Serum leptin in patients with alcoholic liver disease

BACKGROUND: The mechanisms by which overweight makes the liver more susceptible to alcoholic liver injury remain to be determined. Therefore, we conducted the following studies to further elucidate the role of leptin in the pathogenesis of steatosis and cirrhosis caused by chronic alcohol consumption in human beings. METHODS: Two-hundred nine consecutive patients with alcoholic liver disease were studied. Serum leptin concentrations were measured by using radioimmunoassay, and the relationships between serum leptin level and liver lesions were studied. Statistical analysis used logistic regressions. RESULTS: When serum leptin, serum cholesterol, and body mass index (BMI) were considered together in the multiple logistic regression analysis, compared with patients with severe steatosis, serum leptin remains significantly lower in patients without steatosis (p<0.05) and in patients with mild or moderate steatosis (p<0.05). When age, serum leptin, serum cholesterol, and steatosis grade were considered together in the logistic regression analysis, serum leptin (p<0.01) and age (p<0.02) were positively and independently correlated with the presence of cirrhosis. After BMI introduction in the statistical model, serum leptin was no more correlated with the presence of cirrhosis. CONCLUSION: In patients with alcoholic liver disease, serum leptin is independently correlated with steatosis grade and might play an important role in severity of fibrosis as fatty liver is more vulnerable than normal liver to factors that lead to fibrosis.     

Serum bile acids in alcoholic liver disease

Fasting serum bile acids were measured by gas-liquid chromatography in 64 patients with alcoholic liver disease and compared with histological features in their percutaneous liver biopsy specimens. Total bile acid concentrations were normal (<2 g/ml) or minimally increased in 6 patients in whom fatty infiltration was the only hepatic lesion. In the remaining 58 patients with more severe histological lesions, levels were increased in 93%, whereas serum bilirubins were elevated in only 43%. Chenodeoxycholic acid was usually the predomonant serum bile acid, regardless of the degree of necrosis or connective tissue change in the biopsy specimen. Only small amounts of the secondary bile acids, deoxycholic acid and lithocholic acid, were detected. Levels of these secondary bile acids did not correlate with histological features.Dr. Milstein was the recipient of a Summer Student Assistanceship Award from the Howard Hughes Medical Institute during a portion of these studies.     

酒精性肝病发病机制的研究进展

自 8 0年代对酒精性肝病 (alcoholicliverdisease,ALD)发病机制进行深入研究以来 ,已证实乙醇具有直接的肝毒性。乙醇在肝细胞内代谢产生的毒性代谢产物及其引起的代谢紊乱是导致酒精性肝损伤的主要原因[1 ] 。酒精性肝病分为 :酒精性脂肪肝、酒精性肝炎和酒精性肝硬化。一、乙醛的毒性作用乙醇在肝细胞内氧化首先产生的代谢产物就是乙醛 ,后者主要在肝脏线粒体内氧化成乙酸而降解。长期摄入酒精可以使肝脏线粒体功能紊乱 ,氧化乙醛的能力大大下降 ,而乙醇的氧化速度不变甚至提高 ,造成乙醛生成与降解不平衡 ,导致肝内乙醛含量增加。谷胱…     

缺糖转铁蛋白对酒精性肝病的诊断意义

目的 评价缺糖转铁蛋白（CDT）对酒精性肝病的诊断价值。方法 选择76例酒精性肝病,55例嗜酒者,32例非酒精性肝病和27例健康者,分别检测谷氨酰转肽酶（GGT）等肝功能指标和CDT。结果 酒精性肝病组CDT阳性率为93.4%;CDT诊断酒精性肝病的灵敏度为93.4%,特异性为71.9%,诊断价值高于GGT、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）。结论 CDT是诊断酒精性肝病较理想的指标。     

炎症因子在酒精性肝病发生发展中的作用

酒精性肝病(ALD)是全球范围内引起肝损伤的最常见疾病。炎症反应是引起ALD肝损伤的重要原因。酒精入肠后可使肠源性内毒素经肝肠循环入血增多,进而激活肝脏Kupffer细胞中Toll样受体4引起炎症因子的释放。肿瘤坏死因子α等炎症因子引起肝损伤,而白细胞介素(IL)6、10等通过调节炎症反应起到保护肝脏的作用。其中IL-6通过激活信号转导和转录激活因子(STAT)3通路上调肝细胞中多种抗损伤基因的表达,IL-10通过激活Kupffer细胞中STAT3抑制肝脏炎症反应。促炎因子和抗炎因子的失衡和再平衡的过程就是ALD的发展和转归过程。从炎症反应角度系统的综述了炎症因子在ALD发生发展中的作用。     

The influence of HLA antigens on progression of alcoholic liver disease

The aim of our study was to elucidate further possible genetic influences on the incidence and progression of alcoholic liver disease. We determined HLA A, B and DR antigens in a well-controlled group of chronic alcoholics with and without liver disease, in repeated liver biopsies over period of 8.1 years (+/- 0.4 SEM). Patients with the antigen B 35 had an increased incidence of alcoholic liver cirrhosis, and especially a more rapid progression to cirrhosis (p less than 0.01). Increased susceptibility of these patients was shown by a more rapid progression of liver disease, despite the consumation of less alcohol over a shorter period. Results of this long-term study suggest that there is a sub-group of alcoholics genetically predisposed to higher susceptibility with more rapid deterioration of alcohol-induced liver disease.     

Pancreatitis associated with alcoholic liver disease

The prevalence with which alcoholic pancreatitis is associated with alcoholic liver disease is unclear. To investigate this association further, we have reviewed the autopsy findings of 1022 patients who died from alcoholic liver disease and compared these findings with those from 352 patients who died from cardiac or pulmonary disease. All patients who died from liver disease had a history of chronic alcoholism with clinical and biochemical evidence of severe liver damage. Death resulted from hepatic coma, gastrointestinal bleeding, or infection. Liver disease patients were classified into two groups: (1) those with cirrhosis (77%) and (2) those without cirrhosis but with acute and/or chronic sclerosing hyaline necrosis (23%). Anatomic and histopathologic changes characteristic of chronic pancreatitis were found in 203 patients in approximately the same frequency (20% and 18%, respectively) in both groups. Acute pancreatitis without chronic lesions was observed in 8% and 10% of both groups, respectively. In the control group of 352 autopsies (122 cardiac and 230 pulmonary patients), the overall prevalence of pancreatitis, at 2.6%, was significantly (P<0.001) lower than that observed in the alcoholic liver disease groups. A total of 22 cases (50%) dying from acute or chronic sclerosing hyaline necrosis had severe chronic calcifying pancreatitis compared to 29 patients (18%) (P<0.001) dying from cirrhosis. By contrast, dense fibrosis was significantly (P<0.001) more commonly observed in patients with cirrhosis. We conclude that pancreatitis occurs frequently in patients dying from alcoholic liver disease but is an uncommon finding in patients dying from other causes. Biliary tract pathology was more prevalent (P<0.05) in patients dying from cirrhosis without pancreatitis than those patients dying from liver disease with pancreatitis. In the control group of patients dying from pulmonary or cardiac disease, biliary pathology was far less frequently (P<0.01) observed.     

Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C

The role of HCV RNA levels and host factors in the severity of liver injury was studied. Enrolled were 298 consecutive liver biopsy-proven chronic hepatitis (CH) C patients (179 men; median age: 52 years, range 19–68; CH, 198; cirrhosis, 100) and 18 chronic hepatitis C with normal ALT. HCV genotypes were: 1a, 4.3%; 1b, 53%; 2a/c, 28%; 3a, 7%; 4, 1.3%, and mixed 6.4%. Serum HCV RNA levels were similar for all genotypes (median: 2.8 × 10⁶ eq/ml; range <0.2–69). In patients with chronic hepatitis without cirrhosis, the serum HCV RNA levels reflected the grade of liver necroinflammatory activity (R = 0.45; P < 0.001) and the stage of fibrosis (R = 0.51; P < 0.001), regardless of age, gender, HCV genotype, hepatic steatosis, and hepatic iron overload. Patients with high serum HCV RNA levels (3 × 10⁶ eq/ml) had higher ALT values (P < 0.002) than those with lower HCV RNA levels. Patients with normal ALT showed low HCV RNA levels (median: 0.82 × 10⁶ eq/ml) and histological features of minimal or mild chronic hepatitis. Cirrhotic patients showed significantly lower levels of viremia than those with chronic hepatitis with a similar HAI. The data of a subgroup of 62 patients with an established time of infection showed that for a similar duration of disease, patients with serum HCV RNA levels 3 × 10⁶ eq/ml had a significantly higher fibrosis score than those with lower levels. HAI and fibrosis score were significantly higher in patients with HCV RNA levels 3 × 10⁶ eq/ml and grade 3–4 steatosis than those with lower HCV RNA levels and steatosis grades. The data indicate that the liver damage is correlated with the HCV RNA levels and that a high viral load acts together with steatosis in accelerating the progression of liver injury.     

酒精性肝病患者血清瘦素及其受体基因Gln223Arg多态性变化

目的 观察酒精性肝病患者血清瘦素（Lep）水平及其受体（LEPR）基因Gln223Arg多态性变化,并探讨其意义.方法 选择酒精性肝病患者106例,其中酒精性脂肪性肝炎45例（AH组）,酒精性肝硬化61例（AC组）,同期健康体检者65例作为对照组.采用ELISA法检测血清Lep,葡萄糖氧化酶—过氧化物酶法检测空腹血糖（FPG）,化学发光免疫分析法检测空腹血清胰岛素（FINS）,PCR-RFLP法检测LEPR基因Gln223Arg多态性,并计算HOMA-IR.结果 AH组血清Lep、HOMA-IR分别为（8.95±1.81） ng/mL、2.44±0.25,AC组分别为（10.57±2.00） ng/mL、3.21 ±0.17,对照组分别为（4.44±0.81） ng/mL、1.77 ±0.18;AH组、AC组与对照组比较,P均＜0.05.AH组、AC组血清Lep与HOMA-IR均呈正相关（r=0.45、0.38,P均＜0.01）.AH组AA、A/G、GG的例数分别为3、11、31例,AC组分别为0、25、36例,对照组分别为1、12、52例;AC组与对照组比较,P＜0.05.结论 酒精性肝病患者血清Lep、HOMA-IR水平升高,AC组患者LEPR基因Gln223 Arg杂合基因频率高于健康人群,可能通过胰岛素—瘦素轴促进胰岛素抵抗,影响体内脂肪代谢,参与酒精性肝病的发病机制.     

Advances in alcoholic liver disease

Cytokines are mediators of cellular communication produced by multiple liver cell types. Cytokines can directly induce either necrosis or apoptosis. They can also recruit such cells as neutrophils and lymphocytes, which can mediate liver damage. Increased levels of hepatotoxic cytokines such as tumor necrosis factor-’are documented in alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH) and have been shown to play a mechanistic role in both of these disease processes. Transforming growth factor-βs a profibrotic cytokine that is critical in hepatic fibrosis. Beneficial cytokines, such as interleukin (IL)-10 and-6, also exist. Such beneficial cytokines as adiponectin are made outside the liver and appear to protect against ALD and NASH. This article reviews the relevance of cytokines in human and experimental forms of liver injury, focusing on modulation of cytokines and the use of beneficial cytokines in treatment and prevention of liver injury in ALD, NASH, and hepatitis C.     

Autoantibodies in alcoholic liver disease

PURPOSE: To test the hypothesis that since only a proportion of heavy drinkers develop significant alcoholic liver disease (ALD), an autoimmune pathogenesis is likely. PATIENTS AND METHODS: Autoimmune markers were measured in 47 patients with biopsy-proven ALD and compared to measurements in 20 alcoholics without clinical and hematologic evidence of ALD and 28 patients with autoimmune chronic active hepatitis (CAH). RESULTS: Twenty-two percent of patients with ALD were antinuclear antibody-positive, compared to 71% of patients with CAH. Approximately 60% of patients with ALD had either anti-single-stranded or anti-double-stranded DNA antibodies, slightly more than the patients with CAH. Another marker of autoimmunity, as in systemic lupus erythematosus, is the presence of IgM antibodies to autologous and heterologous lymphocytes, which are cytotoxic at 4 degrees C. Seventy-two percent of patients with CAH had positive antilymphocyte antibodies, compared to 59.6% of patients with ALD. Furthermore, more than 90% of the sera from ALD and CAH patients displayed lymphocytotoxicity. Thirty-two percent and 25.5% of CAH and ALD patients, respectively, had all three autoantibodies present. CONCLUSION: These results suggest that autoimmune mechanisms may indeed play a role in the pathogenesis of ALD in at least some patients.     

Fibrogenesis in alcoholic liver disease

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol abstinence is the most effective therapy for ALD. However, targeted therapies are urgently needed for patients with severe ALD (i.e., alcoholic hepatitis) or those who do not abstain from alcohol. The lack of studies and the availability of animal models that do not reflect all the features of this disease in humans inhibit the development of new drugs for ALD. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying fibrosis in ALD are largely similar to those observed in other chronic liver diseases, oxidative stress, methionine metabolism abnormalities, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells may play unique roles in disease-related fibrogenesis. Lipogenesis during the early stages of ALD has recently been implicated as a risk factor for the progression of cirrhosis. Other topics include osteopontin, interleukin-1 signaling, and genetic polymorphism. In this review, we discuss the basic pathogenesis of ALD and focus on liver fibrogenesis.     

Advances in alcoholic liver disease

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. Interactions between acetaldehyde, reactive oxygen and nitrogen species, inflammatory mediators and genetic factors appear to play prominent roles in the development of ALD. The cornerstone of therapy for ALD is lifestyle modification, including drinking and smoking cessation and losing weight, if appropriate. Nutrition intervention has been shown to play a positive role on both an inpatient and outpatient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis and pentoxifylline appears to be a promising anti-inflammatory therapy. Some complementary and alternative medicine agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve quality of life and, in some cases, decrease short-term mortality.