Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease

Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.     

Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases, and gut microbes are the key regulators in maintaining liver homeostasis. Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology, which can contribute to fatty liver disease. In this review, we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology. We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.     

Microbiota-based treatments in alcoholic liver disease

Gut microbiota plays a key role in the pathogenesis of alcoholic liver disease (ALD). Consumption of alcohol leads to increased gut permeability, small intestinal bacterial overgrowth, and enteric dysbiosis. These factors contribute to the increased translocation of microbial products to the liver via the portal tract. Subsequently, bacterial endotoxins such as lipopolysaccharide, in association with the Toll-like receptor 4 signaling pathway, induce a gamut of damaging immune responses in the hepatic milieu. Because of the close association between deleterious inflammation and ALD-induced microbiota imbalance, therapeutic approaches that seek to reestablish gut homeostasis should be considered in the treatment of alcoholic patients. To this end, a number of preliminary studies on probiotics have confirmed their effectiveness in suppressing proinflammatory cytokines and improving liver function in the context of ALD. In addition, there have been few studies linking the administration of prebiotics and antibiotics with reduction of alcohol-induced liver damage. Because these preliminary results are promising, large-scale randomized studies are warranted to elucidate the impact of these microbiota-based treatments on the gut flora and associated immune responses, in addition to exploring questions about optimal delivery. Finally, fecal microbiota transplant has been shown to be an effective method of modulating gut microbiota and deserve further investigation as a potential therapeutic option for ALD.     

酒精性肝病诊断现状

酒精性肝病（Alcoholic liver disease,ALD）是西方国家最常见的肝病。在法国,l/3以上肝硬化病因是过量饮酒。在美国,酒精性肝硬化是最常见死亡原因的第8位,在胃肠道疾病中,其死亡率位列第二[1]。我国酒精的消耗量也在不断增加。尽管中国缺乏大规模ALD的流行病学调查资料,但几个局部地区的报道发现ALD的发病比例在不断上升[2,3]。同时,我国还面临较多的酒精性肝病和/或非酒精性脂肪性肝病（non-alcoholic fatty liver disease,NAFLD）合并病毒性肝病的现实问题。     

酒精性肝病发病机制研究的最新进展

酒精性肝病(alcoholic liver disease,ALD)是由于急慢性酒精暴露导致的肝损害,是一种致病因素单一,发病机制复杂的病种,近期研究表明,蛋氨酸代谢失衡、过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)表达改变、纤溶系统失衡也是酒精性肝病的重要发病机制,本文就其发病机制的研究进展作一概述。     

Challenges in transplantation for alcoholic liver disease

Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist’s assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient’s pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key factor determining the outcome of transplantation for alcoholic cirrhosis is intensive lifelong medical and psychological care. Post-transplant surveillance might be much more important than pre-transplant selection.     

酒精性肝病发病机制研究进展

酒精性肝病（alcoholic liver disease,ALD）是指长期过量饮酒导致的肝脏疾病,包括酒精性脂肪肝（al-coholic fatty liver,AFL）、酒精性肝炎（alcoholic hep-atitis,AH）、酒精性肝纤维化（alcoholic hepatic fibro-sis,AHF）、酒精性肝硬化（alcoholic cirrhosis,AC）和肝细胞癌（hepatocellular carcinoma,HCC）。酒精性肝病是世界范围内慢性肝病的最重要病因之一,约占全球死亡率的3.8%,在发达国家十分常见。2007年美国国家防止酒精滥用及酒精中毒研究所的报告显示肝硬化死亡率位于死亡原因的第12位,其中超过48%的比例与酒精相关。在英国社区综合医院收治的各类肝硬化患者中,酒精性肝硬化占80%。在澳大利亚,酒精性肝硬化占总的疾病负担的5%,占肝病负担的50%,占肝移植病因的15%[1]。在我国,随着社会经济的发展和生活水平的提高以及受“中国酒文化”的影响,ALD发病率呈逐渐上升的趋势,在某些地区已成为继病毒性肝炎之后导致肝损害的第二大病因[2]。虽然饮酒是ALD的根本病因,90%～95%饮酒者可以发展为酒精性脂肪肝,但是只有30%～35%饮酒者发展为比较严重的酒精性肝病,包括酒精性肝炎、肝纤维化、肝硬化及肝细胞癌,说明除了酒精以外还有其他因素参与了ALD的发病机制[3]。现从以下几方面简要介绍近几年国内外对ALD发病机制的研究进展。     

酒精性肝病与精神障碍

酒精性肝病是由于长期大量饮酒所导致的慢性肝脏疾病。酗酒会导致机体多系统受损,其中包括神经损害和精神障碍。临床上,酒精所致的神经精神损害表现复杂多样,常导致诊断困难甚至出现误诊。本文将对酒精所致的精神障碍的机制、5种常见的酒精性精神障碍疾病的识别要点及酒精性相关精神障碍的治疗进行综述。多学科有效协作、社会和家庭各方面相互合作对此类疾病的诊治和预防具有重要意义。     

Liver fibrosis markers in alcoholic liver disease

Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients.     

Therapy for alcoholic liver disease

Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function ≥ 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and portopulmonary hypertension. Alcoholic cirrhotics have increased risk of developing hepatomas. Liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 mo of proven abstinence for eligibility. Alcoholic cirrhotics who maintain abstinence generally have a relatively favorable prognosis after liver transplantation.     

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.     

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

Purpose Altered redox status has been implicated in pathogenesis of alcoholic liver disease (ALD) as well as in nonalcoholic fatty liver disease (NAFLD). This study was planned to find the relative role of redox status in these two diseases. Methods A total of 44 patients with ALD and 32 patients with NAFLD and 25 apparently healthy controls were included in the study. Redox status was estimated by measuring oxidative stress (superoxide dismutase (SOD) and lipid peroxidation products as thiobarbituric acid reactive substances (TBARS)) and antioxidant status (ferric reducing ability of plasma (FRAP) and vitamin C). Results TBARS level was raised significantly in both ALD (3.5 (2.3–9.4) vs. 1.8 (0.5–4.1) nmol/ml; P = 0.0001) and NAFLD (5.1 (1–10.2) vs. 1.82 (0.51–4.1) nmol/ml; P = 0.0001) as compared with controls, but was not different between ALD and NAFLD. SOD was significantly higher in ALD as compared to NAFLD (2.4 (1.3–7.8) vs. 0.68 (0.05–19.1) U/ml; P = 0.0001) and controls (1.12 (0.01–3.5) U/ml; P = 0.001). FRAP was lower in ALD as compared with NAFLD (345.4 (56–615.9) vs. 434.1 (197.6–733.3) μmol of Fe⁺² liberated; P = 0.001) but similar to that of controls (340.9 (141.5–697.5) μmol of Fe⁺² liberated). Conclusions ALD patients have a higher degree of redox imbalance as compared with NAFLD patients     

Predicting utility of a model for end stage liver disease in alcoholic liver disease

AIM: To validate the statistic utility of both the Maddrey Discriminant Function score and the Model for End-Stage Liver Disease as predictors of short term (30 d and 90 d) mortality in patients with alcoholic hepatitis and to assess prognostic factors among clinical characteristics and laboratory variables of patients with alcoholic hepatitis. METHODS: Thirty-four patients with the diagnosis of alcoholic hepatitis admitted to Hippokration University Hospital of Athens from 2000 to 2005 were assessed in the current retrospective study and a statistical analysis was conducted. RESULTS: 30- and 90-d mortality rates were reported at 5.9% (2/34) and 14.7% (5/34), respectively. Significant correlation was demonstrated for the Model for End-Stage Liver Disease (P30=0.094, P90=0.046) and the Maddrey Discriminant Function score (P30= 0.033, P90= 0.038) with 30- and 90-d mortality whereas a significant association was also established for alanine aminotrans-ferase (P = 0.057), fibrin degradation products (P= 0.048) and C-reactive protein (P = 0.067) with 90-d mortality. For 30-d mortality the Area Under the Curve was 0.969 (95%CI: 0.902-1.036, P = 0.028) for the Model for End-Stage Liver Disease score and 0.984 (95%CI: 0.942-1.027, P = 0.023) for the Maddrey Discriminant Function score with the optimal cut off point of 30.5 (sensitivity 1, specificity 0.937) and 108.68 (sensitivity 1, specificity 0.969), respectively. Accordingly, for 90-d mortality the Area Under the Curve was 0.762 (95%CI: 0.559-0.965, P = 0.065) for the Model for End-Stage Liver Disease score and 0.752 (95%CI: 0.465-1.038, P = 0.076) for the Maddrey Discriminant Function score with the optimal cut off point of 19 (sensitivity 0.6, specificity 0.6) and 92 (sensitivity 0.6, specificity 0.946), respectively. The observed Kaplan Meier survival rates for different score-categories were compared with log-rank tests and higher score values were correlated with a lower survival. CONCLUSION: Equivalency of the Model for End-Stage Liver Disease and the Maddrey Discriminant Function score is implied by the current study, verified by the plotted Receiver Operative Curves and the estimated survival rates. A statistically significant utility of C-reactive protein, fibrin degradation products and alanine aminotrans-ferase as independent predictors of 90-d mortality has also been verified.     

肠道微生态与酒精性肝病

<正>酒精性肝病(ALD)的发病机制目前仍不清楚,酒精的脂溶性及毒性可直接破坏肠黏膜屏障,导致宿主肠道通透性增加,失调的肠源性微生物群及其代谢产物通过被破坏的细胞间连接直接进入门脉系统,可能是发生ALD的基础和重要原因~([1,2])。肝病程度越重(如肝硬化)患者比健康人血液有更高水平的细菌数量及其代谢产物,高水平的细菌移位引起的感染极大地增加了酒精性肝硬化(alcoholic     

Advances in alcoholic liver disease:An update on alcoholic hepatitis

Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality(25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material(Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline.     

Non-invasive diagnosis of alcoholic liver disease

Alcoholic liver disease (ALD) is the most common liver disease in the Western world. For many reasons, it is underestimated and underdiagnosed. An early diagnosis is absolutely essential since it (1) helps to identify patients at genetic risk for ALD; (2) can trigger efficient abstinence namely in non-addicted patients; and (3) initiate screening programs to prevent life-threatening complications such as bleeding from varices, spontaneous bacterial peritonitis or hepatocellular cancer. The two major end points of ALD are alcoholic liver cirrhosis and the rare and clinically-defined alcoholic hepatitis (AH). The prediction and early diagnosis of both entities is still insufficiently solved and usually relies on a combination of laboratory, clinical and imaging findings. It is not widely conceived that conventional screening tools for ALD such as ultrasound imaging or routine laboratory testing can easily overlook ca. 40% of manifest alcoholic liver cirrhosis. Non-invasive methods such as transient elastography (Fibroscan), acoustic radiation force impulse imaging or shear wave elastography have significantly improved the early diagnosis of alcoholic cirrhosis. Present algorithms allow either the exclusion or the exact definition of advanced fibrosis stages in ca. 95% of patients. The correct interpretation of liver stiffness requires a timely abdominal ultrasound and actual transaminase levels. Other non-invasive methods such as controlled attenuation parameter, serum levels of M30 or M65, susceptometry or breath tests are under current evaluation to assess the degree of steatosis, apoptosis and iron overload in these patients. Liver biopsy still remains an important option to rule out comorbidities and to confirm the prognosis namely for patients with AH.     

缺氧诱导因子-1与酒精性肝病

缺氧诱导因子(HIF)-1是一种由α和β亚单位组成的二聚体核转录因子,是体内氧平衡调节机制中最重要的转录激活因子,其转录系统主要受细胞内氧浓度的调节,通过下游的信号转导参与病理生理反应,大量研究发现酒精性肝病中存在缺氧状态,本文诣在阐述HIF-1在酒精性肝病发病机制中的作用.     

酒精性肝病治疗进展

酒精性肝病是影响人们健康的常见肝病之一。积极预防、合理治疗可以有效地控制病情进展。过量酒精摄入是导致人体疾患的主要原因,重症酒精性肝病的治疗为该病治疗的重点和热点。 Child-Pugh分级、Maddrey判别函数、MELD模型、GAHS评分、年龄-胆红素-INR-肌酐（ABIC）评分及Lille评分可较好地预测预后,评判疗效。肝移植仍为终末期酒精性肝病的主要治疗手段。     

1例初诊酒精性肝病患者的循证治疗

目的借助循证医学的方法为1例初诊酒精性肝病患者确定治疗方案。方法根据患者情况提出临床问题,在Cochrane图书馆、PubMed、Embase、维普资讯上检索,并对相关证据进行评价,结合医生经验及患者意愿制定治疗方案。结果共纳入相关文献16篇,分析后对该患者确定治疗方案:水飞蓟宾(利加隆胶囊140 mg,tid)降转氨酶+泼尼松龙(40 mg/d,28 d)非特异性抗炎治疗。经10个月的随访,证实该方案对患者安全有效。结论采用循证治疗的方法,为初诊酒精性肝病患者确定合理的治疗方案,可有效提高治疗效果。     

Alcohol metabolites and lipopolysaccharide： Roles in the development and/or progression of alcoholic liver disease

The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol- induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts,and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore,the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflammation inflammation and fibrosis, and play a role in the development and/or progression of ALD.