CURRENT PROBLEMS IN ALCOHOLIC LIVER DISEASE

The development of alcohol-related liver injury is reviewed.Factors predisposing to an individual's susceptibility to cirrhosisare considered and the possible mechanisms by which alcoholmight produce liver injury are discussed. The current clinicalproblems of early recognition. treatment of liver disease, itscomplications and ultimate prognosis are reviewed. Importantarek for future development are indicated.     

NUTRITION IN THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE

The role of diet composition in the pathogenesis of experimentalalcoholic liver disease is discussed, with emphasis on dietaryfat composition and lipid peroxidation of poly-unsaturated fattyacids as the result of the oxidation of ethanol by cytochromeP450-2E1 at high blood alcohol levels.     

DETECTION OF ANTIBODIES TO ACETALDEHYDE-ALBUMIN CONJUGATES IN ALCOHOLIC LIVER DISEASE

The principal metabolite of ethanol, acetaldehyde, conjugateswith various proteins that form antibody-inducing neo-antigens.We have analysed sera from patients with biopsy-proven alcoholicliver disease (hepatitis = 10, cirrhosis = 11, steatosis = 3)and controls = 19 (normal teetotallers and 6 non-alcoholic liverdisease). Sera were examined with an enzyme-linked immunoabsorbentassay (ELISA) for antibodies binding preferentially to an acetaldehyde-albuminconjugate. Reactive sera from alcohol misusers were then purifiedusing an amino-hexyl Sepharose affinity column. Antibodies bindingto the acetaldehyde-albumin epitopes were significantly raised(P < 0.005) in all groups of alcohol misusers, and were presentin greatest titre in those with alcoholic hepatitis. These antibodieswere successfully purified using the gel affinity column. Weconclude that alcohol misusers have significant titres of antibodiesreacting to the acetaldadehyde-albumin complex The role of theseantibodies remains unclear, but may be related to the initiationof an inflammatory response and tissue damage following ethanolconsumption.     

THE ROLE OF HEPATITIS C VIRUS IN ALCOHOLIC LIVER DISEASE

Alcoholism is a major public health problem across the world.However, only a minority of individuals who abuse alcohol developsignificant liver injury. Interactions between alcohol and hepatotrophicviruses, particularly hepatitis C virus, have been recognizedfor some time. The aim of this review is to examine the seroprevalenceof hepatitis C virus in individuals who abuse alcohol, and todiscuss the association between hepatitis C virus infectionand the histopathological and clinical findings in this groupof patients. The possible pathogenesis of interaction betweenalcohol and hepatitis C virus is discussed briefly, and treatmentoptions are examined.     

SERUM {gamma}-GLUTAMYL-TRANSPEPTIDASE ISOFORMS IN ALCOHOLIC LIVER DISEASE

-Glutamyltranspeptidase (GT) appears in serum in multiple forms;their significance and clinical utility in hepatobiliary andpancreatic diseases are still a matter of controversy. Electrophoreticseparation of the multiple forms of GT on agarose gel was performedin 20 alcoholic patients (six with cirrhosis and 14 with fattyliver) and the results compared with those obtained in 50 healthyvolunteers, 43 patients affected with chronic hepatitis C, 36patients with posthepatitic cirrhosis and in 52 epileptic patientson long-term anti-epileptic medication. Multiple forms of GTwere separated into several bands (up to 11), labelled 0a, 0b,la, lb, 2a, 2b, 2c, 3a, 3b, 4a, 4b. In the alcoholic patientsnine fractions were detected, and the electrophoretic patternobserved was significantly different from that observed in healthyvolunteers and in patients with chronic hepatitis C or posthepatiticcirrhosis. No differences were observed in the electrophoreticpatterns in the alcohol abusers and epileptic patients. In alcoholicpatients significant differences were observed in the electrophoreticpatterns in relation to the degree of liver injury; the electrophoreticpatterns in patients with alcohol-related cirrhosis and posthepatiticcirrhosis differed significantly. The separation of multipleforms of GT has high sensitivity and good reproducibility. Itmay be proposed as a complementary test in the diagnosis ofalcoholic liver disease.     

META-ANALYSIS OF HLA-ANTIGEN PREVALENCES IN ALCOHOLICS AND ALCOHOLIC LIVER DISEASE

In the search for genetic factors influencing susceptibilityto the development of alcoholism and alcoholic liver disease,28 studies have been published analysing the distribution ofhuman leucocyte antigens (HLA) in alcoholics compared to healthycontrols. A number of HLA phenotypes has been suspected of beingassociated with both alcoholism and alcoholic liver disease.In the present study a meta-analysis is carried out on the datafrom these studies, subdivided according to race and degreeof liver injury. The conclusion is that none of the HLA-phenotypesso far investigated in Caucasians can be shown to be significantlymore common in any of the studied patient categories than incontrols, whereas the results of Japanese studies are less clear.The limitations of the data material and the design of the studiesare discussed, as well as the strength and limitations of themethod of meta-analysis.     

LEUCOCYTE ADHESION MOLECULES AND ALCOHOLIC LIVER DISEASE

The causative agent of alcoholic liver disease is self-evidentalthough the pathogenesis of the liver damage is not well understood.There is increasing evidence from both animal experiments andhuman studies that inflammation triggered in response to alcoholor its metabolites is Important in the tissue damage and fibrosisof alcoholic liver disease. Both alcoholic hepatitis and alcoholiccirrhosis are characterized by inflammation of the liver, althoughthe nature of the inflammatory infiltrate differs between thetwo diseases. The activation of leucocytes, their migrationinto tissue and subsequent interaction with target cells areall dependent on regulated adhesion. Therefore, leucocyte adhesionmolecules and their counter-receptors will play a crucial rolein determining the nature and activity of leucocytes infiltratingthe liver in alcoholic liver disease. Evidence is now emergingthat suggests roles for particular adhesion pathways in twoaspects of the inflammatory response in alcoholic liver disease,(1) leucocyte recruitment to the liver, and (2) cell-mediatedhepatocyte damage. It is important that these pathways are definedsince therapy aimed at blocking leucocyte adhesion moleculesmight provide an effective future therapy for selected patientswith alcoholic liver disease.     

OCCUPATIONAL RISK FACTORS IN PATIENTS WITH ALCOHOLIC OR NON-ALCOHOLIC LIVER DISEASE

The present study examines the presence of specific occupationalrisk factors in a group of patients suffering from alcoholicliver disease compared with a group of patients with non-alcoholicliver disease. The first group was more dependent on alcohol,with fewer social or psychological alcohol-related problems.The majority of them were employed, although more likely tobe employed in traditional ‘high risk’ occupations.They showed lower job satisfaction, and the total sum of allpreviously reported occupational risk factors was highly significant.This was the fitst empirical evidence in support of the importanceof the specific occupational risk factors previously postulated.     

酒精性肝病患者肠道中6种重要菌群的定量分析

目的对酒精性肝病患者肠道中大肠杆菌、粪球菌、乳杆菌、双歧杆菌、拟杆菌及柔嫩梭菌的含量变化进行定量分析,并就其与肝损伤的相互关系进行初步探讨。方法全自动生化分析仪检测健康人及酒精性肝病患者血清谷丙转氨酶(ALT)、谷草转氨酶(AST)及谷氨转肽酶(GGT)活力;ELISA实验检测血浆中肿瘤坏死因子(TNF-α)、白介素6(IL-6)、D乳酸(DAO)、二氨氧化酶(D-LA)和肠型脂肪酸结合蛋白(FABP2)水平;荧光实时定量PCR技术对粪便中上述6种重要菌群进行定量分析。结果随着肝功能损害程度的加剧、饮酒史及饮酒量的增加,酒精性肝病患者血清ALT、AST、GGT活力,及血浆TNF-α、IL-6、DAO、D-LA和FABP2水平均较健康人群组及各自对应组有不同程度升高(P0.05)。粪便中双歧杆菌和拟杆菌含量均明显降低(P0.05),而大肠杆菌、粪球菌、乳杆菌和柔嫩梭菌含量有所改变,但未见显著性差异(P0.05)。结论肠道微生态失调在酒精性肝病发生发展过程中发挥重要作用,其作用机制可能与酗酒导致肠道中双歧杆菌和拟杆菌等肠道菌群生长受到抑制有关。     

酒精性肝病发病机制的研究进展

本文从乙醛的毒性作用、乙醇代谢酶多态性、氧化应急、NADH/NAD+、CYP2E1等方面对酒精性肝病(ALD)的发病机制作了简要阐述,ALD的发病原因主要是乙醇在肝细胞内产生的毒性代谢产物及其引起的代谢紊乱.ALD分为酒精性脂肪肝、酒精性肝炎和酒精性肝硬化.其致病因素单一,即长期大量的酒精摄入,但发病机制较为复杂,目前尚未完全清楚.因此,继续研究ALD的发病机制非常有意义.     

URINE ETHANOL ASSESSMENT: A HELPFUL METHOD FOR CONTROLLING ABSTINENCE IN ALCOHOLIC LIVER DISEASE

The usefulness of a urine-alcohol determination in the evaluationof abstinence in alcoholic liver disease has been investigatedin 181 patients. Alcohol was tested in morning urine samplescollected on a follow-up visit in 103 patients, and the resultswere compared with those in 78 patients, where three sampleswere collected within the same week; one in the morning andtwo in the evening. Although the percentage of urine samplescontaining alcohol measured in a morning sample was similarto the patients' self-report (31% and 34%, respectively), urineanalysis identified an additional 7% of patients who deniedalcohol intake. Alternatively, serial urine-alcohol determinationswere significantly more effective than patient reports (54%and 35.9%, respectively, P < 0.01), particularly when urinewas collected in the evenings. This difference was due mainlyto the reluctance of women to admit drinking (7.4% of positiveself reports vs 51% of women with alcohol positive urine samples,P < 0.001). We conclude that serial measurements of alcoholin urine were useful tests which should be used to complementpersonal interview in the control of abstinence in patientswith alcoholic liver disease.     

凯西莱治疗酒精性肝病的疗效观察

[目的]探讨凯西莱对酒精性肝病患者肝功能异常及血脂代谢的治疗效果。[方法]将60例酒精性肝病患者随机分两组,治疗组口服凯西莱,并设对照组比较,2个月为疗程。[结果]治疗组与对照组疗效间差异有统计学意义(P﹤0.05),且安全。[结论]凯西莱对酒精性肝病肝功能改善和调节血脂代谢功能有较好疗效。     

高糖对小鼠酒精性肝病影响的实验研究

[目的]探讨高糖对酒精性肝细胞的影响作用.[方法]首先建立小鼠酒精性肝病模型,通过将健康小鼠分为5个试验组,并设立对照组,每组每天灌以不同浓度的酒精(从10%～20%),以前期预实验为基础,4周后每组杀死部分小鼠,取肝脏标本,常规制片,镜检,以确定酒精肝模型的建立.模型建立后,实验组分别灌20%葡萄糖1 ml/次,每天1次,对照组正常饮食.分别于4周、6周、8周、10周处死部分小鼠,取肝脏标本.制片、镜检并观察.[结果]结果分别从一般情况、肝脏标本大体观察、形态学观察、组间比较分析4个方面进行阐述,灌糖前的小鼠食欲减退、行动迟缓、昏昏欲睡,其肝脏颜色呈暗褐色、质地变硬,肝细胞大片坏死,纤维间隔形成等,而灌糖后的小鼠以上情况均有好转.[结论]通过结果分析,可以初步得出高糖对酒精性肝病有一定的积极影响,其具体的影响机制还将进一步研究.     

改进的酒精灌胃法建立大鼠酒精性肝病模型

目的寻找一种简单可靠的方法制作大鼠慢性酒精性肝病模型。方法给大鼠饮用5%递增到22%浓度的酒精,然后再以54%酒精每日3次,每次1.2~1.5 mL灌胃的方法连续5或10周建立大鼠慢性酒精性肝病模型;常规HE染色,光镜观察大鼠肝脏病理学形态改变,并检测血清ALT、AST水平。结果酒精灌胃5周后,40%(8/20)大鼠发生肝脂肪变性,酒精灌胃10周后,85%(17/20)大鼠发生肝脂肪变性,45%(9/20)大鼠出现酒精性肝炎的病理变化;酒精灌胃5、10周后,大鼠血清ALT、AST分别为(61±16)(、81±20)和(90±16)(、130±32)U.L-1,均较同期对照组(33±8)(、58±9)和(46±15)(、51±11)U.L-1有显著升高(P<0.05);酒精灌胃10周后的大鼠血清ALT、AST较酒精灌胃5周后升高(P<0.05)。结论采用梯度浓度酒精、分次少量灌胃的方法,成功地制作了大鼠慢性酒精性肝病模型。     

GENETIC AND ENVIRONMENTAL FACTORS IN THE INDIVIDUAL SUSCEPTIBILITY TO THE DEVELOPMENT OF ALCOHOLIC LIVER DISEASE

Although there is a dose-response relationship between alcoholconsumption and liver damage, less than one-third of alcoholicsdevelop alcoholic liver disease (ALD). This individual susceptibilityto the development of ALD may be explained by genetic and environmentalfactors. Of the genetic factors, female sex is clearly a significantrisk factor, HLA status is probably important but further studiesare needed, abnormalities in alcohol metabolism have not beenshown to be of primary pathogenic importance and the plethoraof immunological disturbances reported appear to be mere epiphenomena.Of the environmental factors, no consistent evidence atteststo the significance of hepatitis B viral infection in the susceptibilityto developing ALD.     

ACTIVITY AND SUBCELLULAR DISTRIBUTION OF PHOSPHATIDATE PHOSPHOHYDROLASE (EC 3.1.3.4) IN ALCOHOLIC LIVER DISEASE

A micromethod was developed to assay the hepatic activity andsubcellular distribution of phosphatidate phosphohydrolase (PAH,EC 3.1.3.4 [EC] ), an important regulatory enzyme in triacylglycerolsynthesis, in human needle biopsy specimens. In normal liverPAH is predominantly cytosolic in distribution, but on treatmentwith oleic acid it shifts to the membranous compartments ofthe cell, its physiologically active site. The hepatic specificactivity of PAH was similar in controls and patients with fattyliver but significantly more of the enzyme was associated withthe membranous compartments in patients with severe alcoholicfatty liver. These observations may explain the enhanced ratesof triacylglycerol synthesis observed in these patients andmay be implicated in the pathogenesis of alcoholic fatty liver.     

PALMITOYL-CATECHIN FOR ALCOHOLIC LIVER DISEASE: RESULTS OF A THREE-MONTH CLINICAL TRIAL

A prospective randomized double-blind trial of 3-palmitoyl-(+)-catechinat a dose of 1500 mg daily (500 mg t.d.s.) for 3 months vs placebohas failed to demonstrate statistically significant clinical,biochemical or histological benefit in patients with biopsy-provenalcoholic liver disease. Nevertheless, this trial has confirmedthe beneficial effect of a reduction in the rate of alcoholconsumption on alcoholic liver disease. Apart from clinicalevidence of a higher rate of alcohol consumption by patientsreceiving the active drug during the trial, no adverse side-effectswere identified and for this reason, it is suggested that afurther trial should be considered with the daily dosage sofar used in man (20 mg/kg) increased toward that (100 mg/kg)employed with benefit in animal experiments.     

DETECTION OF HEPATITIS C VIRUS ANTIBODIES AND HEPATITIS C VIRUS RNA IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

The prevalence of hepatitis C virus (HCV) antibody was determinedin 130 patients with alcoholic liver disease using a second-generationanti-HCV enzyme immunoassay (ELISA 2) and confirmed by a sensitivepolymerase chain reaction procedure measuring HCV RNA. Hepaticdisease was evaluated by clinical and biochemical studies and,whenever possible, by liver biopsy. Seventy-one patients werediagnosed as having cirrhosis, and 59 alcoholic hepatitis (n= 33) or fatty liver (n = 26). The prevalence of anti-HCV inthe total group was 9.2% and did not differ significantly inthe cirrhotics (11.3%) as compared with the non-cirrhotics (6.8%).HCV RNA was detected in six out of eight cirrhotics and threeOut of four non-cirrhotics who were ELISA 2 positive. A positivetest for antibodies to hepatitis core antigen (anti-HBc) wasmore frequent in anti-HCV-positive patients (75%) than in theanti-HCV-negative group (14%, P<0.001). Anti-HBc was alsofound more frequently in the cirrhotics (25.4%) than in thealcoholics without cirrhosis (11.9%). However, the prevalenceof hepatitis B surface antigen was equally low in both groups(cirrhotics 1.4%, non-cirrhotics 1.7%). No correlation was observedbetween the prevalence of anti-HCV antibodies and the severityof liver dysfunction. These results indicate that HCV, and especiallyHCV-viraemia, is less frequent in alcoholics in southern Germanythan suspected in previous studies, and that the prevalenceof HCV markers in alcoholics has been overestimated by ELISA1 used alone.     

(+)-CYANIDANOL-3 FOR ALCOHOLIC LIVER DISEASE: RESULTS OF A SIX-MONTH CLINCIAL TRIAL

A prospective randomized double-blind trial of (+)-cyanidanol-3at a dose of 2 g daily (500 mg qds) for six months versus placebohas failed to demonstrate statistically significant clinical,biochemical or histological benefit in patients with biopsy-provenalcoholic liver disease although certain trends were identified.The group receiving the active drug tended to drink more bothbefore and during the trial and had mean serum aspartate aminotransferase(AsT) and gamma-glutamyltranspeptidase (-GT) levels which werehigher on admission to the trial. After the fourth week of treatment,the mean serum levels of these enzymes remained consistentlylower in the group receiving the active drug. In order to reproduce the beneficial effects of the drug observedin the rat, it is suggested that further trials be conductedwith the dosage so far used in man (ca. 20–40 mg/kg daily)increased toward that successfully employed in animal experiments(200 mg/kg daily).