Serum cytokeratins in alcoholic liver disease: contrasting levels of cytokeratin-18 and cytokeratin-19.

Serum cytokeratin (CK) levels are widely used as tumor markers. Serum levels of CK-18, a tumor marker also known as tissue polypeptide specific antigen (TPS), are increased in patients with alcoholic liver disease. Cytokeratin-18 is the main component of Mallory bodies, a hallmark of alcoholic hepatitis, which may also contain CK-19. Serum levels of CK-18 and CK-19, a tumor marker also known as CYtokeratin FRAgment 21-1 (CYFRA 21-1) were investigated in (a) heavy drinkers with alcoholic liver disease (n=15), (b) patients with malignancy (n=22), and (c) healthy controls (n=10). Serum levels of CYFRA 21-1 (CK-19) were markedly increased in patients with malignancy, but were similar in heavy drinkers and healthy controls. In contrast, serum levels of TPS (CK-18) in heavy drinkers were higher than those of healthy controls, and even tended to be higher than those of patients with malignancy. Both CK-19 and CK-18 levels were higher in cases of alcoholic hepatitis than in cases of fatty liver. Correlation with hepatocyte CK inclusions was stronger for serum TPS (CK-18) than for CYFRA 21-1 (CK-19). In conclusion, serum CYFRA 21-1 (CK-19) and TPS (CK-18) show a different pattern of increase that could reflect the composition of the altered hepatocyte CK network in alcoholic liver disease. Their usefulness as tumor markers, particularly that of serum TPS (CK-18), may be limited in patients with alcoholic liver disease.     

Elevated levels of blood lead in alcoholic liver disease

Summary In order to investigate the effect of alcohol intake on the activity of erythrocyte aminolevulinate dehydratase (ALA-D), serum alcohol concentration and ALA-D activity was determined in 4 groups of patients. Group I: 18 chronic alcoholics (active phase). Group II: 14 chronic alcoholics (inactive phase). Group III: 13 chronic alcoholics suffering from a biopsy verified liver cirrhosis. Group IV: 16 non-alcoholic patients with biopsy verified liver cirrhosis. Blood lead concentration was determined in patients from group III and IV.ALA-D values were found to be within the normal range in patients from group I, II and IV. 8 patients from group III had abnormally low ALA-D values and 4 of these had elevated blood lead values. Data from group III and IV yields a significant (P < 0.001) negative correlation between blood lead and ALA-D values. No correlation could be demonstrated between serum alcohol and ALA-D values from group I and III.It is suggested that patients suffering from liver cirrhosis may accumulate lead at an increased rate and that alcohol intake in these patients may cause a release of lead from the liver to the blood and thereby a depression of ALA-D activity.     

Hemochromatosis and alcoholic liver disease

The close association of excessive alcohol consumption and clinical expression of hemochromatosis has been of widespread interest for many years. In most populations of northern European extraction, more than 90% of patients with overt hemochromatosis are homozygous for the C282Y mutation in the HFE gene. Nevertheless, the strong association of heavy alcohol intake with the clinical expression of hemochromatosis remains. We (individually or in association with colleagues from our laboratories) have performed three relevant studies in which this association was explored. In the first, performed in 1975 before the cloning of the HFE gene, the frequency of clinical symptoms and signs was compared in patients with classical hemochromatosis who consumed 100 g or more of alcohol per day versus in nondrinkers or moderate drinkers who consumed less than 100 g of alcohol per day. The results showed no difference between the two groups except for features of complications of alcoholism in the first group, especially jaundice, peripheral neuritis, and hepatic failure. Twenty-five percent of those with heavy alcohol consumption showed histologic features of alcoholic liver disease (including cirrhosis) together with heavy iron overload. It was concluded that these patients had the genetic disease complicated by alcoholic liver disease. In the second study (2002), 206 subjects with classical HFE-associated hemochromatosis in whom liver biopsy had been performed were evaluated to quantify the contribution of excess alcohol consumption to the development of cirrhosis in hemochromatosis. Cirrhosis was approximately nine times more likely to develop in subjects with hemochromatosis who consumed more than 60 g of alcohol per day than in those who drank less than this amount. In the third study (2002), 371 C282Y-homozygous relatives of patients with HFE-associated hemochromatosis were assessed. Eleven subjects had cirrhosis on liver biopsy and four of these drank 60 g or more of alcohol per day. The reason why heavy alcohol consumption accentuates the clinical expression of hemochromatosis is unclear. Increased dietary iron or increased iron absorption is unlikely. The most likely explanation would seem to be the added co-factor effect of iron and alcohol, both of which cause oxidative stress, hepatic stellate cell activation, and hepatic fibrogenesis. In addition, the cumulative effects of other forms of liver injury may result when iron and alcohol are present concurrently. Clearly, the addition of dietary iron in subjects homozygous for hemochromatosis would be unwise.     

Nutrition and alcoholic liver disease

While the rate of malnutrition is relatively modest in alcoholic patients without alcoholic liver disease, the rate of malnutrition is virtually 100% in patients with alcoholic hepatitis and/or alcoholic cirrhosis. The reasons for malnutrition in the alcoholic hepatitis patient include various factors such as anorexia, poor diet, malabsorption, and altered metabolic state. When the patient is hospitalized, the malnutrition frequently worsens because of fasting for tests, continued anorexia, and complications such as gastrointestinal bleeding. Patients with severe acute hepatitis appear to be both hypermetabolic and hypercatabolic, whereas data are much more conflicting concerning patients with more stable liver disease. Most studies suggest that patients with alcoholic liver disease require at least 60 g of protein per day to maintain positive nitrogen balance. Consistent alterations in plasma amino acid profiles occur in alcoholic liver disease, and specialized nutritional formulations have been devised to correct this amino acid profile with the intent of improving overall nutritional status, hepatic encephalopathy, and mortality. The effects of nutritional support (including use of specialized products) on outcome, on acute hepatic encephalopathy, and on chronic or latent portal systemic encephalopathy are reviewed.     

Nutrition and alcoholic liver disease

Summary  Mounting interest in the potential value of nutritional therapy in the treatment of alcoholic liver disease (ALD) has arisen as a result of the growing body of evidence implicating nutritional intervention as a key player in ameliorating ALD. This review will focus on the involvement of nutrition in the pathogenesis of ALD, with extended focus on the role of micronutrients in the intervention or prevention of ALD. Oxidative damage is a major pathway in the initiation of ALD, and as such, many micronutrients have protective roles owing to their antioxidant properties. This can be either a direct action by scavenging free radicals or an indirect one elicited by increasing the synthesis or recycling of glutathione, the main intracellular antioxidant molecule. Micronutrients should be consumed as part of an energy-sufficient (at least 1400 kcal/day), macronutrient-based diet, as ALD progresses more quickly in people who have substituted a normal diet with alcohol, as opposed to those who drink alcohol in addition to their daily diet. Discontinuing alcohol consumption will enhance recovery, although this is not always possible with alcohol-addicted patients. In conclusion, an energy-sufficient diet high in vitamins and minerals will help protect against the formation and progression of ALD. However, alcohol abstinence is the recommended course of action to aid any recovery.     

Oxidative stress and antioxidant defense in alcoholic liver disease and chronic hepatitis C

In the past decade it became accepted that free radicals, lipid peroxidation and antioxidant defense play a role in various tissues damages, thus in certain liver diseases as well. Since only limited data have been reported concerning the oxidative stress in viral hepatitis, a comparative study was performed in patients (pts) with chronic hepatitis C and alcoholic liver disease. In addition, the effects of a flavonolignan drug silymarin were assessed. 10 pts with chronic hepatitis C, 5 pts with alcoholic hepatitis and 13 pts with alcoholic cirrhosis have been investigated. Biochemical liver tests (serum bilirubin, aminotransferases, ALT, AST, lactate dehydrogenase (LDH), pseudocholinesterase, prothrombin), malandialdehyde (MDA) levels in plasma and red blood cell (RBC) hemolysate, superoxide radical generating capacity of stimulated polymorphonuclear granulocytes (PMN), plasma concentrations of reduced (GSH) and oxidized (GSSG) glutathione, vitamin A, luteine and beta carotene, furthermore RBC superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase activities were determined. The level of plasma MDA--as the marker of lipid peroxidation--was highest in alcoholic cirrhosis (five times of normal) (p < 0.05), the RBC hemolysate MDA was most elevated in chronic hepatitis C (p < 0.05). The mean PMNs' superoxide radical generating capacity was 116.6% of normal control in alcoholic hepatitis, where the mean GSH level was the lowest (89.8% of normal). Plasma vitamin A content was lowest in alcoholic cirrhosis (68% of control) (p < 0.05). SOD activity was elevated in both chronic hepatitis C and alcoholic cirrhosis, where GPx activity was decreased (p < 0.05). There was a correlation between LDH and SOD activities (r = 0.77, p = 0.015). Silymarin treatment of one month duration resulted in normalization of serum bilirubin in 55% of treated pts, AST became normal in 45%, and RBC hemolyzate MDA level normalized in similar rate. A significant increase in both GSH and retinoids was found. Alterations in oxidative stress and antioxidant defense system were shown in chronic hepatitis C, not only in alcoholic liver disease. The parameters of lipid peroxidation and antioxidant defense may be useful surrogate markers for monitoring pts with liver disease during hepatoprotective treatment.     

Obesity and alcoholic liver disease.

Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index-based guidelines for "safe" alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators.     

Nutrition in alcoholic liver disease.

Liver disease secondary to alcohol ranges from alcoholic fatty liver disease to acute hepatitis to cirrhotic liver disease. It is imperative that alcohol be discontinued to allow for any potential improvement in liver function, with most benefit being seen in the early stages of the disease. Alcoholic liver disease has a profound effect on nutrient intake, nutrition status, and metabolism, contributing to a high prevalence of malnutrition in this population. Early intervention with nutrition therapy may improve response to treatment, alleviate symptoms, and improve quality and quantity of life. In this review, nutrition assessment parameters and medical nutrition therapy goals for alcoholic liver disease are discussed.     

Serum leptin levels in alcoholic liver cirrhosis: relationship with gender, nutritional status, liver function and energy metabolism

OBJECTIVE: To determine serum leptin levels in alcoholic liver cirrhosis and the relationship with gender, nutritional status, liver function, energy metabolism, inflammatory state and refeeding. SUBJECTS: Thirty-seven hospitalized alcoholic cirrhotic patients (M/F: 24/13), 27 hospitalized patients at risk of malnutrition but with normal liver function (M/F: 15/12) as control patients, and 31 healthy control subjects (M/F: 17/14) participated. DESIGN: Liver function was assessed from Child-Pugh classification; anthropometric parameters and resting energy expenditure (REE) were measured; caloric intake was evaluated over 5 days; and serum leptin and insulin were assayed. The same protocol was performed after 1 month refeeding in 22 patients. Healthy subjects were studied as controls for anthropometric parameters and serum leptin levels. RESULTS: Serum leptin levels were higher in male cirrhotic patients than in the other two male groups (P=0.0079) and in the same range in the female groups. They were higher in female than in male subjects in the three groups. In female cirrhotic patients, logarithmically transformed serum leptin levels correlated significantly with fat mass (P=0.0043), insulin levels (P=0.0072), REE (P=0.0133), bilirubin levels (P<0.0001), prothrombin time (P=0.0003) and Pugh score (P=0.0266) in simple regression analysis and with insulin levels (P=0.0137), but not with fat mass (P=0.0761), Pugh score (P=0.4472) and REE (P=0.4576) in multiple regression analysis. In the male cirrhotic and control patients, log (leptin) levels correlated with CRP (C reactive protein) (r=0.365, P=0.0223). Log (leptin) levels did not correlate with caloric intake in any of the groups. Leptin levels (P<0.05) and fat mass (P<0.02) increased with refeeding while liver function improved (P<0.01). CONCLUSION: There is a gender difference in regulation of serum leptin level in alcoholic liver cirrhosis. Insulin level is the best determinant of leptin level in female patients while inflammatory state related to alcoholic hepatitis seems to have a greater influence in male patients. Although leptin levels positively correlated with REE in female patients, there is no evidence that leptin reduces caloric intake and fat stores in these patients.     

Pathology of alcoholic liver disease

The history of alcohol consumption has been nearly as long as the history of mankind. Alcohol-related diseases represent a serious problem all over the world and they show a gradually increasing tendency. It can be stated that the frequency of occurrence, severity and mortality of alcohol-related hepatic diseases are in direct correlation with the amount of alcohol consumed. The direct hepatotoxic effect of alcohol and its metabolites has become obvious by now. In addition to this, other mechanisms also play a part in the development of hepatic diseases: their occurrence and severity are significantly influenced by genetic and environmental factors. The rather wide spectrum of alcohol-related hepatic diseases includes steatosis, perivenular fibrosis, alcohol-related hepatitis, occlusive venous lesions, cirrhosis and hepatocellular cancer. All of these disorders are characterized by clearly defined, characteristic but non-specific changes, which need to be supplemented by histological diagnostic criteria. Cirrhosis, which must still be regarded as an irreversibly lethal condition, is thought to develop in two ways. A well-known and widely accepted assumption is that episodes of alcohol-related hepatitis aggravated by progressive fibrosis sooner or later lead to cirrhosis. Another possible explanation is that steatosis facilitating the development and spreading of perivenular fibrosis--even without episodes of hepatitis--may lead to cirrhosis. Thus, alcohol-related hepatic conditions have characteristic pathohistological features, none of which, however, are pathognomonic at the same time. Therefore, the definitive diagnosis of any form of alcohol-related hepatic disorders needs to take evidence of alcohol consumption into account.     

Mitochondrial glutathione depletion in alcoholic liver disease

Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage. These results suggest that depletion of mitochondrial GSH by impairment of its transport from cytosol into mitochondria could be an additional contributing factor in the development of ALD by favoring pro-oxidant production and oxidant stress in mitochondria.     

Monocyte activation in alcoholic liver disease.

Activated monocytes and macrophages have been postulated to play an important role in the pathogenesis of alcoholic liver disease (ALD). Monocyte activation can be documented by measurement of neopterin, adhesion cell molecules, and certain proinflammatory cytokines and chemokines. We first became interested in the role of monocytes and monocyte-derived cytokines in ALD in relation to altered zinc metabolism that occurs regularly in ALD. Patients with ALD have hypozincemia, which responds poorly to oral zinc supplementation. We have shown that in ALD monocytes make a low-molecular-weight substance that, when injected into rabbits, causes prominent hypozincemia. Subsequently, multiple cytokines [especially tumor necrosis factor (TNF) and interleukin (IL)-8] have been shown to be overproduced by monocytes in ALD. We initially showed that monocytes in ALD spontaneously produce TNF and overproduce TNF in response to a lipopolysaccharide (LPS) stimulus, and this could be attenuated by antioxidants in vitro and in vivo. Alterations in the endotoxin-binding protein LPS-binding protein, in CD14, and in the endotoxin receptor Toll-like receptor 4 all may play roles in enhanced proinflammatory cytokine signaling in ALD. Moreover, several groups have documented increased TNF receptor density in monocytes in ALD. Inadequate negative regulation of TNF occurs at multiple levels in ALD. This includes decreased monocyte production of the important antiinflammatory cytokine IL-10 and blunted response to the antiinflammatory properties of adenosine. Finally, generation of reactive oxygen species (which occurs during alcohol metabolism) and products of lipid peroxidation induce production of cytokines, such as TNF and IL-8. In conclusion, there are multiple overlapping potential mechanisms for enhanced proinflammatory cytokine production by monocytes in ALD. We postulate that activation of monocytes and macrophages with subsequent proinflammatory cytokine production plays an important role in certain metabolic complications of ALD and is a component of the liver injury of ALD.     

Genetic background of alcoholic liver disease

The genetic background of alcoholic behaviour and alcoholic liver diseases has long been the target of intense research. The current knowledge of this very interesting topic is herewith summarized with special emphasis on findings and facts which might have clinical significance including results of family studies, gene polymorphisms of enzyme families of alcohol metabolism, cytokines as well as HLA antigens.     

酒精性肝病治疗方法进展

酒精性肝病包括急性酒精性肝炎和酒精性肝硬化.戒酒一直是治疗所有酒精性肝病的基础.近年来,关于乙醇引起肝损伤机制的研究,提出了酒精性肝病治疗发展的前景.本文作者回顾近期资料关于急性酒精性肝损伤治疗的效果,包括营养治疗、皮质激素类、抗炎因子、抗氧化剂和一些直接抗纤维化过程的要素,如秋水仙碱和抗氧化物质.治疗方法包括直接改变肝损伤和修复进程,但无可持续改善酒精性肝损害的疗法.因此,肝移植仍是因慢性酒精性肝损伤致肝功能衰竭病人的最终选择.