Status of blood antioxidant enzymes in alcoholic cirrhosis

Chronic alcohol consumption is associated with increased incidence of variety of illnesses including cirrhosis. Studies have shown that ethanol consumption may result in increased oxidative stress with increased formation of lipid peroxides and free radicals. However, very few reports are available on their involvement in the toxicity of alcoholic cirrhosis. The present study was undertaken in 44 male subjects to evaluate the role of oxidative stress in liver injury with special reference to alcoholic or non alcoholic cirrhosis. It was observed that the parameters of liver function like total bilirubin, Alanine Transaminase (ALT), Aspartate Transaminase (AST), Alkaline Phosphatase (ALP), gamma Glutamyl transfarase (gammaGT) were increased in cirrhotic (alcoholic or non alcoholic) patients as compared to normal controls. However antioxidant enzymes like Superoxide dismutase (SOD) and Glutathine peroxidase (GPx) lipid peroxidation marker, Malondialdehyde (MDA) showed significant changes only in alcoholic cirrhosis and not in non alcoholic cirrhosis when compared with normal controls. The possibility of assessment of antioxidant enzymes to differentiate between alcoholic or non alcoholic or non alcoholic cirrhosis is postulated.     

The Measurement of D,L-2,3-Butanediol in Controls and Patients with Alcoholic Cirrhosis

Plasma D,L-2,3-butanediol was measured in 53 controls and 50 patients with alcoholic cirrhosis, none of whom had measurable amounts of blood ethanol. Thirteen of 50 samples from patients with alcoholic cirrhosis had measurable D,L-2,3-butanediol. (range < 5-154 uM). In one patient with alcoholic cirrhosis who had been abstinent from ethanol for over 5 years plasma levels of D,L-2,3-butanediol ranged between 154 and 211 uM over a one-year period. Only one of the 53 control subjects had detectable levels of D,L-2,3-butanediol. Although it has previously been reported that 2,3-butanediol is present in alcoholics consuming distilled spirits (Runstein et al. (1983) Lancet ii, 534), this is the first report of the persistent presence of these compounds in alcoholics in the absence of ethanol. Clearly in abstinent alcoholics the presence of 2,3-butanediol is not due to the ingestion of undistilled spirits nor is it likely to arise directly from the metabolic products of ethanol. The presence of D,L-2,3-butanediol in patients with alcoholic cirrhosis and its absence in control subjects suggests that this compound may be a marker of some forms of alcoholism.     

Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis

Background Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence and the severity of portal hypertension (PHT). Liver stiffness measurement (LSM) is a non‐invasive method for liver fibrosis assessment. Aims To assess the relationship between LSM and HVPG in patients with compensated cirrhosis related to hepatitis C virus (HCV) or alcohol and to define the performance and the best cut‐off of LSM for the diagnosis of PHT in these patients. Methods Between January 2004 and September 2006, we studied all the consecutive patients with compensated HCV or alcohol‐related‐cirrhosis referred for transjugular liver biopsy with HVPG measurement and LSM performed the same day. Results Ninety‐two patients were eligible, 44 had HCV related‐cirrhosis and 48 alcoholic cirrhosis. LSM was positively correlated to HVPG in both groups. The area under the receiver operating characteristic curve for the diagnosis of significant PHT was 0.76 ± 0.07 in HCV patients (best cut‐off at 20.5 kPa) and 0.94 ± 0.03 (best cut‐off at 34.9 kPa) in alcoholic patients. Conclusions Liver stiffness measurement and HVPG were significantly correlated in patients with compensated cirrhosis because of HCV infection or alcohol. LSM could predict significant PHT in both these groups of patients with a higher cut‐off and a better performance in alcoholic patients.     

Blood antioxidant levels in patients with alcoholic liver disease correlate with the degree of liver impairment and are not specific to alcoholic liver injury itself

BACKGROUND: Enhanced production of reactive oxygen species may play a pathogenic role in alcoholic liver injury. AIMS: To investigate whether various antioxidant parameters in blood are affected in different stages of alcoholic liver disease and how specific the changes are relative to non-alcoholic cirrhosis. METHODS: Patients with alcohol abuse without cirrhosis (n=14), with alcoholic cirrhosis [Child-Pugh scores A (n=9), B (n=5) and C (n=18)] and with non-alcoholic cirrhosis [Child-Pugh score C (n=6)] and healthy controls (n=13) were studied. Levels of reduced glutathione and glutathione peroxidase activity in blood, erythrocytic superoxide dismutase activity and carotenoids, alpha-tocopherol and malondialdehyde in plasma were measured. RESULTS: Levels of reduced glutathione were significantly decreased in Child-Pugh score C cirrhotics, alcoholic or not in origin, whereas oxidized glutathione and glutathione peroxidase activity were not affected. Superoxide dismutase activity and alpha-tocopherol levels were not significantly different in the various groups. Carotenoid levels were significantly lower in alcoholic cirrhotics (Child-Pugh score C) vs. controls. Malondialdehyde levels were elevated only in cirrhotics Child-Pugh score C, alcoholic or non-alcoholic. CONCLUSIONS: Levels of reduced glutathione and malondialdehyde reflect the degree of liver impairment, more than the relation with alcohol intake. Decreases in several antioxidant levels are not specific to alcoholic liver injury.     

GENETIC AND ENVIRONMENTAL DETERMINANTS OF SUSCEPTIBILITY TO ALCOHOL-INDUCED LIVER DISEASE

Although there is an overall relationship between cumulative alcohol intake and the severity of alcohol-related liver damage, there is considerable variation in individual susceptibility to the hepatotoxic effects of alcohol. In this review I shall discuss what factors appear to influence susceptibility. Women develop liver disease after a shorter period of excessive drinking and at a lower alcohol intake than men. This is partly related to differences in body size and composition between the sexes which result in women having preportionately higher blood alcohol levels than men after a standard drink; this probably explains why women are more susceptible to a variety of alcohol-related problems. Other genetic determinants of susceptibility have until recently proved elusive, but certain HLA types, such as HLA-B8, have been shown to increase the risk of chronic liver damage by up to 50%. No genetic variations in the enzymes responsible for alcohol metabolism have been definitely associated with predisposition to liver damage. The more severe lesions — alcoholic hepatitis and cirrhosis — are more common in regular daily drinkers compared with intermittent or ‘qbinge’ drinkers and in moderately dependent patients compared with those who have severe alcohol-withdrawal symptoms. No exogenous agents such as hepatitis viruses of chemicals have yet been shown to contribute to the development of any of the morphological abnormalities of alcoholic liver disease. At the present time there is insufficient information for us to be able to tailor our advice about drinking to the individual patient. We recommend that men should on no account drink more than 80 g alcohol per day and that women should keep below half this amount. People whose intakes approach these amounts should have two alcohol-free days every week. In the future it may be possible to screen specifically for markers of susceptibility to liver damage in populations known to be at risk of alcohol problems.     

Gender difference of clinical features in Japanese patients with alcoholic liver cirrhosis]

Gender difference of alcohol intake and laboratory data was investigated in 165 Japanese patients with alcoholic liver cirrhosis. Mean age of first drinking and habitual drinking were higher in female. Duration of drinking was shorter in female. Although cumulative alcohol intake was larger in male, mean daily alcohol intake did not differ in both gender. Moreover, daily alcohol intake adjusted to body weight was significantly larger in female. Body mass index, serum levels of total protein, albumin and cholinesterase were significantly decreased in female. Platelet counts on admission did not differ in both gender. However, it was significantly increased in female after one month abstinence. C reactive protein, ammonia and serum levels of total bilirubin were significantly higher in female as compared to male. In conclusion, female alcoholics seems to progress to liver cirrhosis earlier because of high daily alcohol intake adjusted to body weight, poor nutritional condition and inflammation caused by endotoxin.     

Economic aspect of alcohol-related disabilities in patients of gastroenterology and hepatology]

Alcoholic patients frequently visit a medical center with the alcohol-related organ damage. The medical utilization and expenses of these patients is not only for the treatment of alcohol dependence, but also mainly for the treatment of alcohol-related organ diseases. This study was conducted to clarify the influence of alcohol dependence on the medical expense of internal medicine, especially of gastroenterology and hepatology. Forty four patients who visited the department of gastroenterology and hepatology of our institute since November 2001 were included in the study. All of the patients were heavy drinkers and were suffered from alcohol damages in various organs. Medical expenses of these patients were calculated from the amount of the claim for health insurance system record of our hospital. Average cumulative number of the patients per month was 15.5 +/- 2.8 in out patient and 4.2 +/- 2.4 in hospitalized patient. Medical expenses in these patients, however, were lower in out patients than in hospitalized patients. Cumulative medical expense per month was 238,000 +/- 66,000 yen and 1,801,000 +/- 1,338,000 yen respectively. Alcoholic liver cirrhosis is one of the most frequently encountered disorder related to heavy drinking and needs hospitalization for the treatment of complications of this end stage liver disease. 13 patients (29.5%) were diagnosed as having alcoholic liver cirrhosis in this study. Some of the patients successfully abstained, but irreversible liver damage necessitated repeated hospitalization for the treatment of decompensated cirrhosis. As a result, cumulative medical expense per patient with alcoholic liver cirrhosis was significantly larger than those with noncirrhotic patient. These results suggest that abstinence from alcohol in early stage of alcoholic liver disease, before development of cirrhosis, is important from economic point of view.     

Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.     

Chronic ethanol abuse and membrane fluidity changes in liver disease.

The long-term effect of ethanol on human red cell membrane fluidity was studied, by fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene as a probe, in 11 healthy subjects, 9 chronic alcoholics without evidence of liver disease, 12 chronic alcoholics with biopsy-proven alcoholic liver disease and 9 abstemious patients with chronic active liver disease, most of them cirrhosis of the liver. Fluorescence polarization values were not significantly different in the two groups without liver disease. Patients with alcoholic and non-alcoholic liver disease showed higher fluorescence polarization values than patients without liver disease. These changes correlated with the severity of liver dysfunction and were not related to alcohol consumption. In conclusion, the decrease in fluidity of the erythrocyte membrane in alcoholic patients with chronic liver disease, is related to liver dysfunction but not to chronic ethanol ingestion. Changes in membrane fluidity in chronic alcoholics are found only in the presence of liver disease.     

Management of alcoholic hepatitis

About 5,000 people die each year from chronic liver disease in England and Wales alone. In many patients, the liver injury is due to chronic excessive alcohol consumption and manifests as alcoholic hepatitis (an acute inflammation of the liver), cirrhosis, or alcoholic hepatitis superimposed on a background of cirrhosis. Mild alcoholic hepatitis may be asymptomatic and reversible, but where the hepatitis is more severe, up to 65% of those affected die from it. The incidence of alcoholic hepatitis in the UK seems set to increase with the rise in heavy drinking, particularly among women. Here we review how patients with alcoholic hepatitis should be managed.     

US Mortality from Liver Cirrhosis and Alcoholic Liver Disease in 1999–2004: Regional and State Variation in Relation to Per Capita Alcohol Consumption

Apparent per-capita alcohol consumption in 2001 in four US regions (West, Northeast, South, and Midwest), and in 50 states was examined in relation to mortality rates (1999–2004) from liver cirrhosis and for the subcategory alcoholic liver disease. Alcohol consumption and mortality rates were highest in the west. The alcoholic liver disease mortality rate by state was strongly correlated with alcohol consumption, but several outlier or mismatch states were identified. Per-capita alcohol consumption should be useful for US public health policy, as suggested for Europe and Canada, but outlier states require further study.     

U.S. mortality from liver cirrhosis and alcoholic liver disease in 1999-2004: regional and state variation in relation to per capita alcohol consumption

Apparent per-capita alcohol consumption in 2001 in four U.S. regions (West, Northeast, South, and Midwest), and in 50 states was examined in relation to mortality rates (1999-2004) from liver cirrhosis and for the subcategory alcoholic liver disease. Alcohol consumption and mortality rates were highest in the west. The alcoholic liver disease mortality rate by state was strongly correlated with alcohol consumption, but several outlier or mismatch states were identified. Per-capita alcohol consumption should be useful for US public health policy, as suggested for Europe and Canada, but outlier states require further study.     

Recent advances in the pathogenesis and treatment of alcoholic liver disease

This paper reviews the recent advances in the pathogenesis and drug therapy of alcoholic liver disease (ALD). Plans for long-term management of patients with ALD have been outlined. No specific drug is available for treating alcoholic cirrhosis at present. As there are no genetic, immunological or biochemical markers to predict the progression of alcohol-induced hepatopathy to date, perivenular sclerosis is the only available hepato-histological marker for developing alcoholic cirrhosis. Total abstinence from drinking alcohol is the primary aim of management. It is also suggested that periodic assessment of synthetic capability of liver might offer warning signal for the deterioration of hepatic lesion in patients with alcoholic cirrhosis.     

乙酰半胱氨酸对大鼠酒精性肝损伤的保护作用

目的：探讨乙酰半胱氨酸对大鼠酒精性肝损伤的保护作用。方法：SD大鼠70只,随机分成6组：正常组（n=10,等渗盐水灌胃和腹腔注射）、模型组（n=12,酒精8.8g·kg^-1·d^-1灌胃）、治疗组（n=12,酒精8.8g·kg^-1·d^-1灌胃,造模同时腹腔注射0.156、0.312、0.625g/kg乙酰半胱氨酸）、阳性对照组（n=12,酒精8.8g·kg^-1·d^-1灌胃,造模同时腹腔注射硫普罗宁16.5mg·kg^-1·d^-1）。10周末处死大鼠,检测血清ALT、AST活性和肝组织谷胱甘肽过氧化物酶（GSH-PX）、超氧化物歧化酶（SOD）、丙二醛（MDA）含量,观察肝组织病理变化。结果：模型组大鼠血清ALT、AST活性、肝组织MDA水平较正常组升高,肝组织GSH-PX、SOD较正常组降低,差异有统计学意义（P〈0.05）;治疗组、阳性对照组与模型组相比,ALT、AST、MDA有明显的降低,肝组织GSH-PX、SOD水平有明显的升高,差异有统计学意义（P〈0.05）。HE染色显示模型组大鼠肝细胞浆出现不同程度脂肪变性,肝小叶可见肝细胞点状坏死,治疗组和阳性对照组脂肪变性和炎症程度轻于模型组。结论：乙酰半胱氨酸对大鼠酒精性肝损伤具有一定的保护作用。     

The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes

Cirrhosis is the end stage of many forms of liver pathologies including hepatitis. The liver is known for its vital role in the processing of xenobiotics, including drugs and toxic compounds. Cirrhosis causes changes in the architecture of the liver leading to changes in blood flow, protein binding, and drug metabolizing enzymes. Drug metabolizing enzymes are primarily decreased due to loss of liver tissue. However, not all enzyme activities are reduced and some are only altered in specific cases. There is a great deal of discrepancy between various reports on cytochrome p450 alterations in liver cirrhosis, likely due to differences in disease severity and other underlying conditions. In general, however, CYP1A and CYP3A levels and related enzyme activities are usually reduced and CYP2C, CYP2A, and CYP2B are mostly unaltered. Both alcohol dehyrogenases and aldehyde dehydrogenases are altered in liver cirrhosis, although the etiology of the disease may determine the expression of alcohol dehydrogenases. Glucuronidation is mainly preserved, but there are a number of factors that determine whether glucuronidation is affected in patients with liver cirrhosis. Low sulphation rates are usually found in patients with liver disease but a decrease in sulfatase activity compensates for the decrease in sulphation rates. In all cases, a reduction in drug metabolizing enzyme activities in liver cirrhosis contributes to decreased clearance of drugs seen in patients with liver abnormalities. The reduction in drug metabolizing enzyme activity must be taken into consideration when adjusting doses, especially in patients with severe liver disease.     

酒精性肝硬化与肝炎后肝硬化PT测定分析

目的对比研究酒精性肝硬化与肝炎后肝硬化凝血状态。方法对25例健康体检人员,25例酒精性肝硬化患者,25例肝炎后肝硬化患者进行PT(凝血酶原时间)检测。结果肝炎后肝硬化患者PT明显高于正常对照组(P<0.05),酒精性肝硬化患者PT明显高于肝炎后肝硬化患者(P<0.05)。结论凝血酶原时间是凝血系统的一个较为敏感的筛选试验,酒精性肝硬化患者比肝炎后肝硬化患者升高明显,所以酒精性肝硬化患者凝血功能障碍明显。     

Clinical and biochemical heterogeneity of alcoholism: the role of family history and alexithymia

Of 100 male patients with alcohol dependence, clinical and biochemical data were analysed in relation to family history of alcoholism and alexithymic personality traits. Family history was found in 38 patients and alexithymic personality traits in 79. No relationship was established between these two factors. In patients with a family history alcoholism began at a younger age with more severe clinical symptoms than in the remaining subjects. Patients with alexithymia had lower intensity of psychopathology but higher frequency of concomitant hypertension. Patients with family history had higher leukocyte counts and lower alcohol-induced elevations of liver enzymes and plasma lipids. In patients with alexithymia, higher values of hemoglobin and hematocrit were found. The results suggest that two predisposing factors to alcohol dependence such as family history of alcoholism and alexithymic personality determine the different clinical and biochemical features of the disease.     

Clinical significance of hepatic and splenic volumes measured by computed tomography in patients with alcoholic liver cirrhosis]

Hepatic and splenic volumes were measured by computed tomography in 43 patients with alcoholic liver cirrhosis (AL-LC), 10 patients with HBs antigen-positive liver cirrhosis (B-LC), 6 patients with HCV associated liver cirrhosis (C-LC) and 6 healthy subjects. Hepatic volume was significantly larger in the patients with AL-LC than in those with B-LC, those with C-LC or healthy subjects. Hepatic volume in patients with AL-LC was also significantly larger in the anti-HBc antibody (anti-HBc)-negative patients than in the anti-HBc-positive patients. This data suggests HBV occult infection may decrease hepatic volume. Hepatic volume showed significantly positive correlations with serum levels of total bilirubin (T. bil), gamma-GTP, type IV collagen levels, continuing alcohol intake and Child-Pugh score, and also showed significant negative correlation with cumulative alcohol intake and prothrombin time (PT). Splenic volume showed significantly positive correlations with serum levels of T. bil and Child-Pugh score, and also showed significantly negative correlations with serum albumin, PT, platelet count and BCAA (branched chain amino acids)/tyrosine ratio. Stepwise logistic regression analysis showed that enlarged hepatic volume, presence of hepatocellular carcinoma and elevated serum gamma-GTP were independently significant risk factors for the development of hepatic failure. Serial determination of hepatic and splenic volume may be useful for the estimation of liver function and prognosis in the patients with AL-LC.     

Fungi–Bacteria Correlation in Alcoholic Hepatitis Patients

Alcohol-related liver disease is one of the most prevalent types of chronic liver diseases globally. Alcohol-related liver disease begins with fatty liver, which further develops into hepatic inflammation, hepatocyte injury, and progresses to fibrosis and cirrhosis. Compositional changes of gut bacteria and fungi were found in patients with alcohol-related liver disease. However, the functional changes of fungi and correlations between fungi and bacteria have not been investigated. In this study, we first examined the functional capacity of fungi in patients with alcohol-related liver disease using shotgun metagenomics. Among 24 MetaCyc pathways contributed by fungi, superpathway of allantoin degradation in yeast was enriched in patients with alcoholic hepatitis. Furthermore, we compared the predictive power of bacteria versus fungi and found that bacteria performed better than fungi to separate patients with alcoholic hepatitis from non-alcoholic controls and patients with alcohol use disorder. Finally, we investigated the associations between the intestinal fungi and bacteria in alcoholic hepatitis patients. Positive association between fungi and bacteria was found between Cladosporium and Gemmiger, meanwhile negative association was found between Cryptococcus and Pseudomonas in alcoholic hepatitis patients.     

酒精性肝炎72例临床分析

目的观察酒精性肝炎的临床表现、治疗及预后。方法对72例酒精性肝炎患者的临床资料进行回顾性分析研究。结果72例酒精性肝炎患者,实验室检查均无病毒性肝炎史,血清肝炎病毒标志物检查亦阴性。经对症治疗后显效40例,有效25例,总有效率为90．28％;转为肝硬化者6例,死亡1例。结论长期大量饮酒是引起酒精性肝病的主要原因,每天饮酒80—120g持续5年以上,90％有脂肪肝,10％～35％有酒精性肝炎,1．5％-8％有酒精性肝硬化。严格戒酒是其良好预后的关键.