Advances in alcoholic liver disease

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. Interactions between acetaldehyde, reactive oxygen and nitrogen species, inflammatory mediators and genetic factors appear to play prominent roles in the development of ALD. The cornerstone of therapy for ALD is lifestyle modification, including drinking and smoking cessation and losing weight, if appropriate. Nutrition intervention has been shown to play a positive role on both an inpatient and outpatient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis and pentoxifylline appears to be a promising anti-inflammatory therapy. Some complementary and alternative medicine agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve quality of life and, in some cases, decrease short-term mortality.     

Autoantibodies in alcoholic liver disease

PURPOSE: To test the hypothesis that since only a proportion of heavy drinkers develop significant alcoholic liver disease (ALD), an autoimmune pathogenesis is likely. PATIENTS AND METHODS: Autoimmune markers were measured in 47 patients with biopsy-proven ALD and compared to measurements in 20 alcoholics without clinical and hematologic evidence of ALD and 28 patients with autoimmune chronic active hepatitis (CAH). RESULTS: Twenty-two percent of patients with ALD were antinuclear antibody-positive, compared to 71% of patients with CAH. Approximately 60% of patients with ALD had either anti-single-stranded or anti-double-stranded DNA antibodies, slightly more than the patients with CAH. Another marker of autoimmunity, as in systemic lupus erythematosus, is the presence of IgM antibodies to autologous and heterologous lymphocytes, which are cytotoxic at 4 degrees C. Seventy-two percent of patients with CAH had positive antilymphocyte antibodies, compared to 59.6% of patients with ALD. Furthermore, more than 90% of the sera from ALD and CAH patients displayed lymphocytotoxicity. Thirty-two percent and 25.5% of CAH and ALD patients, respectively, had all three autoantibodies present. CONCLUSION: These results suggest that autoimmune mechanisms may indeed play a role in the pathogenesis of ALD in at least some patients.     

Advances in alcoholic liver disease

Cytokines are mediators of cellular communication produced by multiple liver cell types. Cytokines can directly induce either necrosis or apoptosis. They can also recruit such cells as neutrophils and lymphocytes, which can mediate liver damage. Increased levels of hepatotoxic cytokines such as tumor necrosis factor-’are documented in alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH) and have been shown to play a mechanistic role in both of these disease processes. Transforming growth factor-βs a profibrotic cytokine that is critical in hepatic fibrosis. Beneficial cytokines, such as interleukin (IL)-10 and-6, also exist. Such beneficial cytokines as adiponectin are made outside the liver and appear to protect against ALD and NASH. This article reviews the relevance of cytokines in human and experimental forms of liver injury, focusing on modulation of cytokines and the use of beneficial cytokines in treatment and prevention of liver injury in ALD, NASH, and hepatitis C.     

Fibrogenesis in alcoholic liver disease

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol abstinence is the most effective therapy for ALD. However, targeted therapies are urgently needed for patients with severe ALD (i.e., alcoholic hepatitis) or those who do not abstain from alcohol. The lack of studies and the availability of animal models that do not reflect all the features of this disease in humans inhibit the development of new drugs for ALD. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying fibrosis in ALD are largely similar to those observed in other chronic liver diseases, oxidative stress, methionine metabolism abnormalities, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells may play unique roles in disease-related fibrogenesis. Lipogenesis during the early stages of ALD has recently been implicated as a risk factor for the progression of cirrhosis. Other topics include osteopontin, interleukin-1 signaling, and genetic polymorphism. In this review, we discuss the basic pathogenesis of ALD and focus on liver fibrogenesis.     

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。     

Glutathione S-transferases in alcoholic liver disease

There is already evidence in alcoholic liver disease, mostly from studies of morphology and cytokeratin distribution, that hepatocytes can undergo a variety of phenotypic changes. This study reports findings of immunohistochemistry using antibodies against members of the glutathione S-transferase supergene family of detoxification enzymes. Hepatocytes in severe alcoholic liver disease coexpressed both alpha and pi class glutathione S-transferase. This coexpression has been previously described only in human fetal liver and in chemically-induced preneoplastic foci in rat liver. The use of function associated markers should provide additional information in the investigation of liver disease.     

Transferrin metabolism in alcoholic liver disease

The metabolism of transferrin was studied using purified 125I-labeled transferrin in 11 alcoholic patients; six with fatty liver and five with cirrhosis. Six healthy subjects whose alcohol intake was les than 40 gm daily were studied as a control group. There were no significant differences in the mean fractional catabolic rate and plasma volume in the alcoholic groups when compared with control subjects. A significantly decreased mean serum transferrin concentration was found in the alcoholic cirrhotic patients (1.8 +/- 0.3 gm per liter vs. 2.9 +/- 0.2; p less than 0.01), resulting from diminished total body synthesis (0.9 +/- 0.2 mg per kg per hr vs. 1.8 +/- 0.2; p less than 0.01). In contrast, in the patients with alcoholic fatty liver, the mean total body transferrin synthesis (2.4 +/- 0.3 mg per kg per hr) was significantly increased when compared with controls (p less than 0.05). For all the alcoholic patients, the serum transferrin correlated with transferrin synthesis (r = + 0.70; p less than 0.01) but the serum iron did not. These results suggest that, in alcoholic cirrhosis, transferrin synthesis is decreased, probably reflecting diminished synthetic capacity by the liver. In contrast, in patients with alcoholic fatty liver, transferrin turnover is accelerated.     

Associated liver disease in alcoholic pancreatitis

Two studies investigating the association of liver disease with acute and chronic pancreatitis in alcoholics are presented. In a retrospective study of 50 patients, no clinical liver disease was found in 9 patients with acute pancreatitis, while 23 (56%) of 41 patients with chronic pancreatitis had liver disease by clinical criteria. Of this latter group, 8 were confirmed histologically; thus 19% of patients with chronic pancreatitis had biopsy-proven cirrhosis. Fifty alcoholic patients with pancreatitis were prospectively evaluated. All who had clinical evidence of liver disease were biopsied. No cases of liver disease were encountered in the 4 patients with acute pancreatitis. Although 28 (60%) cases of clinically diagnosed liver disease were present in 46 patients with chronic pancreatitis, only 20 of these seemed significant (cirrhosis, alcoholic hepatitis, severe fatty liver), for an incidence of 43%. Thus, clinically significant alcoholic liver disease occurs quite frequently in association with alcoholic pancreatitis. This association is meaningful in more effective management of these patients in general and in preoperative assessment of the risk of surgery in particular.Presented in part, at the Annual Meeting of American Pancreatic Study Group held on November 7, 1975, in Chicage, Illinois.     

Fibrinous pericarditis in alcoholic liver disease

The autopsy data at the University of Southern California Liver Unit was studied during a 6-year period to investigate the relationship of fibrinous pericarditis with liver diseases. We found 18 cases of fibrinous pericarditis in 220 patients with alcoholic liver disease but none in 32 patients with fulminant and subacute hepatitis without alcoholism or in 39 patients with nonalcoholic cirrhosis. Although all the 18 patients with pericarditis had azotemia, 3 patients had pericarditis develop only in mild renal function impairment. These findings suggest that chronic alcoholism may precipitate pericarditis during the hepatorenal syndrome.     

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.     

Oxidative damage in alcoholic liver disease

OBJECTIVE: The metabolic effects of alcohol are due both to its direct action and to that of its first metabolite, and can also be connected with the changes in redox state. Differences in ethanol distribution, bioavailability and hepatic metabolism can provide insight into the protective and predisposing factors in alcoholism, as well as gender differences of alcohol toxicity. Oxidative stress occurs following various conditions of ethanol consumption. DESIGN: Twenty-six Caucasian patients with alcoholism and 32 healthy, abstinent controls of both sexes were investigated with special regard to reduction-oxidation status and ad hoc free-radical-antioxidant balance. METHOD: Plasma free SH-group concentration, H-donating ability, and reducing power property were measured by simple spectrophotometric methods. Total scavenger capacity was determined by a newly developed chemiluminometric method in plasma and erythrocytes. RESULTS: Alcoholics showed a decrease of free SH-group concentration, hydrogen-donating ability and an increase of reducing power property in plasma. A decreased total scavenger capacity of erythrocytes and plasma of alcoholic patients, combined with gender differences, could be detected. CONCLUSIONS: Alcoholic dependence causes gradual exhaustion of the antioxidant capacity of erythrocytes, therefore this non-invasive measurement may be useful as a follow-up of the evolution of alcoholic liver disease. The results also suggest a gender susceptibility of alcohol toxicity.     

Bone changes in alcoholic liver disease

Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis (primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. Decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels (a “marker” of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin D and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies.     

Management strategies in alcoholic liver disease

Alcoholic liver disease (ALD) and its complications is still one of the most frequent causes of death in the Western world. Treatment modalities for both alcoholic steatohepatitis (ASH; the major inflammatory complication of ALD) and alcoholic liver cirrhosis are insufficient. Severe ASH is associated with a high mortality; although glucocorticoid treatment has been reported to improve survival, meta-analyses of clinical trials performed to date have failed to show a convincing benefit of such an approach. Most of the progress in understanding these diseases, especially ASH, has come from studies of cytokines. Various proinflammatory cytokines, such as tumor necrosis factor (TNF), have been proposed to have an important role in the pathophysiology of ALD and its complications. Pilot studies on the use of anti-TNF drugs, such as pentoxifylline or infliximab, in the treatment of ASH have now been performed with various levels of success. The treatment of patients with alcohol-related cirrhosis is mainly symptomatic and no therapies are currently available except orthotopic liver transplantation for end-stage liver disease. Independent of the stage of disease, abstinence from alcohol is the cornerstone of management. New treatment modalities for these diseases are eagerly awaited.     

酒精性肝病的内毒素损伤机制

据统计，酗酒者中，只有30％进展到肝硬化，提示在酒精诱导的肝损伤中还需要其它辅助因素，肠道的内毒素就是其中一种重要的辅因子。许多动物实验及临床研究均证实，酒精性肝损伤时常伴发内毒素血症，肠源性内毒素血症在酒精性肝病（ALD）的发生，发展及预后转归中起着重要作用。     

Immunological response in alcoholic liver disease

The development of alcoholic liver disease (ALD) can be attributed to many factors that cause damage to the liver and alter its functions. Data collected over the last 30 years strongly suggests that an immune component may be involved in the onset of this disease. This is best evidenced by the detection of circulating autoantibodies, infiltration of immune cells in the liver, and the detection of hepatic aldehyde modified proteins in patients with ALD. Experimentally, there are numerous immune responses that occur when proteins are modified with the metabolites of ethanol. These products are formed in response to the high oxidative state of the liver during ethanol metabolism, causing the release of many inflammatory processes and potential of necrosis or apoptosis of liver cells. Should cellular proteins become modified with these reactive alcohol metabolites and be recognized by the immune system, then immune responses may be initiated. Therefore, it was the purpose of this article to shed some insight into how the immune system is involved in the development and/or progression of ALD.     

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.