酒精性肝病发病机制

酒精性肝病（alcoholic liver disease, ALD）是因长期过量饮酒引起的肝脏疾病,其中包括轻症ALD、酒精性脂肪肝、酒精性肝炎、酒精性肝纤维化和酒精性肝硬化,我们就氧化应激、内质网应激、硝化应激及调脂因子在酒精性肝病发病机制中的作用等进行阐述。     

Cardiac findings in alcoholic liver disease

In a prospective study 53 patients with alcohol-induced liver disease (fatty liver in 27, cirrhosis in 26) were studied clinically and with non-invasive techniques (electrocardiogram, systolic time intervals, M-mode echocardiography, upright bicycle stress test) to detect a possible cardiac involvement. Mean daily alcohol consumption was comparable in both groups (136 g/day over 16 years vs 124 g/day over 14 years). 15 to 41% of patients (more patients with fatty liver) complaint of angina pectoris and dyspnea at exercise or had palpitations. Echocardiography and systolic time intervals demonstrated in both groups (in patients with cirrhosis despite of a more intensive therapy with digitalis and diuretics) a marked enlargement of left ventricular dimensions with a significant (p less than 0.05) degree of dysfunction (PEP/LVET). Electrocardiography showed abnormalities in 26 to 44% of patients: signs of right ventricular enlargement in 26% of patients with fatty liver, and a prolongation of myocardial repolarisation (QTc) in 44% of patients with cirrhosis. Patients with alcohol-induced liver disease deserve more attention of their cardiac complaints, clinical and functional findings.     

Caput medusae in alcoholic liver disease

Caput medusae and palmar erythema are cardinal signs in cirrhosis of liver with portal hypertension. Palmar erythema is described more often as a marker for alcoholic etiology of chronic liver disease. The peripheral stigmata of chronic liver disease are not routinely seen now a days due to early diagnosis and better therapy. We recently encountered an interesting patient of alcoholic liver disease with two classical signs of the disease and report the same for this unusual presentation.     

酒精性肝病治疗研究进展

目前,长期过度摄入酒精而引发的酒精性肝病已经成为一个社会性的健康问题,给患者、家庭及社会带来了极大的经济负担。酒精性肝病包括酒精性脂肪肝、酒精性肝炎、肝硬化以及肝癌等。酒精性肝病的诊断一般基于临床上的症状,如饮酒史、肝病指标及临床化验指标等。目前酒精性肝病的治疗最重要的是戒酒,再根据病情采取相应的治疗措施,主要的治疗手段包括药物治疗、精神治疗及外科肝移植治疗等。严重的酒精性肝病临床上推荐使用皮质类固醇或己酮可可碱。干细胞治疗是肝硬化患者的一个可能的治疗措施。肝移植除了合适的肝脏供体,移植后使用的免疫抑制剂可能导致新的癌症的发生。新型的安全高效的病理生理主导的治疗方法是治疗酒精性肝病的必然趋势,可能的靶点包括CXC细胞因子、IL-22、TNF受体超家族、补体和脂多糖(LPS)等。     

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.     

Biochemistry of alcoholic liver disease.

The biochemistry of alcohol liver disease as it relates to clinical medicine and experimental alcohol liver disease is presented. Clinical features are emphasized in the diagnosis of alcohol liver disease, particularly as it relates to staging the disease and predictors of prognosis. Currently, it is true that the biochemical diagnosis of alcohol liver disease is at best very limited in terms of the sensitivity tests and specificity of the test. It is particularly difficult to detect alcohol liver disease biochemically in the early stages when steatohepatitis is not severe. Consequently, 50% of the patients have already developed cirrhosis at the time they are diagnosed clinically. In this review indicators of malnutrition are emphasized because they have the strongest implications regarding survival during the acute hospitalization stage of the disease. They are also the best indicators of response to therapy during the recovery phase. With respect to experimental work on the pathogenesis of alcohol liver disease, it appears that necrosis is due to the inability to increase blood flow to compensate for increased oxygen utilization. The hypothesis that mitochondrial damage is the cause of liver cell damage is regarded as less important in the pathogenesis of necrosis. The shift in the redox state during alcohol metabolism accounts for the fatty change noted in the central lobular area of the liver in animals fed alcohol. Apparently, there is strong experimental evidence that highly reactive intermediates are important in the pathogenesis of liver damage due to the induction of the isozyme cytochrome P450 IIE1 by alcohol ingestion. This mechanism is enhanced by a diet high in polyunsaturated fatty acids.     

Fasting plasma somatostatin in alcoholic liver disease

Fasting level of somatostatin-like immunoreactivity (SLI) in plasma was measured by a highly sensitive radioimmunoassay in 36 patients with alcoholic liver disease verified by histopathology (10 patients with steatosis and 26 with cirrhosis of the liver). The median value of SLI was markedly elevated in patients with steatosis of the liver as compared to normal subjects, P less than 0.01, while the median value of SLI in the cirrhotic group was even higher, P less than 0.05, as compared to the steatotic group. Correlations of SLI to se-bilirubin and p-coagulation factors 2, 7 and 10 were significant, P less than 0.001 and P less than 0.01, respectively, whereas no correlation to plasma insulin could be elicited. These results suggest that in alcoholic liver disease fasting plasma somatostatin is correlated to the degree of hepatic failure and indicate that the liver is an important site for clearance of portal vein somatostatin.     

Novel morphologic findings in alcoholic liver disease

OBJECTIVES: To study light and electron microscopic changes in alcohol-liver disease (ALD) patients, and characterize the expression pattern of Kupffer and stellate cells, correlating changes with serum cytokine levels. DESIGN AND METHODS: Liver biopsies studied in 35 ALD patients were compared to 51 normal histology patients. Quantitation was done using immunochemistry for Kupffer cells and morphometry, electron microscopy for stellate cells. ELISA was used to measure serum cytokines in 80 controls and ALD patients. RESULTS: Biopsies of ALD patients confirmed increased number of perisinusoidal, multivesicular, and stellate cells compared to controls. There was a significant increase in the number and activity of multivesicular stellate cells in ALD patients (p < 0.001). These changes were associated with significant increase in the degree of perisinusoidal collagenisation (p < 0.001). The number of Kupffer cells, serum tumor necrosis factor (TNFalpha), interleukins-6 (IL-6) and IL-12 levels, were also significantly higher in ALD patients than controls. CONCLUSIONS: In non-cirrhotic ALD, stellate cells may be involved in lipid transport and a cytokine network may influence liver inflammation.     

Plasma fibronectin and alcoholic liver disease

The authors examined, in 58 chronic alcoholics, the behaviour of plasma fibronectin, SGPT and seric albumin. Among the patients, ten were without liver damage while the others were affected with alcoholic liver disease at different stages, such as steatosis (12), steatofibrosis (14), evolutive chronic hepatitis (10), cirrhosis (12). The levels of plasma fibronectin appeared significantly increased in the cases with steatofibrosis, evolutive chronic hepatitis and cirrhosis; unimportant changes were noted in the cases with steatosis. SGPT always resulted increased, showing the existence of cytolysis related with plasma fibronectin levels, while seric albumin was constantly reduced with negative ratio to fibronectin levels, except in cases of decompensated cirrhosis. The authors believe that the monitoring of plasma fibronectin in chronic alcoholics may be a suitable means to reveal an increased liver fibrosis.     

Biochemical testing in patients with alcoholic liver disease

We evaluated physicians' laboratory utilization patterns for hospitalized patients with alcoholic liver disease and examined the relationship between the frequency of test ordering and certain variables in clinical outcome. During the study, 185 patients with alcoholic liver disease were hospitalized 378 times at the VA Medical Center, Long Beach, California. Physicians ordered liver panels (including serum albumin, alkaline phosphatase, total bilirubin, lactic dehydrogenase, glutamic pyruvate transaminase, and glutamic oxaloacetic transaminase) an average of 7.4 times per hospitalization. Increased biochemical testing did not decrease length of stay or improve clinical outcomes such as development of complications or survival of hospitalization. Since the treatment of alcoholic liver disease is largely supportive and not dependent upon frequent biochemical testing, we recommend that these tests be ordered only when patients are admitted to or discharged from the hospital, and when there has been a clinical change.     

Hormone and metabolite profiles in alcoholic liver disease

Abstract. Circulating hormone and metabolite profiles have been studied in ten patients with alcoholic cirrhosis, five patients with alcoholic hepatitis and/or fatty liver, and nine normal controls over a 12-h period of meals and activity. Blood glucose was elevated throughout the day in both cirrhotic and non-cirrhotic alcoholics (mean 12-h glucose; controls 5.38 ± 0.16 (SEM) mmol/l; cirrhotics 6.98 ± 0.30 mmol/l, P < 0.001; non-cirrhotics 7.18 ± 0.26 mmol/l, P < 0.001). Non-cirrhotic alcoholics had an exaggerated insulin response to meals, whereas cirrhotic patients had hyperinsulinaemia throughout the day (mean 12-h insulin; controls 16.3 ± 2.3 mU/l; cirrhotics 35.8 ± 6.6 mU/l, P < 0.02). Growth hormone levels were elevated only in patients with cirrhosis (mean 12-h growth hormone, 7.06 ± 1.35 v. 0.85 ± 0.17 μg/l, P < 0.001). Serum Cortisol was persistently elevated in cirrhotics but only in the evening in non-cirrhotic alcoholics. Lactate and pyruvate responses to meals were exaggerated in non-cirrhotic patients whereas in cirrhotics, levels were persistently raised. Blood glycerol was elevated in all alcoholic patients whereas ketone body levels were normal. Hypertriglyceridae-mia was observed only in non-cirrhotic patients. No relationship between the endocrine and metabolic state was observed in either cirrhotic or non-cirrhotic patients.     

改良小鼠酒精性肝损伤模型的建立

目的探索建立简便和稳定的酒精性肝病（ALD）的动物模型。方法利用简易胃造漏的方法,将实验动物分为四组,A组为正常小鼠（n=12）;B组为胃造瘘后给予生理盐水（n=12）;C组为胃造瘘后给予酒精（18g·kg-1·d-1）（n=22）;D组小鼠给予自制的ZQ液（n=22）。实验动态观察12周,分别在第4周、6周、8周、12周测四组小鼠肝重、体重值并检测肝脏ALT和AST水平,同时收集肝脏标本经HE染色后光镜观察肝组织的结构变化。结果 C组模型与A组和B组比较也出现不同程度的肝脏损害,但损害的程度较D组轻。D组小鼠在4周开始出现了肝细胞脂肪变性,8周开始出现酒精性肝炎和轻度的肝纤维化,12周时出现肝脏纤维化的表现。结论简易胃造瘘法配合ZQ液可以建立简便和稳定的酒精性肝损伤模型。     

Collagen biosynthesis in liver disease of the alcoholic.

Percutaneous liver biopsies obtained from patients with a history of chronic alcoholism and normal liver, fatty liver, alcoholic hepatitis, or active cirrhosis were incubated with tritiated proline to determine the pattern of collagen biosynthesis in these conditions. Incorporation of labeled proline and hydroxyproline into salt-soluble and insoluble fractions of collagen was evaluated by radiochemical analysis and tissue localization documented by autoradiography. Biopsy specimens of alcoholic hepatitis and cirrhosis exhibit a significant increase in the amount of radioactive proline and hydroxyproline in salt-soluble and insoluble collagen. Marked accumulation of radioactivity occurred over bile ducts, fibroblasts, and collagen fibers in the portal area and over hepatocytes, fibroblasts, and collagen fibers in the centrilobular area. Fatty liver is associated with an increase in uptake of proline and hydroxyproline in the salt-soluble fraction of collagem; silver grains appear in the periphery of fat-laden cells and in areas of focal inflammation. Digestion by collagenase indicates that labeling over fibroblasts and collagen reflects active synthesis, whereas, entry of proline into the cell protein pool is responsible for accumulation of radioactivity in other sites. In vitro ethanol causes a significant increase in the incorporation of proline and hydroxyproline into collagen in biopsy specimens of alcoholic hepatitis or active cirrhosis, but has no effect on collagen synthesis by normal or fatty liver.     

慢性酒精性肝病病人心因性因素的调查分析及临床干预

[目的]探讨慢性酒精性肝病病人不能彻底戒除酒瘾的心因性因素。[方法]采用密西根酒精依赖调查表(MAST)、饮酒问卷(ADS)、症状自评量表(SCL-90)对26例住院的慢性酒精性肝病病人(研究组)进行测评,并与30例社交饮酒者(对照组)进行比较分析。[结果]研究组MAST、ADS的总分均高于对照组(P<0.001)。SCL-90总分及各项因子分均高于对照组,尤其在躯体化、焦虑、抑郁、人际关系、精神病性等方面较显著(P<0.001)。[结论]慢性酒精性肝病病人酒依赖的程度较为严重,且心理健康状况较差,应重视家庭、社会的支持,为个案制定相应的戒酒目标,从而进行行之有效的护理干预。