Effect of liver disorders on ethanol elimination and alcohol and aldehyde dehydrogenase activities in liver and erythrocytes

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1.2.1.3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 mumol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH.(ABSTRACT TRUNCATED AT 250 WORDS)     

1-14C]Ethanol breath test in alcoholic liver disease

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.     

Pathogenesis, diagnosis, and treatment of alcoholic liver disease

Alcohol-related liver disease is a major cause of morbidity and mortality in the United States. Alcoholic liver disease encompasses a clinicohistological spectrum, including fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Fatty liver is a benign and reversible condition, but progression to alcoholic hepatitis and cirrhosis is life-threatening. Alcoholic hepatitis is diagnosed predominantly on clinical history, physical examination, and laboratory testing, although liver biopsy is often necessary to secure the diagnosis. The major focus of management is abstinence from alcohol, supportive care, treatment of complications of infection and portal hypertension, and maintenance of positive nitrogen balance through nutritional support. Corticosteroid therapy is controversial but should be considered in patients with a discriminant function greater than 32 and/or presence of spontaneous hepatic encephalopathy in the absence of infection, gastrointestinal bleeding, and renal failure. The only curative therapy for advanced alcoholic cirrhosis is liver transplantation. Several recent advances in understanding the pathogenesis of alcoholic liver disease may lead to novel future treatment approaches, including inhibition of tumor necrosis factor a, antioxidant therapy, stimulation of liver regeneration, and stimulation of collagen degradation.     

Alcoholic Liver Disease

Alcoholic liver disease consists of well defined entities. Fatty liver is the commonest hepatic abnormality in alcoholics and in most cases it is reversible. Possibly a sustained fatty liver occasionally may induce fibrosis. Alcoholic hepatitis or subclinical necrosis may also proceed to hepatic fibrosis. The latter can regress if no further injury occurs or it may develop into frank cirrhosis in case of continuing liver injury. A general model of alcoholic liver disease is presented.     

Liver Transplantation: Present Results and Problems

Mechanisms of the hepatotoxicity of ethanol are reviewed, including effects resulting from alcohol dehydrogenase (ADH) mediated excessive hepatic generation of NADH and acetaldehyde. Gastric ADH explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some commonly used drugs. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 25 years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P-450 (2E1) which causes metabolic tolerance to ethanol and to various commonly used medications, enhanced degradation of testosterone and vitamin A (with vitamin A depletion) and selective hepatic perivenular toxicity. The latter results from free radical generation and activation of various xenobiotics, causing increased vulnerability of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A and β-carotene. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation which promotes GSH depletion and lipid peroxidation and other toxic effects. Nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other ‘supemutrients’ include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates.     

Effect of ethanol administration on the metabolism of ethanol in baboons

To determine the mechanism whereby alcohol consumption accelerates ethanol metabolism, baboons were fed a diet containing ethanol (50% of calories) or an isocaloric control diet for 2 to 7 years. In alcohol-fed animals, the rate of ethanol metabolism per kilogram of body weight was accelerated by 34% at 50 mM concentrations of blood ethanol and liver size (estimated radiologically) increased by 23%. However, the rate of ethanol metabolism per gram of liver was not significantly increased. There was a 35% decrease in alcohol dehydrogenase (ADH) activity expressed per gram of liver and a 19% decrease per kilogram of body weight. Furthermore, the mitochondrial capacity to handle reducing equivalents was strikingly decreased as assessed by the rate of oxygen consumption at state 3 with glutamate and by the decrease in the activities of NADH and glutamate dehydrogenases. Thus, both factors presumed to be rate limiting for the ADH pathway (ADH activity and NADH reoxidation) were found to be decreased after chronic alcohol feeding. Therefore, even taking the increased liver size into consideration, the ADH pathway could not account for the rate of ethanol metabolism. By contrast, it was found that the activity of the microsomal ethanol-oxidizing system increased significantly after chronic alcohol consumption (by 22% expressed per gram of liver and by 54% expressed per kilogram of body weight). There were no significant changes in the content of cytochrome P-450.(ABSTRACT TRUNCATED AT 250 WORDS)     

高原藏族酒精性肝病的临床病理和电镜观察

探讨酒精性肝病（ＡＬＤ）的超微结构特点及其与肝功能损害程度的关系。方法对２０例高原藏族ＡＬＤ患者行肝穿活检组织病理学观察。结果性脂肪肝（ＡＦＬ）、酒精性肝炎（ＡＨ）、酒精性肝硬化（ＡＬＣ）常相继发生或同时存在,主要表现为肝细胞大泡性脂变,窦周纤维化,肝细胞滑面内质网增生,小叶内灶状坏死伴中性粒细胞浸润。     

Alcoholic liver disease

Alcoholic liver disease presents a wide spectrum of clinical manifestations ranging from mild asymptomatic fatty liver to alcoholic hepatitis and severe life-threatening liver failure with ascites, hemorrhaging esophageal varices, and encephalopathy. Although still poorly understood, the mechanism of this injury is probably the result of numerous direct toxic and metabolic effects of alcohol on the hepatocyte. Therapy consists primarily of abstinence and supportive care. However, several newer treatments are actively being studied. These include prednisolone, anabolic steroids, glucagon and insulin, propylthiouracil, and cyanidanol. Colchicine is promising as an agent to inhibit fibrosis. Complications of cirrhosis, including ascites and variceal hemorrhage, are the result of end stage disease. A return to old techniques of ascitic fluid management suggests that therapeutic large-volume paracentesis with albumin infusion is a safe and effective form of therapy. Variceal hemorrhage is best treated with sclerotherapy, vasoconstrictors, and balloon tamponade. Little has been done to alter the ultimately dismal prognosis and long-term survival of alcoholic liver disease.     

Alcoholic liver disease in Scotland and northeastern England: presenting features in 510 patients

A study of 510 patients in Scotland and northeastern England with histological evidence of alcohol-induced liver disease showed no difference in the age of presentation between males and females. Single men and widowed females were particularly susceptible to alcoholic liver disease. The social class distribution was similar to the population in general. Women were more reluctant to volunteer a history of alcoholism than men, they had a higher incidence of previous psychiatric illness (usually due to alcohol abuse) and they developed liver disease at lower consumption thresholds of alcohol than men. Patients under 40 years of age were more likely to have alcoholic fatty liver and less likely to have active cirrhosis than those over 40. Most often, the presenting symptoms were non-specific and tended to be related to the gastrointestinal system, particularly in women. Five per cent of patients were asymptomatic and 14% came to hospital for conditions other than alcoholic liver disease. Important clues to asymptomatic alcoholic liver disease included hepatomegaly, clubbing of the fingers and abnormal liver function tests. Gastro-oesophageal varices accounted for 40% of instances of haemorrhage and the mortality from upper gastrointestinal bleeding was 17%. Anaemia was the most common haematological abnormality. Alcoholic hepatitis was observed more frequently in the Glasgow area then elsewhere.     

Alcohol and drug interactions

Alcohol metabolism occurs mainly in the liver, where in abstainers the alcoholdehydrogenase (ADH) pathway plays the major role. After chronic alcohol consumption, the microsomal ethanol-oxidizing system (MEOS), involving the ethanol-inducible cytochrome P450 2E1, increases in importance with a four- to ten-fold increase in the contribution to alcohol metabolism. Because of the fact that this enzyme system catalyses not only the metabolism of ethanol but also activates a great number of drugs, it is a very common site of alcohol-drug interactions. Clinically relevant interactions will be discussed. Only a small amount of alcohol is metabolized outside the liver, mainly in the stomach by gastric ADH, which leads to the so-called first-pass metabolism of ethanol. Its significance in alcohol metabolism is reviewed. The only way to prevent severe alcohol-drug interactions is to make medical doctors as well as their patients more aware of these possible secondary effects.     

Cirrhosis: diagnosis, management, and prevention

Cirrhosis is the 12th leading cause of death in the United States. It accounted for 29,165 deaths in 2007, with a mortality rate of 9.7 per 100,000 persons. Alcohol abuse and viral hepatitis are the most common causes of cirrhosis, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary care physicians share responsibility with specialists in managing the most common complications of the disease, screening for hepatocellular carcinoma, and preparing patients for referral to a transplant center. Patients with cirrhosis should be screened for hepatocellular carcinoma with imaging studies every six to 12 months. Causes of hepatic encephalopathy include constipation, infection, gastrointestinal bleeding, certain medications, electrolyte imbalances, and noncompliance with medical therapy. These should be sought and managed before instituting the use of lactulose or rifaximin, which is aimed at reducing serum ammonia levels. Ascites should be treated initially with salt restriction and diuresis. Patients with acute episodes of gastrointestinal bleeding should be monitored in an intensive care unit, and should have endoscopy performed within 24 hours. Physicians should also be vigilant for spontaneous bacterial peritonitis. Treating alcohol abuse, screening for viral hepatitis, and controlling risk factors for nonalcoholic fatty liver disease are mechanisms by which the primary care physician can reduce the incidence of cirrhosis.     

大庆地区994例肝硬化患者临床流行病学分析

目的通过分析2000—2005年大庆地区综合医院消化内科肝硬化病人的病例资料，找出肝硬化的常见病因、并发症和病死率，为进一步防治肝硬化提供依据。方法采用回顾性调查方法，对大庆地区三家医院消化科2000—2005年6年间住院确诊为肝硬化的994例病历资料进行分析。结果本组患者男：女为3．01：1；发病年龄24—83岁，41-70岁为高发年龄段；6年来大庆地区肝硬化的发病构成比无明显变化。病因以病毒性肝炎最多见，占74．45％，其中与乙型肝炎相关肝硬化占70．32％；洒精性肝炎为第二位，占21．93％；病毒性肝炎和／或酒精性肝炎发生的肝硬化占肝硬化发病率的96．38％。肝硬化患者就诊的主要原因是发生腹水（30．58％）和上消化道出血（39．03％）。肝硬化最常见的并发症是上消化道出血（42．96％）。最常见的死亡原因是上消化道出血（47．55％）。结论病毒性肝炎和酒精性肝炎是大庆地区肝硬化的主要病因，防治病毒性肝炎，减低饮酒量是预防肝硬化的重要手段。积极防治肝硬化并发症是提高患者生活质量，延长患者生命最重要的环节。     

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.     

Natural History of Alcoholic Hepatitis. IV. GLYCOSAMINOGLYCURONANS AND COLLAGEN IN THE HEPATIC CONNECTIVE TISSUE

The extractable and nonextractable collagen and glycosaminoglycuronans (GAG) were estimated and characterized in 32 dried, defatted human livers obtained at necropsy. 10 had normal livers. 22 of the 32 livers were from patients who drank in excess: 5 had fatty livers, 7 had alcholic hepatitis, and 10 had cirrhosis. Livers with alcoholic hepatitis or cirrhosis had significantly increased total and 1 N NaCl-extractable collagen. Only alcoholic hepatitis livers had significantly increased Tris-buffer-extractable GAG, but the amino acid composition of these GAG (proteoglycans) was no different from that of normal livers. The major fraction of these GAG had isoelectric pH (pI) 相似文献   

酒精性肝病 90例临床分析

目的:分析酒精性肝病患者发病情况及临床特点。方法:根据门诊及住院患者的饮酒量、饮酒时间、临床表现、肝功能检查、影像学检查、相应并发症、治疗等临床资料,进行分析和讨论。结果:酒精性肝病发病有增多趋势,长期饮酒史和AST/ALT、GGT、TBiL对酒精性肝炎的诊断有重要意义。A/G比值随疾病进展而降低。慢性病毒性肝炎的饮酒者预后差,死亡的主要原因是肝硬化的晚期并发症。结论:酒精性肝病病情和预后与长期饮酒史(包括饮酒量、饮酒时间)有关。对于有饮酒嗜好的病人,应对其进行健康教育劝其戒酒,并定期监测AST/ALT、GGT、TBiL等生化指标,及早进行治疗,改善预后。     

Liver disease of the alcoholic.

Significant liver disease including fatty metamorphosis, alcoholic hepatitis, cirrhosis, and hepatoma occur in two thirds of subjects who consume alcoholic beverages in sufficient quantities to interfere with work and social responsibilities; this is of major importance in the rapidly escalating morbidity and mortality from alcoholism. Chronic alcoholics should be routinely evaluated for the presence of altered liver function and structure. Clearance of indocyanine green using dichromatic ear densitometry and computer and analysis provides a simple and sensitive method for mass screening of such patients. Clinical studies of lymphocyte reactivity to purified alcoholic hyaline may be valuable in recognizing alcoholic hepatitis, the precursor of cirrhosis. Ethanol toxicity, malnutrition and constitutional factors contribute to the development of hepatic fibrosis and cirrhosis in alcoholics. Ethanol and/or acetaldehyde and the supernatant from lymphocytes stimulated by alcoholic hyaline cause a significant increase in the incorporation of proline into collagen of the damaged liver. Abstinence and correction of nutrient deficits are the cornerstones of treatment for alcoholic liver disease; a daily meal and dietary supplements should be provided for those with liver injury who continue to imbibe. Alcoholics with progressive liver disease despite supportive therapy may be aided by pharmacologic agents which suppress immunologic response and reduce fibrogenesis.     

酒精性肝病患者血清TGF-β、IL-6和IL-8水平及临床意义

目的探讨酒精性肝病患者血清转化生长因子（transforming growth factor-β,TGF-β）白细胞介素-6（inter-leukin-6,IL-6）和白细胞介素-8（interleukin-8,IL-8）在酒精性肝病中的作用。方法 60例酒精性肝病患者按酒精性脂肪肝（n=20）、酒精性肝炎（n=20）和酒精性肝硬化（n=20）分为3组。采用ELISA法检测20例健康对照组和60例各类酒精性肝病患者血清中TGF-β、IL-6和IL-8水平。结果血清TGF-β、IL-6和IL-8水平随着肝脏病变程度加重而递增,酒精性脂肪肝组、酒精性肝炎组和酒精性肝硬化组3项指标水平均高于正常对照组,差异显著（P〈0.01）,其中以酒精性肝硬化组3项指标水平为最高。结论 TGF-β、IL-6和IL-8在酒精性肝病中具有重要作用,酒精性肝病患者血清TGF-β、IL-6和IL-8水平的检测可作为酒精性肝病病情监测和预后判断的有效指标。     

Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise.

Chronic liver disease is the 10th leading cause of death in the United States. Hepatitis C virus infection is the most frequent cause of chronic liver disease and the most common indication for liver transplantation. Preventive care can significantly reduce the progression of liver disease. Alcohol and hepatitis C virus are synergistic in hastening the development of cirrhosis; therefore, patients with hepatitis C infection should abstain from alcohol use. Because superinfection with hepatitis A or B virus can lead to liver failure, vaccination is recommended. Potentially hepatotoxic medications should be used with caution in patients with chronic liver disease. In general, nonsteroidal anti-inflammatory drugs should be avoided; acetaminophen in a dosage below 2 g per day is the safest choice. Many herbal remedies are potentially hepatotoxic, and only milk thistle can be used safely in patients who have chronic liver disease. Weight reduction and exercise can improve liver function in patients with fatty liver.     

Ethanol metabolism

Alcohol is metabolized by two pathways in humans: the ADH pathway which accounts for the bulk of the metabolism, and the MEOS pathway which contributes to the increased rate of ethanol elimination at high blood alcohol levels. The increased rate of elimination which results from chronic alcohol consumption is due to an increase in MEOS activity. The activities of these pathways are influenced by environmental factors such as smoking, diet, and endocrine factors. In addition, individuals inherit different types of ADH isoenzymes which have different kinetic properties. Individuals with different phenotypic variants, e.g. the beta 1 vs beta 2 isoenzymes, appear to have different rates of ethanol elimination. The cloning of the ADH genes and the availability of molecular hybridization methods now make it possible to genotype individuals and to correlate the genotype with both alcohol elimination rates and with the risk of developing medical complications of alcoholism or even of developing alcoholism itself.