver disease(NAFLD)has increased as the etiology of cirrhosis in the world and associated hepatocellular cancer(HCC).Recently,the terminology has been changed to metabolic-dysfunction associated steatotic liver disease(MASLD)(1).Importantly,a recent validation of the criteria revealed that 99.5%of NAFLD patients in a large cohort of Sweden met the MASLD criteria(2).The authors concluded that previous natural history data can be used.

Alcoholic liver disease: A current molecular and clinical perspective

Heavy alcohol use is the cause of alcoholic liver disease(ALD).The ALD spectrum ranges from alcoholic steatosis to steatohepatitis,fibrosis,and cirrhosis.In Western countries,approximately 50%of cirrhosis-related deaths are due to alcohol use.While alcoholic cirrhosis is no longer considered a completely irreversible condition,no effective anti-fibrotic therapies are currently available.Another significant clinical aspect of ALD is alcoholic hepatitis(AH).AH is an acute inflammatory condition that is often comorbid with cirrhosis,and severe AH has a high mortality rate.Therapeutic options for ALD are limited.The established treatment for AH is corticosteroids,which improve short-term survival but do not affect long-term survival.Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH,but patients must abstain from alcohol use for 6 months to qualify.Additional effective therapies are needed.The molecular mechanisms underlying ALD are complex and have not been fully elucidated.Various molecules,signaling pathways,and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression.This review highlights established and emerging concepts in ALD clin-icopathology,their underlying molecular mechanisms,and current and future ALD treatment options.

Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease

Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis.Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases.Impaired autophagy prevents the clearance of excessive lipid droplets(LDs),damaged mitochondria,and toxic protein aggregates,which can be generated during the progression of various liver diseases,thus contributing to the development of steatosis,injury,steatohepatitis,fibrosis,and tumors.In this review,we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases.We also examine the mechanisms of defects in autophagy,and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD),focusing mainly on steatosis and liver injury.Finally,we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.

Targeting the gut barrier for the treatment of alcoholic liver disease

Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide.Intriguingly,dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease(ALD).A functional gut barrier,which consists of a mucus layer,an intact epithelial monolayer and mucosal immune cells,supports nutrient absorption and prevents bacterial penetration.Compromised gut barrier function is associated with the progression of ALD.Indeed,alcohol consumption disrupts the gut barrier,increases gut permeability,and induces bacterial translocation both in ALD patients and in experimental models with ALD.Moreover,alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations.Here,we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD.Unfortunately,there is no effectual Food and Drug Administration-approved treatment for any stage of ALD.Therefore,we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD.The principle behind antibiotics,prebiotics,probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function.Nutrientbased treatments,such as dietary supplementation with zinc,niacin or fatty acids,have been shown to regulate tight junction expression,reduce intestinal inflammation,and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings.Interestingly,saturated fatty acids may also directly control the gut microbiome.In summary,clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.

Microbiome dysbiosis and alcoholic liver disease

Microbiome dysbiosis is strongly associated with alcoholic liver disease(ALD).Recent studies on comprehensive analyses of microbiome compositional and functional changes have begun to uncover the mechanistic relation between microbiome and the pathogenesis of ALD.Importantly,targeting the microbiome has become a potential strategy for the prevention and treatment of ALD.In this review,we summarize the clinical evidence of microbiome dysbiosis in ALD patients,and experimental advances in microbiome and metabolomic functional changes in animals with different species and genetic backgrounds in ALD.We also summarize the studies in humanized intestinal microbiome and fecal microbiota transplantation in mice.We introduce new developments in the studies on the role of the circulating bacterial microbiome,oral bacterial microbiome and fungal microbiome in the development of ALD.We highlight the potential mechanisms by which microbiome dysbiosis contributes to ALD,including short chain fatty acid changes,bile acid metabolism,intestinal barrier function,release of bacterial and fungal products,and inflammation.In addition,we summarize the recent developments targeting the microbiome in prevention and treatment of ALD,including dietary nutrient interference,herbal medicine,antibiotics,anti-fungal agents,probiotics,engineered bacterial therapy,fecal transplantation and oral hygiene.Although recent preclinical studies have advanced our understanding of the microbiome and ALD,clinical studies,especially prospective studies with large samples,are needed to better understand the cause-effect of microbiome dysbiosis in ALD.Identifying new precision-based strategies targeting the microbiome are expected to be developed as more effective therapies in ALD.©2019 The Third Affiliated Hospital of Sun Yat-sen University.Publishing Services by Elsevier B.V.on behalf of KeAi Communications Co.,Ltd.This is an open access article under the CC BY-NC-ND license.

The French guidelines for alcohol-related liver disease-what’s new, what’s not and what’s still needed

Louvet et al.recently published the French Association for the Study of the Liver(AFEF)and the French Alcohol Society clinical guidelines(1).The AFEF guidelines are the first specific to the screening and care of alcohol-related liver disease(ALD)in France.We compared these to the guidelines of American Association for the Study of Liver Diseases[AASLD,2020;(2)]and European Association for the Study of Liver[EASL,2018(3)];some noticeable differences and similarities emerge(Table 1).

Functions of hepatic non-parenchymal cells in alcoholic liver disease

Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.

Alcoholic liver disease and mast cells:What's your gut got to do with it?

Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role of mast cells(MCs)during liver disease progression has been demonstrated in a number of animal models and in human liver diseases.The interaction between the gut microbiota and MCs has been investigated,and links between the gut and these immune cells are being uncovered.The interplay between the gut microbiota and MCs during ALD has been evaluated and studies suggest that there could be an important link between MCs,their mediators and gut inflammation during the progression of ALD.

Dietary fatty acids and bioactive fatty acid metabolites in alcoholic liver disease

Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.

Unveiling the effect of estrogen receptors in alcoholic liver disease:A novel outlook

Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.

Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

内源性大麻素系统在肝脏病中作用的研究进展

内源性大麻素系统(endocannabinoid system,ECS)是由多种长链不饱和脂肪酸类似物如花生四酰乙醇酰胺(anandamide,AEA)和2-花生四酰甘油(2-arachidonoyl glycerol,2-AG)及其特异性结合G蛋白偶联受体大麻素受体1(cannabinoid receptor 1,CB1R)和大麻素受体2(cannabinoid receptor 2,CB2R)等组成。通过对细胞物质与能量代谢等方面的影响,ECS几乎影响了机体所有细胞的生命进程和生物学活性。在肝脏,生理性ECS仅低水平表达,肝损伤因素的作用,会强烈刺激肝内ECS的表达和分泌。ECS是多种肝脏疾病共同的参与者。已知,ECS参与了肝细胞脂肪变性过程,促进了非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)和酒精性肝病(alcoholic liver disease,ALD)的形成和发展;参与了肝脏疾病的炎症损伤过程,对肝组织的免疫炎症损伤反应有重要影响;参与了肝纤维形成,促进了肝纤维化和肝硬化的发生与发展。文章通过例举脂代谢相关性肝病(NAFLD和ALD)和其他肝脏病,进一步深入阐述了ECS在肝脏疾病发生发展中的作用及机制。

Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic Iiver disease

Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.

酒精性肝病病人肝移植后酒瘾复发评估工具的研究进展

从肝移植酒瘾复发的概念及现状出发,对国内外酒精性肝病病人肝移植后酒瘾复发评估工具的内容、特点及适用情况等方面进行综述,并对各评估工具的基本情况及应用现状进行比较分析,对现有评估工具存在的问题提出建议,以期为我国酒精性肝病肝移植受者酒瘾复发的预防控制和评估工具的构建提供参考。

Rodent models of fatty liver diseases

Fatty liver diseases including alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are leading causes of chronic liver diseases worldwide.ALD and NAFLD encompass a broad spectrum of liver disorders ranging from simple steatosis to steatohepatitis,fibrosis,cirrhosis and superimposed hepatocellular carcinoma.Despite considerable advances in our understanding of the pathogenesis of fatty liver diseases over the past 40 years,effective diagnostic,prognostic,and therapeutic tools are still lacking.The use of animal models is crucial to investigate the cellular and molecular mechanisms underlying the development and progression of fatty liver diseases and develop novel therapeutic strategies.Although no animal model to date can faithfully replicate all the clinical and histological features of ALD or NAFLD,existing models can mimic specific aspects of human diseases.This review provides an overview of the most commonly used and recently developed rodent models of ALD and NAFLD and discusses their major strengths and shortcomings.

Functional roles of CCL5/RANTES in liver disease

Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.

Cytokines and fatty liver diseases

Cytokines are considered crucial players in inflammatory-associated disorders throughout the body.Fatty liver diseases such as alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are commonly characterized by lipid accumulation and in a substantial subset of patients with inflammation in the liver.Amount of inflammation affects long-term outcome of liver disease including evolution of liver fibrosis,cirrhosis and hepatocellular carcinoma.Especially the pro-inflammatory cytokines Interleukin(IL)-1(αandβ)and tumor necrosis factor(TNF)αplay a central role in many stages of liver diseases mediating fundamental aspects of those diseases including acute phase protein synthesis,lipid metabolism,cholestasis and degree of fibrosis.These key cytokines released mainly by mononuclear cells affect all liver cell types and orchestrate the production of many other mediators relevant in chronic liver diseases.Inflammatory cytokines also regulate crucially the development of insulin resistance,a key component of NAFLD.Blocking these critical mediators of inflammation by specific antibodies,especially TNFα,has so far not been proven successful in alcoholic steatohepatitis,a cytokine-driven disorder.In summary,inflammatory cytokines are continuously present locally and systemically in patients with advanced fatty liver diseases,mediating and affecting the clinical phenotype and many features of these disorders.

大鼠酒精性肝损伤模型的建立

目的:建立大鼠酒精性肝损伤模型,为进一步研究药物对肝损伤的保护机制奠定实验基础。方法:将70只SD大鼠随机分为5组,分别为阴性对照组(生理盐水),1周白酒胃灌注模型组(1周组),2周白酒胃灌注模型组(2周组),4周白酒胃灌注模型组(3周组)和8周白酒胃灌注模型组(4周组)。阴性对照组胃灌注生理盐水3d,1周组、2周组、4周组和8周组分别给于白酒胃灌注1周、2周、4周和8周。实验结束后,收集肝脏标本进行病理组织学检查,检测血清中丙氨酸转氨酶ALT、AST、TG活性及肝组织中SOD活性、MDA含量。结果:与阴性对照组比较,2周组ALT活性(89.73±15.06)高于阴性对照组(78.59±11.62)升高(89.73±15.06 vs.78.59±11.62,P<0.05)外,模型1周和2周组ALT、AST和TG活性无明显差异;模型8周组AST和TG活性升高(166.49±15.73 vs.154.07±9.38;0.93±0.21 vs.0.71±0.19;均P<0.05),而ALT活性显著上升(112.36±9.84 vs.78.59±11.62,P<0.01)。与空白组比较,模型1周和2周组SOD活性和MDA含量无明显差异;模型4周组SOD活性显著下降(98.41±12.60 vs.127.52±13.09,P<0.01),而MDA含量升高(6.05±1.47 vs.4.62±1.24,P<0.05);模型8周组SOD活性降低(109.76±23.05 vs.127.52±13.09,P<0.05),而MDA含量无变化。显微镜下显示,4周组大鼠出现明显的脂肪变性,而8周组大鼠则出现典型的酒精性肝纤维化表现。结论:采用酒精浓度为45%的白酒灌胃,观察到大鼠不同时期酒精性肝损伤的改变,可将该模型运用于护肝药物对大鼠酒精性肝损伤保护作用的研究。

酒精性肝病细胞凋亡的相关机制研究

目的探讨大鼠酒精性肝病细胞凋亡与细胞色素P4502E1、TNF-α及氧自由基的关系。方法采用灌胃法制备大鼠酒精性肝病(ALD)模型,模型组用40%酒精8g/(kg·d)分2次灌胃,共8周,对照组灌等量的生理盐水。采用TUNEL法检测肝细胞的凋亡、用PCR法测定细胞色素P4502E1的表达、放射免疫法检测血清TNF-α含量、硫代巴比妥酸(TBA)法测血清丙二醛(MDA)的含量、黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)的活力。结果模型组凋亡的肝细胞明显增多,主要分布在中央静脉周围、点状和灶状坏死区。CYP2E1表达:对照组c1基因频率为91.65%、c2基因频率为8.35%;模型组c1基因频率为53.35%、c2基因频率为46.65%,差异均有显著性(P<0.05)。血清TNF-α水平与肝细胞凋亡指数及SOD与MDA水平之间有相关性(TNF:AI,r=+0.836;SOD:MDA,r=-0.582)。结论长期酒精摄入可引起肝细胞凋亡增多,CYP2E1基因PstI及RsaIRFLPs与酒精性肝病有关,其中c2基因可能与大鼠酒精性肝病的发生有关,TNF-α和氧自由基及脂质过氧化损伤在酒精性肝病的肝细胞凋亡过程中起一定作用。