Severe Alcoholic Liver Disease Research Articles

Porphyromonas gingivalis as a promotor in the development of the alcoholic liver disease via ferroptosis

Alcoholic liver disease (ALD) is a liver disease caused by heavy drinking. Porphyromonas gingivalis (P.g), a major cause of periodontitis, whose antibodies are elevated in severe ALD patients in the plasma. The purpose of this study is to further study the role and the molecular mechanism of P.g in the progress of ALD. In this study, saliva of patients with ALD was collected. Then, an animal model of ALD with oral P.g administration was established, pathology of liver and spleen, intestinal microorganisms and metabolites were analyzed. The molecular mechanism of P.g on ALD was analyzed in vitro. ALD and intestinal microflora and metabolite changes were observed more serious in the alcohol and P.g groups than the alcohol group. Moreover, ferroptosis was aggravated by P.g in the liver. Meanwhile, P.g promoted ferroptosis accomplication with alcohol in vitro, which can be reversed by ferroptosis inhibitors. In conclusion, P.g aggravates ALD through exacerbation gut microbial metabolic disorder in mice with alcohol, which maybe depend on ferroptosis activation in hepatocytes. The study provides a new strategy for prevention and treatment of ALD by improving the oral micro-environment.

Alcohol dependence syndrome in patients with alcoholic liver disease

ABSTRACT Background: Excessive alcohol use leads to a spectrum of liver disease. While physicians treat liver disease, the cause, i.e. alcohol, often remains untreated. This portends a poor overall outcome as such patients may continue to consume alcohol for the want of appropriate treatment directed at alcohol dependence or abuse. Our study aimed to assess the prevalence and severity of alcohol dependence among patients with Alcoholic Liver Disease (ALD). Methods: A cross-sectional observational study was conducted among patients with varying severity of ALD (steatosis, hepatitis, and cirrhosis) where 75 were included. They were evaluated for alcohol dependence using clinical interview and M.I.N.I 6.0. The severity of dependence was rated using the SADQ (Severity of Alcohol Dependence Questionnaire). Appropriate statistical tests were applied to identify correlations. Results: All the patients of ALD met the criteria of Alcohol Dependence Syndrome (Clinical interview and ICD 10 criteria). Among them, 40% were severely dependent (SADQ >30). Among those with ALD, 57.3% had alcoholic hepatitis, 18.7% had steatosis, and 24% suffered cirrhosis. Patients with cirrhosis had higher median SADQ scores compared to those with steatosis or hepatitis. Conclusions: All the patients with ALD suffered from Alcohol Dependence Syndrome. Those with the most severe ALD had a higher severity of dependence. To ensure effective treatment and lasting outcomes, there is a need for greater awareness of this fact among physicians. Psychiatric referral of those suffering from ALD will ensure concurrent treatment of Alcohol Dependence Syndrome.

Novel potential biomarkers for severe alcoholic liver disease.

Alcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring. Label-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers. A total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target. This proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.

Rare causes of anemia in liver diseases.

Anemia is a common finding among patients with liver diseases. Patients who suffer from anemia are at a higher risk of liver function decompensation and hospitalization. It affects significantly their quality of life and contributes to mortality. Anemia is present in 70% of patients with liver cirrhosis and with varying incidence accompanies other liver disorders. As the etiology of anemia in liver diseases is multifactorial, various cases represent different clinical entities. Anemia accompanying hepatic disorders can be broadly divided into several types, such as anemia associated with blood loss, as well as aplastic, hemolytic and micronutrient deficiency anemia. However, it is sometimes difficult to delineate between those types in the clinical practice, as several pathophysiological causes can be present in one patient. It is reported that the most common cause of anemia in liver disease is blood loss and iron deficiency. Still, the incidence of unclear cases reaching over 50% suggests that other types of anemia can be underdiagnosed. This review comprehensively describes less frequent types of anemia associated with liver disease, namely hemolytic and aplastic anemia (AA). Hemolytic anemia can complicate autoimmune liver diseases or be a manifestation of membranopathy of red blood cells, dependent on severe hepatic function impairment or alcoholic liver disease. Aplastic anemia is best known as a sequela of viral hepatitis, but some degree of bone marrow inhibition can complicate virtually all advanced liver diseases.

A mini-review of the rodent models for alcoholic liver disease: shortcomings, application, and future prospects.

Rodents are the most common models in studies of alcoholic liver disease (ALD). Although several rodents ALD models have been established and multiple mechanisms have been elucidated based on them, these models have some non-negligible shortcomings, specifically only inducing early stage (mainly steatosis, slight to moderate steatohepatitis) but not the whole spectrum of human ALD. The resistance of rodents to advanced ALD has been suggested to be due to the physiological differences between rodents and human beings. Previous studies have reported significant interstrain differences in the susceptibility to ethanol-induced liver injury and in the manifestation of ALD (such as different alteration of lipid profiles). Therefore, it would be interesting to characterize the manifestation of ethanol-induced liver damage in various rodents, which may provide a recommendation to investigators of ALD. Furthermore, more severe ALD models need to be established for the study of serious ALD forms, which may be achieved by using genetic modified rodents.

Increase in the incidence of alcoholic pancreatitis and alcoholic liver disease in Iceland: impact of per capita alcohol consumption

Objective: To analyze the incidence of acute alcoholic pancreatitis and of severe alcoholic liver disease (ALD) and its association with per capita alcohol consumption with identification of both alcoholic cirrhosis (AC) and severe alcoholic hepatitis (AH), in a population-based setting.Methods: A search was undertaken in diagnoses database for diagnostic codes in order to find patients hospitalized with incident acute alcoholic pancreatitis (AP) and alcoholic liver disease in Iceland in 2001–2015. Diagnoses were verified in all patients who were retrospectively reviewed. Those with ALD had either AC or AH. Alcohol sales during the study period were obtained from Statistics Iceland.Results: Overall, 273 patients with acute AP, mean age at diagnosis 50 (14) years, 74% males and 159 patients with ALD, mean age 57 (11) years, 73% males, were identified. Mean per capita alcohol consumption was 6.95 (0.4) liters and increased by 21% over the study period. The annual incidence of AP increased from 4.2 per 100.000 to 9.5 and ALD from 1.6 to 6.1 per 100.000. Trend analysis showed a significant annual increase of 7% (RR 1.07, 95%CI 1.04–1.10) for AP and an annual increase of 10.5% (RR 1.10, 95%CI 1.06–1.15) for ALD. The increase was only significant in males.Conclusions: Increase per capita alcohol consumption over a 15 year study period was associated with an increase in the incidence of severe alcoholic liver disease and alcohol-related acute pancreatitis in males but not in females.

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease.

Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n=15) and Reverse Transcription Polymerase Chain Reaction (n=32). The activation of dynamin-1-like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n=8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24hours to increasing doses of ethanol (EtOH; 50 to 250mM). A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.

Clinical effect of glucocorticoids versus pentoxifylline in patients with severe alcoholic liver disease: A Meta-analysis

Objective To systematically review the clinical effect of glucocorticoids used alone or in combination with pentoxifylline in patients with severe alcoholic liver disease. Methods PubMed, Embase, Chinese Scientific Journal Full-Text Database, CBM, China Scientific Journal Database, and Chinese Medical Association Digital Journal Database were searched for related articles published up to November 2018, and related journals and collected papers from conferences were searched manually. The clinical effect of glucocorticoids versus placebo, glucocorticoids versus pentoxifylline, and glucocorticoids combined with glucocorticoids versus glucocorticoids alone was analyzed.The effect of glucocorticoids and pentoxifylline used alone or in combination on 28-day survival rate and hepatorenal syndrome in patients with severe alcoholic liver disease was assessed. Odds ratio ( OR) and 95% confidence interval ( CI) were used to evaluate outcome indicators. RevMan 5. 3 software was used for data analysis. Results A total of 22 studies were included, with 1956 patients in total. The glucocorticoid group had a significantly lower 28-day mortality rate than the control group ( 25. 12% vs 30. 67%, OR = 0. 71, 95% CI: 0. 55-0. 93, P = 0. 01) . Subgroup analysis showed that there was a significant difference in 28-day mortality rate between the glucocorticoid group and the pentoxifylline group ( OR = 0. 68, 95% CI: 0. 48-0. 97, P = 0. 03) , while there was no significant difference between the glucocorticoid + pentoxifylline group and the glucocorticoid group ( OR = 0. 92, 95% CI: 0. 66-1. 29, P = 0. 64) . Compared with the glucocorticoid group, the glucocorticoid + pentoxifylline group had a significantly lower incidence rate of hepatorenal syndrome ( 3. 94% vs8. 03%, OR = 0. 45, 95% CI: 0. 24-0. 83, P = 0. 01) . Funnel plots showed no publication bias. Conclusion Glucocorticoids combined with pentoxifylline can reduce the incidence rate of hepatorenal syndrome in patients with severe alcoholic liver disease.

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.

Executive Functioning Moderates Responses to Appetitive Cues: A Study in Severe Alcohol Use Disorder and Alcoholic Liver Disease.

To examine subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task, and its relation to alcoholic liver disease and assess whether executive functioning is associated with appropriate regulation of cue-elicited responses in individuals with severe alcohol use disorder (AUD). Seventeen treatment-seeking alcoholic liver disease patients and a control group of treatment-seeking severe AUD participants completed neuropsychological executive functioning measures (Stroop task; Trail-making test) and the cue reactivity task, whereby control (water) and alcohol beverage cues were presented, followed by respective recovery periods. Subjective alcohol craving and heart rate variability were recorded across the task. Overall cue reactivity and consequent recovery after cue offset during the cue reactivity task was observed, and alcoholic liver disease participants demonstrated a reduced overall recovery effect. Better Stroop performance related to greater overall and alcohol-specific cue reactivity within the control AUD group, and alcoholic liver disease participants showed dysfunctional activity regardless of executive functioning performance. No group differences in recovery effects according to executive functioning performance were seen. Among patients with AUD, having alcoholic liver disease seems to reduce overall regulation of responses to eliciting cues. Executive functioning moderated the magnitude of responses during cue exposures in our AUD sample overall; having alcoholic liver disease did not appear to affect regulation related to executive functioning during recovery.

Plasma levels of soluble ST2, but not IL-33, correlate with the severity of alcoholic liver disease.

Alcoholic liver disease (ALD) is a complication that is a burden on global health and economy. Interleukin‐33 (IL‐33) is a newly identified member of the IL‐1 cytokine family and is released as an “alarmin” during inflammation. Soluble suppression of tumourigenicity 2 (sST2), an IL‐33 decoy receptor, has been reported as a new biomarker for the severity of systemic and highly inflammatory diseases. Here, we found the levels of plasma sST2, increased with the disease severity from mild to severe ALD. Importantly, the plasma sST2 levels in ALD patients not only correlated with scores for prognostic models (Maddrey's discriminant function, model for end‐stage liver disease and Child‐Pugh scores) and indexes for liver function (total bilirubin, international normalized ratio, albumin, and cholinesterase) but also correlated with neutrophil‐associated factors as well as some proinflammatory cytokines. In vitro, lipopolysaccharide‐activated monocytes down‐regulated transmembrane ST2 receptor but up‐regulated sST2 mRNA and protein expression and produced higher levels of tumour necrosis factor‐α (TNF‐α). By contrast, monocytes pretreated with recombinant sST2 showed decreased TNF‐α production. In addition, although plasma IL‐33 levels were comparable between healthy controls and ALD patients, we found the IL‐33 expression in liver tissues from ALD patients was down‐regulated at both RNA and protein levels. Immunohistochemical staining further showed that the decreased of IL‐33‐positive cells were mainly located in liver lobule area. These results suggested that sST2, but not IL‐33, is closely related to the severity of ALD. Consequently, sST2 could be used as a potential biomarker for predicting the prognosis of ALD.

Severe acute alcoholic hepatitis and liver transplant: A never-ending mournful story.

Severe acute alcoholic liver disease (SAAH) unresponsive to medical therapy shows one-year-mortality rates of up to 90%. Most transplant centers request six months of alcohol abstinence prior to transplantation, the so-called “6-month rule.” This regulation is not based on strong evidence, repeatedly making it a topic of controversial debates. The majority of patients with SAAH will die before fulfilling the 6-month rule. Therefore, liver transplantation (LT) protocols are becoming more flexible towards the rigid abstinence regulation, especially concerning SAAH patients. We conducted a literature review regarding LT in SAAH and its outcomes, including post-transplant mortality and recidivism. We studied available data on PubMed from 2011 and onwards whilst including articles dealing with genetic components, medical therapy and historic snapshots of alcoholism. Emerging studies recommend LT in SAAH not responding to medical therapies even without realizing the required abstinence period, since the majority of these patients would die within 6 months. SAAH without response to medical therapy has one-year-mortality rates of up to 90%. The 6-month rule is not based on strong evidence and is repeatedly a topic of controversial debates. There is genetic linkage to alcoholism and medical therapy is not as effective as estimated, yet. The 6-months-regulation has not shown to evidently decrease the risk of recidivism post-LT, which is a lifesaving treatment in SAAH patients. Insisting on rigid sobriety rules results in excluding patients with a low risk of recidivism from being transplanted. Moreover, the genetic linkage of alcoholism must be recognized.

Chances of Renal Recovery or Liver Transplantation After Hospitalization for Alcoholic Liver Disease Requiring Dialysis.

Acute kidney injury in the setting of alcoholic liver disease portends a poor prognosis without liver transplant. Using a tertiary care population, we aimed to evaluate the outcomes of renal replacement therapy in patients with alcoholic liver disease and acute kidney injury with < 6months sobriety. A retrospective review of hospitalized patients with alcoholic hepatitis/acute on chronic alcoholic cirrhosis and hepatorenal syndrome or acute tubular necrosis was performed. Analyzed variables included patient comorbidities, mode of dialysis, MELD-Na score, CLIF-C ACLF score, and CLIF-C OF score. Forty-seven patients were included, 21.3% of which survived 6months of sobriety to be eligible for transplant evaluation. Despite renal replacement therapy, mortality was 78.7%. Of survivors, 4 received transplants and 6 recovered without transplant. Lower CLIF-C ACLF (p < 0.001) and CLIF-C OF (p = 0.001) predicted 6-month survival and lower MELD-Na (p = 0.016), CLIF-C ACLF (p < 0.001), and CLIF-C OF (p = 0.006) predicted renal recovery. There was no difference in survival or renal recovery between etiologies of kidney injury. Modality of initial dialysis with intermittent hemodialysis compared to continuous renal replacement therapy predicted improved survival (41.2 vs. 10.0%, p = 0.01) and nearly reached significance for renal recovery (23.5 vs. 6.7%, p = 0.054). Although severe alcoholic liver disease with acute kidney injury is associated with a high mortality irrespective of the etiology of renal failure, over 20% of patients in this study survived 6months to be evaluated for liver transplant and 12.8% recovered renal function. These outcomes should be considered when weighing the decision of initiating dialysis.

Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.

Alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease. We present the first study to compare outcomes in patients of severe alcoholic hepatitis (SAH) on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor fecal transplantation (FMT) and discuss distinct microbial community and microbiome metabolic functional changes after FMT. Out of 1271 liver disease patients, 809 (63.7%) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT) were included. Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3months were analyzed between groups. Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT. All the patients were male. The proportions of patients surviving at the end of 1 and 3months in the steroids, nutrition, pentoxifylline, and FMT group were 63%, 47%, 40% and 75% [p = 0.179] and 38%, 29%, 30%, and 75% [p = 0.036], respectively. When compared with FMT, relative risk and hazard ratios for death were higher in all the other groups. Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes. Healthy donor FMT for SAH improves survival beyond what is offered by current therapies and can function as a cost-effective bridge to liver transplant (LT) or for improving transplant-free survival. Larger studies and randomized trials are unmet needs.

One year of baclofen in 100 patients with or without cirrhosis: a French real-life experience

Several studies have suggested the efficacy of baclofen in reducing alcohol consumption, leading to a temporary recommendation for use in France. Our aim was to report our experience in using baclofen in alcohol-dependant patients with or without liver cirrhosis. Consecutive patients from two liver and alcohol units were recruited over a 3-year period and received increasing doses of baclofen associated with social, psychological, and medical care. One hundred patients were treated, of whom 65 were cirrhotic. After 1 year, 86 patients were still being followed up. At a mean dosage of 40 mg/day (extremes: 30-210), the median daily alcohol consumption reduced from 80 to 0 g/day (P<0.001). Twenty patients drank a small amount of alcohol of up to 30 g/day and 44 patients were completely abstinent. These declarative results were associated with a significant improvement in alcohol-related biological markers in this 'low-consumption' group of 64 patients: the median γ-glutamyl transferase decreased from 3.9 to 2.0 UNL (P<0.001), the mean aspartate transaminase decreased from 2.6 to 1.2 UNL (P<0.001), and the mean corpuscular volume decreased from 101 to 93 µm (P<0.001). In cirrhotic patients, bilirubinemia decreased significantly from 22 to 11 µmol/l (P=0.026), prothrombin time increased from 68 to 77% (P<0.001), and albuminemia increased from 34.1 to 37.4 g/l (P<0.001). Twenty patients reported grades 1-2 adverse events. No liver or renal function deterioration occurred in cirrhotic patients. In our cohort, baclofen associated with a global care was very well tolerated even in cirrhotic patients. The marked reduction in alcohol consumption in 64 patients translated into a significant improvement in biological markers and in liver function tests. Baclofen could be very useful, especially in cases of severe alcoholic liver disease.

IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages

Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied. Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33-/- and ST2-/- mice in several models. Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33-/- and ST2-/- mice compared to wild-type mice. Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage. In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.

Role of gp91phox in hepatic macrophage programming and alcoholic liver disease.

Hepatic macrophages (MΦs) are important in the development and progression of alcoholic liver disease (ALD). This study investigates the role of gp91phox (nicotinamide adenine dinucleotide phosphate oxidase 2) in the severity of ALD and specifically in regulating hepatic MΦ efferocytic capability and the subsequent reprogramming associated with resolution of inflammation. After 4 weeks of ethanol feeding, more severe ALD developed in gp91phox−/− mice than in wild‐type (WT) C57Bl/6J mice, evidenced by increased liver injury and inflammation. This phenomenon was not sex dependent, and thus the majority of experiments were performed with female mice. While total hepatic MΦ numbers did not differ between genotypes, hepatic infiltrating MΦs (IMs) were slightly more numerous in gp91phox−/− mice, and both IMs and resident Kupffer cells displayed enhanced proinflammatory and reduced tissue‐restorative programming compared with these cells from WT mice. The ratio of proinflammatory IMs with higher expression of Ly6C (Ly6Chi) to anti‐inflammatory IMs with lower expression of Ly6C (Ly6Clow) was significantly higher in gp91phox−/− mice compared to WT mice. Greater numbers of apoptotic cells accumulated in the liver of gp91phox−/− mice compared to WT mice, and receptors for binding and engulfing apoptotic cells were expressed at much lower levels on both Kupffer cells and IMs of gp91phox−/− mice. Interactions with apoptotic cells (binding and engulfment) in vitro were significantly fewer for gp91phox−/− MΦs than for WT MΦs, resulting in diminished expression of tissue restorative mediators by hepatic MΦs of gp91phox−/− mice. Conclusion: gp91phox plays a critical role in the differentiation of proinflammatory hepatic MΦs to a tissue‐restorative phenotype, likely through programming for efferocytosis, and thereby lessens the severity of ALD. These findings enhance our understanding of the tissue environmental cues that regulate MΦ phenotypes. This knowledge could help in designing MΦ‐targeting strategies to prevent and treat ALD. (Hepatology Communications 2017;1:765–779)

Research advances in risk factors for alcoholic liver disease

Only a small number of people may develop severe alcoholic liver disease after continuous or excessive drinking, which is different from the harm caused by smoking, and some people may even develop alcoholic liver disease associated with inflammation, liver cirrhosis, or primary liver cancer. There are complex risk factors for liver injury in these people; besides ethnic and genetic factors, drinking volume, and drinking duration, more important factors are involved in the pathophysiological changes of the liver, such as the type and quality of alcohol, drinking pattern, socioeconomic status, and government public policy, which may be the determining factors for the development of alcoholic liver disease. On the basis of literature review, this article proposes the concept that "liquor does not equal to alcohol" , which has important guiding significance for healthy drinking and the prevention of alcoholic liver disease.

Pathophysiology and Management of Alcoholic Liver Disease: Update 2016.

Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.

Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.

Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5-/-) mice develop more severe alcoholic fatty liver than Cyp2a5+/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα-/-) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5-/- mice. Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. More severe alcoholic fatty liver disease was developed in Cyp2a5-/- mice than in Cyp2a5+/+ mice. Basal FGF21 levels were higher in Cyp2a5-/- mice than in Cyp2a5+/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5-/- mice while FGF21 was induced by ethanol in Cyp2a5+/+ mice. Basal levels of serum FGF21 were lower in Pparα-/- mice than in Pparα+/+ mice; ethanol induced FGF21 in Pparα+/+ mice but not in Pparα-/- mice, whereas ethanol induced hypertriglyceridemia in Pparα-/- mice but not in Pparα+/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα-/- mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα-/-/Cyp2a5-/-) mice developed more severe alcoholic fatty liver than Pparα+/+/Cyp2a5-/- mice. These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease.